Acne And Fructose/Animal Protein

[Alien]

I am a 23 year old male and suffer with very severe cystic acne. However, I have found over the past few years that I can make it go completely away if I eat a diet that does not include both animal protein and fructose of any kind (even the fructose from vegetables such as sweet potato, tomato, brussel sprouts, peppers, etc.) within the same diet.

In other words, I could eat a strictly vegan diet with no animal protein whatsoever and eat all the fructose I want without a sign of acne. Or, I could eat a diet that included animal protein but was completely devoid of any fructose without any acne.

Dairy in either context will break my skin out within a day, so I have eaten no dairy whatsoever for the past couple of years.

I remember researching acne on Ray Peat forums a few years ago and tried some of the suggestions to no avail. Since then I have experimented with a multitude of different diets, supplements, etc. and the only thing I have ever had success with is totally eliminating dairy and not mixing animal protein and fructose within the same diet.

I am wondering if anyone has any suggestions for me.

Also: Do you believe a diet that included liver, eggs, oysters, animal protein and starch but absolutely no fructose would be more conducive to a healthy metabolism and thyroid, or do you think that a diet that included ample fructose but no liver, eggs, oysters, and animal protein would be more health promoting? If I eliminate the liver, eggs, oysters, etc, can I make up for them with vitamin and mineral supplements?

Or, is there something else going on here other than fructose and animal protein that I am missing?

Thanks.

 

[Travis]

I am a 23 year old male and suffer with very severe cystic acne. However, I have found over the past few years that I can make it go completely away if I eat a diet that does not include both animal protein and fructose of any kind (even the fructose from vegetables such as sweet potato, tomato, brussel sprouts, peppers, etc.) within the same diet.

In other words, I could eat a strictly vegan diet with no animal protein whatsoever and eat all the fructose I want without a sign of acne. Or, I could eat a diet that included animal protein but was completely devoid of any fructose without any acne.

Dairy in either context will break my skin out within a day, so I have eaten no dairy whatsoever for the past couple of years.

I remember researching acne on Ray Peat forums a few years ago and tried some of the suggestions to no avail. Since then I have experimented with a multitude of different diets, supplements, etc. and the only thing I have ever had success with is totally eliminating dairy and not mixing animal protein and fructose within the same diet.

I am wondering if anyone has any suggestions for me.

Also: Do you believe a diet that included liver, eggs, oysters, animal protein and starch but absolutely no fructose would be more conducive to a healthy metabolism and thyroid, or do you think that a diet that included ample fructose but no liver, eggs, oysters, and animal protein would be more health promoting? If I eliminate the liver, eggs, oysters, etc, can I make up for them with vitamin and mineral supplements?

Or, is there something else going on here other than fructose and animal protein that I am missing?

Thanks.

I think you're partially correct. The acne from certain foods seems to be a function of androgens in dairy and eggs—not the protein. Certainly high lysine, low tryptophan, and low histidine can cause skin issues but this cannot be what's going on.

Androgens act on a nuclear receptor. This binding event is characterized by the migration of the receptor—which is also a transcription factor—to the cell's nucleus. What happens next is an increase in mRNA for the enzyme wax ester synthase. Analytical studies have determined that acne is characterized by a relative increase in sebum wax esters; on a physical level, this acts to raise the melting point and viscosity of sebum—leading to a propensity for clogging, a consequent of reduced fluidity.

androgen ⟶ wax ester synthase ⟶ wax ester ⟶ clogged pore​

This means that practically no protein should cause acne; only dairy, and to a lesser extent eggs, seem capable of doing this. I wouldn't expect egg whites to cause acne, and I cannot think of a logical reason why they would. The fundamental cause appears to be androgens, and most body builders seem aware of this.

Interpersonal variation can probably be explained—at least partially—on account of variable levels of circulating sex‐steroid binding globulin. A change in this could impact the amount of androgens transported to the skin. Also, there is some interpersonal variation in the enzymes responsible for androgen metabolism.

 

[Koveras]

I think you're partially correct. The acne from certain foods seems to be a function of androgens in dairy and eggs—not the protein. Certainly high lysine, low tryptophan, and low histidine can cause skin issues but this cannot be what's going on.

Androgens act on a nuclear receptor. This binding event is characterized by the migration of the receptor—which is also a transcription factor—to the cell's nucleus. What happens next is an increase in mRNA for the enzyme wax ester synthase. Analytical studies have determined that acne is characterized by a relative increase in sebum wax esters; on a physical level, this acts to raise the melting point and viscosity of sebum—leading to a propensity for clogging, a consequent of reduced fluidity.

androgen ⟶ wax ester synthase ⟶ wax ester ⟶ clogged pore​

This means that practically no protein should cause acne; only dairy, and to a lesser extent eggs, seem capable of doing this. I wouldn't expect egg whites to cause acne, and I cannot think of a logical reason why they would. The fundamental cause appears to be androgens, and most body builders seem aware of this.

Interpersonal variation can probably be explained—at least partially—on account of variable levels of circulating sex‐steroid binding globulin. A change in this could impact the amount of androgens transported to the skin. Also, there is some interpersonal variation in the enzymes responsible for androgen metabolism.

What about protein's effect on stimulating [the non-androgen hormones] insulin and IGF-1?

Insulin-Like Growth Factor-1 Increases the Expression of Inflammatory Biomarkers and Sebum Production in Cultured Sebocytes.

"It is suggestive that IGF-1 might be involved in the pathogenesis of acne by increasing both expression of inflammatory biomarkers and also sebum production in sebocytes."

Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.

"Acne vulgaris, an epidemic inflammatory skin disease of adolescence, is closely related to Western diet. Three major food classes that promote acne are: 1) hyperglycemic carbohydrates, 2) milk and dairy products, 3) saturated fats including trans-fats and deficient ω-3 polyunsaturated fatty acids (PUFAs). Diet-induced insulin/insulin-like growth factor (IGF-1)-signaling is superimposed on elevated IGF-1 levels during puberty, thereby unmasking the impact of aberrant nutrigenomics on sebaceous gland homeostasis. Western diet provides abundant branched-chain amino acids (BCAAs), glutamine, and palmitic acid. Insulin and IGF-1 suppress the activity of the metabolic transcription factor forkhead box O1 (FoxO1). Insulin, IGF-1, BCAAs, glutamine, and palmitate activate the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the key regulator of anabolism and lipogenesis. FoxO1 is a negative coregulator of androgen receptor, peroxisome proliferator-activated receptor-γ (PPARγ), liver X receptor-α, and sterol response element binding protein-1c (SREBP-1c), crucial transcription factors of sebaceous lipogenesis. mTORC1 stimulates the expression of PPARγ and SREBP-1c, promoting sebum production. SREBP-1c upregulates stearoyl-CoA- and Δ6-desaturase, enhancing the proportion of monounsaturated fatty acids in sebum triglycerides. Diet-mediated aberrations in sebum quantity (hyperseborrhea) and composition (dysseborrhea) promote Propionibacterium acnes overgrowth and biofilm formation with overexpression of the virulence factor triglyceride lipase increasing follicular levels of free palmitate and oleate. Free palmitate functions as a "danger signal," stimulating toll-like receptor-2-mediated inflammasome activation with interleukin-1β release, Th17 differentiation, and interleukin-17-mediated keratinocyte proliferation. Oleate stimulates P. acnes adhesion, keratinocyte proliferation, and comedogenesis via interleukin-1α release. Thus, diet-induced metabolomic alterations promote the visible sebofollicular inflammasomopathy acne vulgaris. Nutrition therapy of acne has to increase FoxO1 and to attenuate mTORC1/SREBP-1c signaling. Patients should balance total calorie uptake and restrict refined carbohydrates, milk, dairy protein supplements, saturated fats, and trans-fats. A paleolithic-like diet enriched in vegetables and fish is recommended. Plant-derived mTORC1 inhibitors and ω-3-PUFAs are promising dietary supplements supporting nutrition therapy of acne vulgaris."

Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris.

IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway.

Correlation of facial sebum to serum insulin-like growth factor-1 in patients with acne.

