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How does Accutane work?
I've been meditating on why Accutane reduces sebaceous gland activity. Hypervitaminosis A typically causes oily skin. Accutane causes oily skin initially but after enough poisoning it drastically reduces sebum levels. Why?
Grant says it's because it poisons the sebaceous gland stem cells. Perhaps that's true, I'd like to see