Growth hormone and insulin-like growth factors have different effects on sebaceous cell growth and differentiation.

And then of course there is the impact of lipid peroxidation

Clinical implications of lipid peroxidation in acne vulgaris: old wine in new bottles

"In the past, it was thought that follicular plugging (comedones) preceded Propionibacterium acnes (P. acnes) colonization, which subsequently resulted in inflammation (papules and pustules). This sequence of events has been called into question in recent years. It has been discovered that subclinical inflammatory events are occurring in acne-prone skin even prior to hyperproliferative and abnormal differentiation events [11,12]. The reason for elevated pro-inflammatory factors, such as interleukin-1 (IL-1), around the clinically normal pilosebaceous follicles of acne patients remains unknown. At this point it simply highlights that the release of inflammatory chemicals is indeed one of the earliest events to occur in the acne process. Furthermore, oxidative stress within the pilosebaceous unit alters the environment from one that is unsuitable to harbor anaerobic bacteria to one that is perfectly suited for the colonization of such species [13]. P. acnes, once thought to be the initiating factor of inflammatory acne, might never make the pilosebaceous unit its home were it not for this initial inflammatory insult to the sebum. Oxidation of sebum alters oxygen tension in the follicle, resulting in the micro-aerophilic environment required for P. acnes to survive. Apparently, inflammation and oxidative stress might set the stage for all subsequent pathogenic factors leading to acne."

"It was also noted, a quarter century ago, that the therapeutic value of tetracycline antibiotics in acne might be due to their ability to act as antioxidants [29]."

"Hydrogen peroxide is a reactive oxygen species (ROS) produced by neutrophils, and as with other ROS, it is well capable of promoting inflammation, causing tissue damage and further lipid destruction. Hydrogen peroxide production was measured from whole blood samples taken from adults with inflammatory acne vs. healthy controls. Patients with inflammatory acne had significantly higher production of hydrogen peroxide, 43% more than healthy controls. After treatment with minocycline there was a 25% reduction in whole blood, microbial and chemically stimulated, neutrophil hydrogen peroxide production."

"[..]since minocycline and other tetracycline antibiotics are now known to have clear antioxidant properties, particularly in reducing lipid peroxidation in potency similar to vitamin E [38], the results lend further support to the suggestion - 17 years earlier - that this class of antibiotics may be helping via non-antimicrobial pathways in reduction of ROS. Indeed, a recent investigation showed that doxycycline, at sub-antimicrobial doses, reduced papules and pustules by over 80% after 3 months in those with moderate facial acne [39]."
@Such_Saturation

"Some of the emerging studies have also measured plasma and serum levels of antioxidant nutrients in acne patients. Among 100 newly diagnosed and untreated acne patients, plasma levels of vitamins A and E were significantly lower than controls."

"Low serum levels of vitamin A in untreated acne patients had been previously documented in 1978 [42]. The contemporary investigation also added in an additional blood enzyme as an end-point - platelet monoamine oxidase (MAO) - the activity of which has been implicated in a variety of mental health disorders, including anxiety and depression. The investigators found low MAO activity in acne, a finding which, while not universal, is consistent with previous investigations in affective disorders [43]. As we will discuss shortly, this finding has enormous implications in the lipid peroxidation theory of acne and its overlap with the emerging research showing oxidative stress is not a mere consequence of mental health disorders."

"In support of previous research, it has become increasingly clear that squalene production is highly upregulated in acne. Overall acne patients have 59% more sebum than healthy controls, yet it is squalene that emerges as the specific lipid that is being produced in abundance - 2.2-fold higher vs. controls [44]. As expected, an increase in squalene sets the stage for significantly higher levels of squalene peroxides and diminished vitamin E in the sebum of acne patients [45]. Squalene peroxides also diminish the important skin antioxidant glutathione, while pre-treatment with glutathione depleting agents (DL-buthionine sulfoximine and diethyl maleate) makes the comedogenic potential of squalene peroxides even worse [46]. In smokers with acne the squalene peroxidation and vitamin E reduction is even more pronounced [47]. Not only are the squalene peroxides confirmed to be highly comeodogenic [48], they have recently been reported to set an inflammatory cascade in motion. Specifically, exposure of peroxidated squalene products to human keratinocyte cells stimulates production of inflammatory cytokines and upregulates lipoxygenase (LOX) activity [49]."

"Examination of comedo samples (20-30 comedones from each patient) removed from acne patients shows that lipid peroxidation is evident even in the earliest microcomedo. As the disease progresses to inflamed lesions there is an up to 4-fold increase in lipid peroxide levels [53]. The marked increase in lipid peroxidation once inflammation is ongoing is to be expected. Undoubtedly ROS can provoke the secretion of inflammatory cytokines; however, once initiated, inflammatory chemicals cause a subsequent increase in ROS production [54]."

"Why is it that despite marked clinical success with topical and oral interventions, a number of studies using validated measurements of depression, mood and quality of life, indicates that the mental outlook remains unchanged [55-58]?"

"[..]oral vitamin E consumption can take weeks before sebum levels are significantly elevated [125]."

"It has been well documented that a period of insulin resistance occurs during puberty [139], one coinciding with the development of acne, depression and/or anxiety."

"BP [Benzoyl Peroxide] reduces epidermal vitamin E by up to 95% and vitamin C by up to 70% [154]."

 

[Travis]

But increased sebum production isn't acne; the viscosity of the sebum is acne. Androgens both increase the production rate of sebum, and increase it's viscosity.

Here's a new one I haven't read:

Zouboulis, C. "Acne is an inflammatory disease and alterations of sebum composition initiate acne lesions." Journal of the European Academy of Dermatology and Venereology (2014)​

But I am willing to bet that it will remark on a change in wax ester concentration...[reading]...

'Human sebaceous glands secrete a lipid mixture containing squalene and wax esters, as well as cholesterol esters, triglycerides and possibly some free cholesterol.' ―Zouboulis

'For a long time hyperseborrhoea has been considered as a major aetiopathogenetic factor for acne. However, emerging data on alterations of sebum lipid composition in acne patients indicate that sebum composition may be more important for the development of acne lesions than the secreted amount.' ―Zouboulis

'For example, high levels of linoleate, an essential ω−6 fatty acid, may protect from the development of comedonal acne and its topical application reduces microcomedones and inhibits steroid 5α-reductase activity. On the other hand, low linoleate levels have been observed in skin surface lipids of acne patients.' ―Zouboulis

'Current evidence indicates that sebum composition (lipid quality) and not quantity plays a central role in the development of acne.' ―Zouboulis​

No mention of androgens, however Zouboulis implicates the physical properties of oils in comodogenesis. This is important, and whitehead sebum is obviously less fluid than skin oil emanating from a coconut‐eating islander. The Zouboulis references (Nº's 22, 24, and 25) could potentially have some good data, but I do remember reading a few from the '80s showing a significant increase in wax esters. Wax esters and cholesterol esters would increase viscosity, while unsaturated fatty acids (unoxidized) would lower it.

[22] Picardo M. Sebaceous gland lipids. Dermatoendocrinol 2009
[23] Pappas A. Epidermal surface lipids. Dermatoendocrinol 2009
[24] Makrantonaki E. An update on the role of the sebaceous gland in the pathogenesis of acne. Dermatoendocrinol 2011
[25] Pappas A,. Sebum analysis of individuals with and without acne. Dermatoendocrinol 2009
​

The last Zouboulis citation (Nº25) seems promising:

'The specific lipid that differed the most between the two groups was squalene, which was upregulated in acne subjects by 2.2-fold on a quantitative basis. Squalene also represented a significantly greater proportion of the total sebaceous lipids in acne patients compared to controls. The increase in the amount of squalene could represent a lipid marker for acne prone skin.' ―Pappas​

'As seen in Figure 3, sebum from acne subjects contains 2.2-fold more squalene, 1.84-fold more triglycerides, 1.59-fold more sebum, 1.49-fold more sapienic acid, 1.33-fold more wax esters and reduced free fatty acid levels (0.79-fold) than the sebum of control subjects.' ―Pappas​

So there is an increase in squalene, wax esters, triglycerides, and sapienic acid. I'm fairly certain that PPARγ transcribes for fatty acid synthase, and that androgens transcribe for the rest.

'Androgens have profound effects on the physiology of the sebaceous gland. Using the hamster ear sebaceous gland model, we performed a detailed kinetic study to clarify the mechanism of androgen action on sebaceous gland function. We demonstrated that the growth of sebaceous glands observed after androgen treatment was due to both an increase in sebocyte proliferation and a parallel induction of sebocyte terminal differentiation, as evidenced by the induction of the synthesis of specific sebaceous lipids such as cholesterol esters, triglycerides, and squalene.' ―Rosignoli​

​

'The synthesis of triglycerides, squalene, and cholesterol esters, the main sebum components, was strongly induced (10–20-fold compared with 2–5-fold for other lipids) by the hormone.' ―Rosignoli​

―――――――――――――――――――――――――――――――――――――――――――――――――――――――

This represents an enrichment of wax esters, cholesterol esters, and squalene at the expense of free fatty acids―exactly the trend seen in acne (Pappas, 2009). I think if you were to add the published melting points of these lipids you would see a sum increase in melting point, translating to higher viscosity and increased comodogenic potential.

click to embiggen​

There are also a few good articles out there detailing the androgens found in dairy. Most assays only measure testosterone, but there are a few other androgens which exist in higher concentrations. I am of the opinion that the inflammatory response seen in acne—the cytokines—are generally the result of a clogged pore, not the cause.

But you'd think anything which increases sebum production when the ratio is top‐heavy with comodogenic lipids (i.e. androgen‐activated) would increase acne. So ligands if PPARγ, insulin, transforming growth factor, insulin‐like growth factor, and perhaps even prolactin could play a supporting role. I still see androgens as primary; acne increases during teenage years is best explained by this (there is no real increase of insulin in adolescents, although growth hormone could play a role).

Acne appears absent in traditional islanders.

Rosignoli, C. "Involvement of the SREBP pathway in the mode of action of androgens in sebaceous glands in vivo." Experimental dermatology (2003)
​

 

[Koveras]

But increased sebum production isn't acne; the viscosity of the sebum is acne. Androgens both increase the production rate of sebum, and increase it's viscosity.

Here's a new one I haven't read:

Zouboulis, C. "Acne is an inflammatory disease and alterations of sebum composition initiate acne lesions." Journal of the European Academy of Dermatology and Venereology (2014)​

But I am willing to bet that it will remark on a change in wax ester concentration...[reading]...

'Human sebaceous glands secrete a lipid mixture containing squalene and wax esters, as well as cholesterol esters, triglycerides and possibly some free cholesterol.' ―Zouboulis

'For a long time hyperseborrhoea has been considered as a major aetiopathogenetic factor for acne. However, emerging data on alterations of sebum lipid composition in acne patients indicate that sebum composition may be more important for the development of acne lesions than the secreted amount.' ―Zouboulis

'For example, high levels of linoleate, an essential ω−6 fatty acid, may protect from the development of comedonal acne and its topical application reduces microcomedones and inhibits steroid 5α-reductase activity. On the other hand, low linoleate levels have been observed in skin surface lipids of acne patients.' ―Zouboulis

'Current evidence indicates that sebum composition (lipid quality) and not quantity plays a central role in the development of acne.' ―Zouboulis​

No mention of androgens, however Zouboulis implicates the physical properties of oils in comodogenesis. This is important, and whitehead sebum is obviously less fluid than skin oil emanating from a coconut‐eating islander. The Zouboulis references (Nº's 22, 24, and 25) could potentially have some good data, but I do remember reading a few from the '80s showing a significant increase in wax esters. Wax esters and cholesterol esters would increase viscosity, while unsaturated fatty acids (unoxidized) would lower it.

[22] Picardo M. Sebaceous gland lipids. Dermatoendocrinol 2009
[23] Pappas A. Epidermal surface lipids. Dermatoendocrinol 2009
[24] Makrantonaki E. An update on the role of the sebaceous gland in the pathogenesis of acne. Dermatoendocrinol 2011
[25] Pappas A,. Sebum analysis of individuals with and without acne. Dermatoendocrinol 2009
​

The last Zouboulis citation (Nº25) seems promising:

'The specific lipid that differed the most between the two groups was squalene, which was upregulated in acne subjects by 2.2-fold on a quantitative basis. Squalene also represented a significantly greater proportion of the total sebaceous lipids in acne patients compared to controls. The increase in the amount of squalene could represent a lipid marker for acne prone skin.' ―Pappas​

'As seen in Figure 3, sebum from acne subjects contains 2.2-fold more squalene, 1.84-fold more triglycerides, 1.59-fold more sebum, 1.49-fold more sapienic acid, 1.33-fold more wax esters and reduced free fatty acid levels (0.79-fold) than the sebum of control subjects.' ―Pappas​

So there is an increase in squalene, wax esters, triglycerides, and sapienic acid. I'm fairly certain that PPARγ transcribes for fatty acid synthase, and that androgens transcribe for the rest.

'Androgens have profound effects on the physiology of the sebaceous gland. Using the hamster ear sebaceous gland model, we performed a detailed kinetic study to clarify the mechanism of androgen action on sebaceous gland function. We demonstrated that the growth of sebaceous glands observed after androgen treatment was due to both an increase in sebocyte proliferation and a parallel induction of sebocyte terminal differentiation, as evidenced by the induction of the synthesis of specific sebaceous lipids such as cholesterol esters, triglycerides, and squalene.' ―Rosignoli​

View attachment 7725​

'The synthesis of triglycerides, squalene, and cholesterol esters, the main sebum components, was strongly induced (10–20-fold compared with 2–5-fold for other lipids) by the hormone.' ―Rosignoli​

――――――――――――――――――――――――――――――――――――――――――――――――――――――――――――――――――――

This represents an enrichment of wax esters, cholesterol esters, and squalene at the expense of free fatty acids―exactly the trend seen in acne (Pappas, 2009). I think if you were to add the published melting points of these lipids you would see a sum increase in melting point, translating to higher viscosity and increased comodogenic potential.

View attachment 7726 click to embiggen​

There are also a few good articles out there detailing the androgens found in dairy. Most assays only measure testosterone, but there are a few other androgens which exist in higher concentrations. I am of the opinion that the inflammatory response seen in acne—the cytokines—are generally the result of a clogged pore, not the cause.

Rosignoli, C. "Involvement of the SREBP pathway in the mode of action of androgens in sebaceous glands in vivo." Experimental dermatology (2003)
​

IGF-1 would seem to increase the production of squalene, wax esters, and cholesterol as well

 

[Travis]

IGF-1 would seem to increase the production of squalene, wax esters, and cholesterol as well

Insulin‐like growth factor is doing essentially the same thing as androgens:

'Insulin and IGF-1 stimulate sebaceous gland lipogenesis. IGF-1 increases expression of sterol response element-binding protein-1 (SREBP-1), a transcription factor that regulates numerous genes involved in lipid biosynthesis. SREBP-1 expression, in turn, stimulates lipogenesis in sebocytes.' ―Smith​

They both increase the sterol response element-binding protein. So it looks like there are two logical causes so far for the lipid changes seen in acne: androgens, and insulin-like growth factor one . . . There is only one way to settle this:

'Objectives To determine if insulin-like growth factor 1 (IGF-1) and androgen levels (1) correlate with the presence and severity of acne in adult men and women, and (2) correlate directly with each other and interact in affecting acne.' ―Cappel

Design Case-control study and single-center examination of hormone levels in a cohort of volunteers.' ―Cappel

Patients Thirty-four subjects (8 women and 8 men with clinical acne, 10 women and 8 men without clinical acne). Clinical acne is defined by a history of persistent acne (acne present on most days for several years), recent acne treatment, and the presence of 10 or more inflammatory acne lesions and 15 or more comedones.'―Cappel

Main Outcome Measures Serum levels of IGF-1 and androgens were determined, adjusted for age, and compared based on the presence or absence of clinical acne using an analysis of covariance. Correlations between hormone levels and acne lesion counts were calculated within each subgroup. Correlations were also calculated between serum levels of IGF-1 and androgens. Further statistical testing was conducted to determine whether IGF-1 or androgens had a greater effect on acne lesion counts....[☁ ]... ' ―Cappel​

I can feel the excitement. What's it going to be?

'Levels of IGF-1 were determined by acid ethanol extraction and double antibody radioimmunoassay with intra-assay and interassay variance of 3.0% and 6.0%, respectively.Since IGF circulates as a complex with binding proteins that inhibit its interaction with IGF-1 receptors, IGF binding protein 3 (IGFBP-3) was also determined from banked serum from the female subjects. Levels of IGFBP-3 were also measured via double antibody radioimmunoassay with an intra-assay variance of 3.4% to 8.0% and an interassay variance of 5.3% to 6.3%. Androstenedione, testosterone, DHEAS, and DHT levels were determined by means of radioimmunoassay methods as previously reported.' ―Cappel​

Insulin‐like growth factor correlated slightly better in females, but androgens did correlate much better in males (r ≈ .78):

'Results Dehydroepiandrosterone (DHEAS), dihydrotestosterone (DHT), and IGF-1 correlated positively with acne lesion counts in women. Androstenedione and DHEAS correlated with acne lesion counts in men. Although the age-adjusted mean serum levels of IGF-1 were higher in women with clinical acne than in women without clinical acne, this difference did not achieve statistical significance. No difference in IGF-1 level was noted in men based on the presence of clinical acne. In women with clinical acne, IGF-1 correlated with DHT. In men with clinical acne, IGF-1 correlated with DHEAS and androstenedione. In men and women with clinical acne, the effects of androgens on increased acne lesion counts were dependent on the influence of IGF-1.' ―Cappel​

click to embiggen
​

'Conclusions Increased IGF-1 levels in addition to androgens may influence acne in adult men and women. While IGF-1 appears to have a stronger effect on acne in women, androgens may play a greater role in acne for men. However, in both men and women these hormones are interrelated, possibly owing to reciprocal effects on hormone production.' ―Cappel​

The original poster appears to be a male; but due to the similarity of IGF‐1 with insulin, perhaps this should also be looked into. I also wonder if high leucine or zinc could play a supporting role? (Zinc is known to help release SREBP from its inactive binding site.)

Smith, Terry M. "IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway." Journal of investigative dermatology (2008)
Cappel, M. "Correlation between serum levels of insulin-like growth factor 1, dehydroepiandrosterone sulfate, and dihydrotestosterone and acne lesion counts in adult women." Archives of dermatology (2005)​

 

[Palpatine]

Interpersonal variation can probably be explained—at least partially—on account of variable levels of circulating sex‐steroid binding globulin. A change in this could impact the amount of androgens transported to the skin. Also, there is some interpersonal variation in the enzymes responsible for androgen metabolism

Travis, you're a smart dude... and I try to understand what you post... but it's waaay above my head. However, I did find this interesting as I was reading in a different post somewhere on the forum regarding SHBG levels being higher in people who took Accutane, which I did (2 courses about 20-25 years ago, now 45)... and so far every hormone panel I've taken shows high SHBG. My cystic acne is gone since taking the second course of Accutane... I get the occasional small pimple here and there but nothing to complain about. My androgen levels last checked were very good for my age btw.

 

[Koveras]

Insulin‐like growth factor is doing essentially the same thing as androgens:

'Insulin and IGF-1 stimulate sebaceous gland lipogenesis. IGF-1 increases expression of sterol response element-binding protein-1 (SREBP-1), a transcription factor that regulates numerous genes involved in lipid biosynthesis. SREBP-1 expression, in turn, stimulates lipogenesis in sebocytes.' ―Smith​

They both increase the sterol response element-binding protein. So it looks like there are two logical causes so far for the lipid changes seen in acne: androgens, and insulin-like growth factor one . . . There is only one way to settle this:

'Objectives To determine if insulin-like growth factor 1 (IGF-1) and androgen levels (1) correlate with the presence and severity of acne in adult men and women, and (2) correlate directly with each other and interact in affecting acne.' ―Cappel

Design Case-control study and single-center examination of hormone levels in a cohort of volunteers.' ―Cappel

Patients Thirty-four subjects (8 women and 8 men with clinical acne, 10 women and 8 men without clinical acne). Clinical acne is defined by a history of persistent acne (acne present on most days for several years), recent acne treatment, and the presence of 10 or more inflammatory acne lesions and 15 or more comedones.'―Cappel

Main Outcome Measures Serum levels of IGF-1 and androgens were determined, adjusted for age, and compared based on the presence or absence of clinical acne using an analysis of covariance. Correlations between hormone levels and acne lesion counts were calculated within each subgroup. Correlations were also calculated between serum levels of IGF-1 and androgens. Further statistical testing was conducted to determine whether IGF-1 or androgens had a greater effect on acne lesion counts....[☁ ]... ' ―Cappel​

I can feel the excitement. What's it going to be?

'Levels of IGF-1 were determined by acid ethanol extraction and double antibody radioimmunoassay with intra-assay and interassay variance of 3.0% and 6.0%, respectively.Since IGF circulates as a complex with binding proteins that inhibit its interaction with IGF-1 receptors, IGF binding protein 3 (IGFBP-3) was also determined from banked serum from the female subjects. Levels of IGFBP-3 were also measured via double antibody radioimmunoassay with an intra-assay variance of 3.4% to 8.0% and an interassay variance of 5.3% to 6.3%. Androstenedione, testosterone, DHEAS, and DHT levels were determined by means of radioimmunoassay methods as previously reported.' ―Cappel​

Insulin‐like growth factor correlated slightly better in females, but androgens did correlate much better in males (r ≈ .78):

'Results Dehydroepiandrosterone (DHEAS), dihydrotestosterone (DHT), and IGF-1 correlated positively with acne lesion counts in women. Androstenedione and DHEAS correlated with acne lesion counts in men. Although the age-adjusted mean serum levels of IGF-1 were higher in women with clinical acne than in women without clinical acne, this difference did not achieve statistical significance. No difference in IGF-1 level was noted in men based on the presence of clinical acne. In women with clinical acne, IGF-1 correlated with DHT. In men with clinical acne, IGF-1 correlated with DHEAS and androstenedione. In men and women with clinical acne, the effects of androgens on increased acne lesion counts were dependent on the influence of IGF-1.' ―Cappel​

View attachment 7731 click to embiggen
​

'Conclusions Increased IGF-1 levels in addition to androgens may influence acne in adult men and women. While IGF-1 appears to have a stronger effect on acne in women, androgens may play a greater role in acne for men. However, in both men and women these hormones are interrelated, possibly owing to reciprocal effects on hormone production.' ―Cappel​

The original poster appears to be a male; but due to the similarity of IGF‐1 with insulin, perhaps this should also be looked into. I also wonder if high leucine or zinc could play a supporting role? (Both are known to increase SREBP, however slightly)

Smith, Terry M. "IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway." Journal of investigative dermatology (2008)
Cappel, M. "Correlation between serum levels of insulin-like growth factor 1, dehydroepiandrosterone sulfate, and dihydrotestosterone and acne lesion counts in adult women." Archives of dermatology (2005)​

Maybe with an unfavourable IGF1 polymorphism

J Eur Acad Dermatol Venereol. 2013 Feb;27(2):254-7.
Insulin-like growth factor-I gene polymorphism in acne vulgaris.
Tasli L1, Turgut S, Kacar N, Ayada C, Coban M, Akcilar R, Ergin S.
BACKGROUND:
Acne vulgaris is a multifactorial disease of the skin. Several studies have shown that elevated levels of serum insulin-like growth factor-I (IGF-I) correlate with overproduction of sebum and acne. Recently functional relationship between IGF-I (CA) polymorphism and circulating IGF-I levels in adults has been reported.
AIMS:
The aim of our study was to investigate for the first time whether IGF-I (CA) polymorphism might be involved in the pathogenesis of acne or not.
METHODS:
We included 115 acne patients and 117 healthy subjects to the study. The clinical grade of acne was assessed based on the Global Acne Grading System. Participants were questioned about diabetes mellitus, PCOS and other systemic disease. We searched for the IGF-I (CA) 19 polymorphism in this study. The IGF-I (CA) 19 polymorphism was performed by polymerase chain reaction.
RESULTS:
We categorized the IGF-I (CA) 19 polymorphism area into three groups as lower than 192 bp, 192–194 bp and higher than 194 bp. We found that the frequency of genotype IGF-1 (CA) 19 gene was significantly different between control and acne patients (P = 0.0002). A significant association between IGF-I (CA) genotypes and severity of acne was found (P = 0.015). No significant difference was found between male and female patients (P > 0.05).
CONCLUSIONS:
Our results suggest that IGF-I (CA) 19 polymorphism may contribute to a predisposition to acne in Turkish patients.

 

[Travis]

Travis, you're a smart dude... and I try to understand what you post... but it's waaay above my head. However, I did find this interesting as I was reading in a different post somewhere on the forum regarding SHBG levels being higher in people who took Accutane, which I did (2 courses about 20-25 years ago, now 45)... and so far every hormone panel I've taken shows high SHBG. My cystic acne is gone since taking the second course of Accutane... I get the occasional small pimple here and there but nothing to complain about. My androgen levels last checked were very good for my age btw.

Well, the DNA encoding SHBG is under the control of the transcription factor SP1, and this has been shown to dimerize with either the retinoic acid receptor (RAR) or the retinoid X receptor (RXR). This is could be how 13‐cis‐retinoic acid (Accutane™) increases sex hormone binding globulin. These retinoic acid receptors are nuclear receptors, transcription factors, and physically interact with DNA.

'In addition, a sequence (5-GGGGGAGGAGT) within FP12 resembles a consensus SP1 binding site (5-GGGGCGGGG(C/ T)) by analysis using the TRANSFAC data base.' ―Hogeveen*​

The retinoic acid receptor acting in unison with SP1 has been shown to increase the expression of transforming growth factor fourfold, with SP1 alone having no effect. Sex hormone binding globulin is made in the liver, and retinol is stored in the liver.

'Here, we report that upon autoinduction of RARs by RA, RAR/RXR interacts with Sp1. The interaction appears to change the conformation of Sp1 and induces gene expression, at least in part, by potentiating Sp1 binding to the functional GC box motifs that have the 3`-flanking region consisting of the mixture of purine and pyrimidine bases.' ―Shimada†​

'these results implied that a conformational change would be induced in Sp1 upon association with RAR and RXR, and this may link to increased affinity of Sp1 to the GC box motifs. We next confirmed that endogenous Sp1 binds to GC box motifs and that either RA treatment or RAR/ RXR overexpression results in an enhancement of Sp1 binding.' ―Shimada†​

So theoretically—and based on your experience—I think it's fair to assume that retonoic acid would increase SHBG since it has an SP1 response element. This has actually been demonstrated in mice.

'In these experiments, both FSH and retinoic acid increased human SHBG secretion by these cells over an 8-day period (Fig. 4, A and B). Estradiol also increased SHBG secretion but only when added at a concentration 100 nM, whereas testosterone at this and lower concentrations had no effect.' ―Selva​

So if you'd want to lower circulating SHBG, I think logic would suggest lowering retinol intake. This can be stored in the liver for months, and the great majority of Americans seem to get enough from food.

Data from autopsies show a great variation in liver retinol, ranging from zero to quite alot. But retinol isn't hormonal, and needs to be transformed twice before it becomes active retinoic acid. The normal feedback mechanisms of the body keep circulating retinoic acid in a very tight range, and there is remarkably little interpersonal variation in concentrations.

If you really want it lowered, withaferin A appears to inhibit the transcription factor SP1—perhaps that would work. Vitamin D appears to be capable of lowering SHBG about four nanomoles per liter, or about ten percent.§ Vitamins A and D seem to antagonize eachother on certain levels—perhaps by their receptors competing for transcription factors. They can also synergize by forming the RAR·VDR heterodimer, occupying the retinoic acid receptor in that way.

I think the articles suggest that it's either the RAR·SP1 interaction or the RXR·SP1 interaction which transcribes sex hormone binding globulin.

[*] Hogeveen, Kevin N. "Human sex hormone-binding globulin promoter activity is influenced by a (TAAAA) n repeat element within an Alu sequence." Journal of Biological Chemistry (2001)
[†] Shimada, Jun. "Transactivation via RAR/RXR-Sp1 interaction: characterization of binding between Sp1 and GC box motif." Molecular Endocrinology 15.10 (2001): 1677-1692.
[‡] Selva, David M. "Repression of the human sex hormone-binding globulin gene in Sertoli cells by upstream stimulatory transcription factors." Journal of Biological Chemistry (2005)
[§] Wehr, Elisabeth. "Association of vitamin D status with serum androgen levels in men." Clinical endocrinology (2010)​

 

[Travis]

Maybe with an unfavourable IGF1 polymorphism

J Eur Acad Dermatol Venereol. 2013 Feb;27(2):254-7.
Insulin-like growth factor-I gene polymorphism in acne vulgaris.
Tasli L1, Turgut S, Kacar N, Ayada C, Coban M, Akcilar R, Ergin S.
BACKGROUND:
Acne vulgaris is a multifactorial disease of the skin. Several studies have shown that elevated levels of serum insulin-like growth factor-I (IGF-I) correlate with overproduction of sebum and acne. Recently functional relationship between IGF-I (CA) polymorphism and circulating IGF-I levels in adults has been reported.
AIMS:
The aim of our study was to investigate for the first time whether IGF-I (CA) polymorphism might be involved in the pathogenesis of acne or not.
METHODS:
We included 115 acne patients and 117 healthy subjects to the study. The clinical grade of acne was assessed based on the Global Acne Grading System. Participants were questioned about diabetes mellitus, PCOS and other systemic disease. We searched for the IGF-I (CA) 19 polymorphism in this study. The IGF-I (CA) 19 polymorphism was performed by polymerase chain reaction.
RESULTS:
We categorized the IGF-I (CA) 19 polymorphism area into three groups as lower than 192 bp, 192–194 bp and higher than 194 bp. We found that the frequency of genotype IGF-1 (CA) 19 gene was significantly different between control and acne patients (P = 0.0002). A significant association between IGF-I (CA) genotypes and severity of acne was found (P = 0.015). No significant difference was found between male and female patients (P > 0.05).
CONCLUSIONS:
Our results suggest that IGF-I (CA) 19 polymorphism may contribute to a predisposition to acne in Turkish patients.
View attachment 7732 View attachment 7733

The role of IGF‐1 is becoming undeniable, but some evidence suggests that it lies upstream of the androgens. Unlike the androgen receptor, IGF‐1 is not a transcription factor so the signalling event to the nucleus isn't as direct. Here are some paragraphs about how IFG‐1 increases androgens:

Melnik, Bodo C. "Role of insulin, insulin‐like growth factor‐1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris." Experimental dermatology (2009)​

'Adrenal gland: The fetal adrenal cortex derives from a common adrenogonadal precursor lineage that also gives rise to the steroidsecreting cells of the gonads. The GH-IGF-1 axis plays an important role for the ACTH-dependent production of DHEAS of the human adrenal gland (30,31). IGF-1 enhances the sensitivity of the adrenal for ACTH, and induces the expression and activity of key enzymes of adrenal androgen biosynthesis (31). In healthy prepubertal girls as well as prepubertal girls with premature adrenarche, a positive correlation between IGF-1 and DHEAS serum levels has been reported (32). Serum IGF-1 levels rise and fall in a pattern similar to serum DHEAS, and normal puberty is characterized by a state of transient insulin resistance associated with an increase in gonadal sex steroid production and adrenal androgens (30).' ―Melnik

'5a-Reductase: Addition of IGF-1 to cultures of rat and human skin scrotal fibroblasts significantly increased 5a-reductase activity in a dose-dependent manner (40). Conversion of testosterone to DHT increases androgen signalling. The IGF-1-induced activation of 5a-reductase points to an important role of IGF-1 as a peripheral amplifier of androgen metabolism in the skin (40) (Fig. 2).' ―Melnik

Androgen receptor: Insulin like growth factor-1 induces androgen receptor (AR) trans-activation. In the nucleus, AR binds to the AR repressive protein Foxo1. IGF-1, as well as insulin activates PI3K, which leads to Akt-mediated Foxo1 phosphorylation. Phosphorylated Foxo1 leaves the AR and translocates from the nucleus into the cytoplasm (41). By this mechanism, IGF-1 signalling alleviates AR repression resulting in AR gain-of-function. Thus, IGF-1 has direct influence on the intracrine androgen regulation of the skin and potentiates androgen signalling by the induction of 5a-reductase activity and activation of AR.' ―Melnik

'IGF-1 is an inducer of 5a-reductase activity (40), whereas isotretinoin significantly reduces the activity of 5a-reductase in the skin of acne patients (53).' ―Melnik

Induction of acne by IGF-1 treatment: Recombinant human IGF-1, approved for the treatment of the short child, elicits androgenesis and acne (68). Laron syndrome is characterized by GH resistance, molecular defects of the GHR or postreceptor pathways leading to inability to synthesize IGF-1. During IGF-1 treatment of six female patients with Laron syndrome, four developed oligo ⁄ amenorrhoea and acne associated with significant elevations in serum testosterone and androstenedione (69). Reduction of the IGF-1 dose or interruption of IGF-1 treatment normalized androgen levels and resulted in a resolution of acne and oligomenorrhoea (69).' ―Melnik
​

And there's some interesting epidemiological findings (citing Cordain):

'Epidemiological observations point to a role of Western diet in the development or aggravation of acne. Cordain et al. (70) studied 1200 Kitavan islanders of Papua New Guinea and 115 Ache´ hunter-gatherers of Paraguay who do not consume dairy products and have low glycaemic diets. No case of acne has been detected in these two non-westernized populations.' ―Melnik
​

And the association of dairy with acne is confounded by IGF-1 present in the milk itself:

'Association between milk consumption and acne: Prospective cohort studies in the United States in 4273 teenage boys and 6094 teenage girls demonstrated a correlation between milk consumption and acne (73,74). In boys, the strongest association has been found between intake of skim milk and acne (74). Thus, it is conceivable that not the lipophilic androgenic steroids enriched in milk fat (75), but more likely the hydrophilic protein fraction in cow’s milk, which increases insulin ⁄IGF-1 signalling, might have a stronger influence on the milk-induced aggravation of acne. [He appears to be under the assumption that skim milk has less steroids just because steroids are fat‐soluble—this is true. There appears to be about a 50% reduction in androgens in skim milk.] Cow’s milk contains active IGF-1 and IGF-2 (76). High levels of IGF-1 are still detectable after pasteurization and homogenization of milk. Intriguingly, bovine and human IGF-1 shares the same amino acid sequence and thus binds to the human IGF1R. Several lines of evidence indicate that IGFs in milk may survive digestion and remain bioactive in the plasma of milk-consumers.' ―Melnik

Courant, Frédérique. "Determination of naturally occurring oestrogens and androgens in retail samples of milk and eggs." Food additives and contaminants (2007)
​

'Milk consumption increases IGF-1 serum levels: High milk consumption is associated with a 10–20% increase in circulating IGF-1 levels among adults and a 20– 30% increase among children (77–80). In 2109 European women, serum IGF-1 levels were positively related with the intake of milk (81). Milk and dairy products increase IGF-1 levels more than other dietary sources of protein such as meat (78). Moreover, milk consumption raises the ratio of IGF-1 ⁄IGFBP-3 indicating an increased bioavailability of IGF-1. Prolonged consumption of ultraheat-treated (UHT) milk shifts the GH ⁄IGF-1 axis in children to higher levels (82). After a month of drinking 710 ml of UHT milk daily, Mongolian children, who had not previously consumed milk, had a higher mean plasma level of IGF-1, higher IGF-1 ⁄IGFBP-3 and GH levels (82). Their mean serum IGF-1 levels were significantly raised after 4 weeks of milk consumption by 23.4% (82).' ―Melnik​

It should be noted that recombinant bovine growth hormone increases IGF‐1:

Prosser. "Increased secretion of insulin-like growth factor I into milk of cows treated with rBGH." Journal of Dairy Research (1989)​

Although my skin is at its best on a vegan diet, and worse‐off with cheese, I eat mostly raw food. I cannot say from this observation alone whether or not glycemic issues could be a problem since I don't eat high‐glyemic foods. It's also difficult to judge whether androgens or IGF‐1 is the greater etiological factor as dairy contains both.

 

[Koveras]

Unlike the androgen receptor, IGF‐1 is not a transcription factor so the signalling event to the nucleus isn't as direct.

Good stuff

On the other hand I've read that a sufficient hormonal environment (androgens and estrogens) and nutrient status (insulin) are necessary for the formation of IGF-1 from GH - and in the absence of sufficient androgens, estrogens, and insulin - this effect of GH is greatly reduced and it's action is then primarily catabolic (lazy for references atm)

One common pathway between insulin, IGF-1, and androgens appears to be REDD1/DDIT4 - also regulated by glucocorticoids, hypoxia, and oxidative stress.

A pathway some researchers have titled a "metabolic éminence grise"

Lipina, C., & Hundal, H. S. (2016). Is REDD1 a Metabolic Eminence Grise? Trends Endocrinol Metab, 27(12), 868-880. doi:10.1016/j.tem.2016.08.005



Insulin

Regazzetti, C., Bost, F., Le Marchand-Brustel, Y., Tanti, J. F., & Giorgetti-Peraldi, S. (2010). Insulin induces REDD1 expression through hypoxia-inducible factor 1 activation in adipocytes. J Biol Chem, 285(8), 5157-5164. doi:10.1074/jbc.M109.047688

"Insulin-induced REDD1 expression occurs through phosphoinositide 3-kinase/mTOR-dependent pathways. Moreover, using echinomycin, a hypoxia-inducible factor 1 (HIF-1) inhibitor, and HIF-1alpha small interfering RNA, we demonstrate that insulin stimulates REDD1 expression only through the transcription factor HIF-1. In conclusion, our study shows that insulin stimulates REDD1 expression in adipocytes."

IGF-1

Frost, R. A., Huber, D., Pruznak, A., & Lang, C. H. (2009). Regulation of REDD1 by insulin-like growth factor-I in skeletal muscle and myotubes. J Cell Biochem, 108(5), 1192-1202. doi:10.1002/jcb.22349

"Although REDD1 protein was elevated 5-6 h after addition of IGF-I to myotubes, protein synthesis measured during this 1 h window was paradoxically greater in myotubes expressing more REDD1. In contrast to the IGF-I induced increase in REDD1 mRNA, REDD2 mRNA was decreased by IGF-I. We conclude that IGF-I stimulates REDD1 expression in skeletal muscle and myotubes but under these conditions the REDD1 response is not sufficient to repress protein synthesis."

Although you would expect increased REDD1 to decrease protein synthesis, this is perhaps balanced by the stimulation of other pathways by insulin & IGF-1 (see figure below)



Androgens

Wu, Y., Zhao, W., Zhao, J., Zhang, Y., Qin, W., Pan, J., . . . Cardozo, C. (2010). REDD1 is a major target of testosterone action in preventing dexamethasone-induced muscle loss. Endocrinology, 151(3), 1050-1059. doi:10.1210/en.2009-0530

"Dexamethasone changed expression of 876 probe sets by at least 2-fold. Among these, 474 probe sets were changed by at least 2-fold in the opposite direction in the dexamethasone plus testosterone group (genes in opposition). Major biological themes represented by genes in opposition included IGF-I signaling, myogenesis and muscle development, and cell cycle progression. Testosterone completely prevented the 22-fold increase in expression of the mammalian target of rapamycin (mTOR) inhibitor regulated in development and DNA damage responses 1 (REDD1), and attenuated dexamethasone induced increased expression of eIF4E binding protein 1, Forkhead box O1, and the p85 regulatory subunit of the IGF-I receptor but prevented decreased expression of IRS-1. Testosterone attenuated increases in REDD1 protein in skeletal muscle and L6 myoblasts and prevented dephosphorylation of p70S6 kinase at the mTOR-dependent site Thr389 in L6 myoblast cells. Effects of testosterone on REDD1 mRNA levels occurred within 1 h, required the androgen receptor, were blocked by bicalutamide, and were due to inhibition of transcriptional activation of REDD1 by dexamethasone"

White, J. P., Gao, S., Puppa, M. J., Sato, S., Welle, S. L., & Carson, J. A. (2013). Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle. Mol Cell Endocrinol, 365(2), 174-186. doi:10.1016/j.mce.2012.10.019

"Testosterone loss (TL) significantly decreased volitional grip strength, body weight, and gastrocnemius (GAS) muscle mass, and ND reversed these changes. Related to muscle mass regulation, TL decreased muscle IGF-1 mRNA, the rate of myofibrillar protein synthesis, Akt phosphorylation, and the phosphorylation of Akt targets, GSK3β, PRAS40 and FoxO3a. TL induced expression of FoxO transcriptional targets, MuRF1, atrogin1 and REDD1. Muscle AMPK and raptor phosphorylation, mTOR inhibitors, were not altered by low testosterone. ND restored IGF-1 expression and Akt/mTORC1 signaling while repressing expression of FoxO transcriptional targets."

Hypoxia/Energy Stress

Gharibi, B., Ghuman, M., & Hughes, F. J. (2016). DDIT4 regulates mesenchymal stem cell fate by mediating between HIF1alpha and mTOR signalling. Sci Rep, 6, 36889. doi:10.1038/srep36889

Sofer, A., Lei, K., Johannessen, C. M., & Ellisen, L. W. (2005). Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol, 25(14), 5834-5845. doi:10.1128/MCB.25.14.5834-5845.2005



If estrogen is necessary for the formation of IGF-1, maybe that's partly why this study Haidut referenced noted a relationship between estradiol and acne in men

Aizawa, H., & Niimura, M. (1992). Serum hormone levels in men with severe acne. J Dermatol, 19(7), 404-407.

"In order to evaluate the hormonal milieu in young men with severe acne, we measured serum estradiol (E2), total testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEA-S), and sex hormone binding globulin (SHBG) levels in sixteen male patients aged 20-30 years with severe acne, including twelve cases of nodular-cystic acne, and in seventeen age-matched normal controls. There were no significant differences in the serum levels of T, FT, DHT, DHEA-S, or SHBG between the patients and the controls, but serum E2 was significantly higher in the patient population. Thus, the hemodynamics of serum androgens in male patients with acne do not seem to differ significantly from that of normal controls. Elevated E2 levels might affect the inflammatory response of acne vulgaris through the release of thymic hormones, as reported in the literature."

Ray wrote several times that acne and its occurrence in "syndromes" like PCOS is an estrogen-driven phenomenon. However, the medical profession is firmly holding onto its dear idea that it is androgens like DHT, DHEA, T, and androsterone that are causing the acne and the insulin resistance in PCOS.
This study found no link between any androgen and acne. It concludes that previous studies linking acne and androgens suffer from methodological flaws - i.e. the population as a whole has very high (50%+) prevalence of acne and other studies have not really been able to isolate a true control group without acne in order to properly compare links between androgens and acne. Now, given that the connection between non-bacterial acne and one or more hormones is pretty well established, what remains is mostly estrogen and progesterone. And given that progesterone is commonly reported to ease acne, estrogen remains as the lone likely culprit as the second study below shows (at least in males).

Acne is not associated with abnormal plasma androgens. - PubMed - NCBI
"...Our data would be consistent with a weak relationship between acne and free DHT. However, it is important that this correlation should not be regarded as implying causation. Male DHT levels are much higher than female levels. Even the males with the lowest acne grades had mean DHT levels of at least three times that of the females with severe acne. Clearly, circulating DHT is not causing acne. However, DHT arises partly by peripheral conversion from testosterone and the results are consistent with greater rates of conversion in skin containing active sebaceous glands."

"...To conclude, there is little evidence that high levels of androgens are responsible for some young people having particularly severe acne. Circulating androgens play, at the most, a permissive role in acne. Much of the published clinical evidence is based upon an unsound experimental approach that fails to recognize the consequences ofthe high prevalence of acne."

Serum hormone levels in men with severe acne. - PubMed - NCBI
"...In order to evaluate the hormonal milieu in young men with severe acne, we measured serum estradiol (E2), total testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEA-S), and sex hormone binding globulin (SHBG) levels in sixteen male patients aged 20-30 years with severe acne, including twelve cases of nodular-cystic acne, and in seventeen age-matched normal controls. There were no significant differences in the serum levels of T, FT, DHT, DHEA-S, or SHBG between the patients and the controls, but serum E2 was significantly higher in the patient population. Thus, the hemodynamics of serum androgens in male patients with acne do not seem to differ significantly from that of normal controls. Elevated E2 levels might affect the inflammatory response of acne vulgaris through the release of thymic hormones, as reported in the literature."

 

[Travis]

"In order to evaluate the hormonal milieu in young men with severe acne, we measured serum estradiol (E2), total testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEA-S), and sex hormone binding globulin (SHBG) levels in sixteen male patients aged 20-30 years with severe acne, including twelve cases of nodular-cystic acne, and in seventeen age-matched normal controls. There were no significant differences in the serum levels of T, FT, DHT, DHEA-S, or SHBG between the patients and the controls, but serum E2 was significantly higher in the patient population. Thus, the hemodynamics of serum androgens in male patients with acne do not seem to differ significantly from that of normal controls. Elevated E2 levels might affect the inflammatory response of acne vulgaris through the release of thymic hormones, as reported in the literature."

That protein, the target of rapamycin, appears to be quite important in steroid metabolism.

So there appears to be two primary agents. If IGF‐1 is doing it by upregulating SREBP‐1, then androgens would do it to since they do the same. Both dihidrotestosterone and IFG‐1 transcribe for SREBP‐1, increasing it's concentration within the cell. Thousands of people take androgens yearly, many illicitly, and the increase in acne reported is undeniable:

Melnik, Bodo. "Abuse of anabolic‐androgenic steroids and bodybuilding acne: an underestimated health problem." JDDG: Journal der Deutschen Dermatologischen Gesellschaft (2007)​

'Doping prevalence and anabolic androgenic steroids: Use of doping agents, especially of androgenic steroids , is no longer limited to competitive sports, but has, as medical studies in USA show, spread to leisure sports, especially to fitness sports and bodybuilding. The main reason for taking AAS is the identification of adolescents and young adults with the exaggerated ideal body image suggested by western mass media. Striegel's estimate that visitors of fitness centers in Germany spend about 85 million Euros yearly for anabolic ergogenic substances. In the USA, 11 % of boys in grades 11 and 12 consume androgenic steroids , as do 2.5% of girls. In England, 9% of male fitness studio attendants take androgenic steroids. The drugs are known among users as ‘‘Sus’’ and ‘‘Deca’’. ‘‘Sus’’ (sustanon) is a mixture of four testosterone esters, ‘‘Deca’’ is nandrolone decanoate.The prevalence of androgenic steroids among Australian high school students is reported at 3.2%. In the subgroup of bodybuilders and weightlifters in Flanders, the prevalence of androgenic steroid abuse between 1988 and 1993 was 38–58%. Doping prevalence among college athletes in the USA is reported to be 17–20%, among amateur bodybuilders even 80 % in men and 40 % in women. An increase in the prevalence in androgenic steroid abuse has also been observed in Italy and Sweden. The doping prevalence in Northern Germany is best represented by the Lübeck study, a survey of 24 fitness studios in Schleswig-Holstein and Hamburg. The average age of the athletes was 27.9 years with users being most frequently (37%) in the age group 21–25 years. Of the interviewed men 24% and of the women 8% admitted to using anabolic drugs. In 94 % potentially highly hepatotoxic substances were taken, mainly procured on the black market, but prescribed by physicians in 14 % (Table 2). As the return of questionnaires in the Lübeck study was 52%, a much higher rate of use must be anticipated. A recently published report by Striegel et al. from the Institute for Sports Medicine of the University of Tübingen, Germany, revealed the results of a nationwide poll of 113 fitness centers. Of participants, 13.5% admitted to having used anabolic ergogenic substances at least once. Abuse correlates with cocaine abuse, years of training, frequency of training and showed negative correlation with educational status and alcohol consumption. Especially disturbing is the fact that 48.1% of the users of anabolic ergogenic agents obtain them through health care providers and 32.1% of these are under physician supervision. A similar situation can be found in Sweden. An analysis of 25,835 calls to the anti-doping hotline of the Institute for Clinical Pharmacology of the Huddinge University Hospital in Stockholm from 1993 to 2000 shows that most calls were in regard to side effects of AAS, especially, testosterone, nandrolone decanoate, methandienone and stanozolol. Of the ten most common side effects of androgenic steroids, acne was third following psychological changes such as aggression and depression, among clinically visible.'​

click to embiggen
​

You can even find testamonials online, in the bodybuilder forums.
​

It appears at the moment that the cause is simply the comodogenic lipid change executed by transcription factor SREBP‐1—under the control of either IFG‐1 or DHT—leading to much heavier oils on the skin.

 

[Runenight201]

I notice that consumption of coconut cream improves my skin quality drastically. It’s a night and day difference. Nothing worked for my oily skin, even avoidance of dairy, meat, and eggs (I was still eating lots of wheat and beans during this time period). I struggle to stop touching my face because I’m shocked at how smooth it becomes eating coconuts.

I have for sure noticed the connection to cystic acne with dairy, and to animal flesh as well, but I am slightly concerned about protein intake levels, especially because I like to do calisthenics and want to progress on certain movements in that arena. Perhaps I might try egg whites, and if those prove problematic, resort to trying the potato protein that others have talked about on this forum.

Does butter contain IGF-1 or is it considered a safe dairy product to use? I used some in my rice for dinner, because I need the extra calories, and I don’t quite enjoy mixing coconut cream and rice together. Last time I did that with refined coconut oil I had a really bad experience.

Maple syrup and coconut cream is a really good combo :)

 

[Sourdoughbanana]

wouldn't coconut oil or anything coconut work better topically? A bit wary of the 5ar inhibition I've seen here and there upon coconut consumption.

A very interesting topic, much better quality in only a few short posts, compared to all the junk science reported on other forums. Glad I'm reading this. Travis, are you a researcher?

Also for the OP: is it when eating those foods together at the same time? When I'm sticking to fruits in the AM only, then proteins with my tubers+greens in the PM, even though there's a bit of fructose in said tubers, everything is much better than on a YOLO-template of eating. I also like the idea of a "protein intermittent fasting".

 

[Runenight201]

@Sourdoughbanana I certainly hope that 5ar claim doesn’t hold a lot of weight lol, but either way, I’d trade-off some dht for zero acne and smooth skin and hair. I’m sure topically it would help too, but I’ve always been a diet oriented type of a guy. Topically I use a salicylic acid face wash before a benzoyl peroxide 2.5% lotion to keep everything manageable, but ideally I’d be ditching these once I get my internal environment under control.

 

[Travis]

I notice that consumption of coconut cream improves my skin quality drastically. It’s a night and day difference. Nothing worked for my oily skin, even avoidance of dairy, meat, and eggs (I was still eating lots of wheat and beans during this time period). I struggle to stop touching my face because I’m shocked at how smooth it becomes eating coconuts.

I have for sure noticed the connection to cystic acne with dairy, and to animal flesh as well, but I am slightly concerned about protein intake levels, especially because I like to do calisthenics and want to progress on certain movements in that arena. Perhaps I might try egg whites, and if those prove problematic, resort to trying the potato protein that others have talked about on this forum.

Does butter contain IGF-1 or is it considered a safe dairy product to use? I used some in my rice for dinner, because I need the extra calories, and I don’t quite enjoy mixing coconut cream and rice together. Last time I did that with refined coconut oil I had a really bad experience.

Maple syrup and coconut cream is a really good combo :)

The thing about butter is that it should have low IGF-1 concentration, which is water-soluble, yet it would of course have the highest concentration of sterols among dairy products. I personally do no know what is more causal towards acne in your average rBGH whole milk, either the androgens or IGF-1, yet I am nearly certain that they can both induce it. Egg yolk is essentially the only common food as far as I can tell that has a considerable about of androgens and no IGF-1. This means that you could perhaps try whole-eggs with butter, yet no cheese, and if you do get acne then it should likely be the androgens—the lesser ones like androstenedione.

Egg white is an affordable, available, convenient, and versatile food with a very high protein density. However, it is hydrolyzed and absorbed very quickly and is one of the classic serotonergic foods—along with soy and whey—according to leading researcher John Fernstrom. It is also somewhat immunogenic if not completely broken down, which depends on such things as stomach pH and intestinal permeability—among other things. I would imagine this would be more-or-less safe for most people if it's mixed with something that would both lower the Fernstrom ratio and not interfere with digestion, perhaps even slow it down to a degree. Egg white has such a high tryptophan content that it increases brain serotonin synthesis, and too much protein at once can increase plasma ammonia if not detoxified at a high rate.

 

[Travis]

A very interesting topic, much better quality in only a few short posts, compared to all the junk science reported on other forums. Glad I'm reading this. Travis, are you a researcher?

I research scientific topics , for the articles I write myself, by reading a good amount of scientific articles beforehand. There are literally 10 million scientific articles on GoogleScholar and not one person can ever read them all, but the more you read the more you know. And also, the more you know the faster you can read because of familiarity with the materials and methods and also because you refine your habits in the process: Reading about these topics is perhaps the best way to find-out what influences brain glucose rates, acetylcholine, dopamine, psychology, etc.

 

[Runenight201]

Very interesting...I'll have to give whole eggs with potatoes a try once my residual inflammation clears up from my recent flesh eating/milk drinking fiasco. Actually I'll think I'll start with just the egg whites, and then move onto the whole eggs, testing each one individually. I don't like eating my eggs plain, and so will be eating with potatoes and probably broccoli, tomatoes, onions, mushrooms, garlic, salt, butter =P

In regards to the Fernstrom ratio, I calculated the ratio for various foods myself from the information from nutritiondata.com (100g of calculated food item), and I found that whole egg had a lower ratio (.04 mg / 100g) than potatoes (.066) , sweet potatoes (.08), and plantains (.088). I am using tryopthan / sum (Tyrosine, phenylalanine, valine, isoleucine, leucine).

Perhaps the carbohydrates in these foods have something to do with not being as serotonergic? I thought that carbs increase brain serotonin levels, so now I'm confused about Fernstrom's conclusion and egg whites.

 

[Runenight201]

Hmmm well I’m tilting towards the androgen theory for acne in my case. Meat makes me inflamed, and today I got one more inflamed cyst on my shoulder, and the only animal product I’ve been using has been butter in my rice. So I think for those who are super sensitive to androgens, it’s best to eliminate all animal products until all inflammation has cleared up, stick to safe starches like white rice and potatoes and then eat veggies, fruit, and sugar in unlimited quantities. And of course include the holy coconut. Perhaps once the inflammation/sebum subsides, a little meat can be added in every now and then but only so far as the acne and oily skin stay clear.

If this doesn’t work, then the next step is to start looking for food intolerances, but I really don’t wanna go there, the orthorexia can only go so far

 

[Stramonium]

Have you try progest e? It has an almost immediate overnight effect on my acne, skin is much less inflamed and smother, almost glowing, it's hard to explain but it even helped with the scars I had. Besides keeping estrogen at bay it regulates iron and copper which are also related to skin inflammation/aging when consumed in excess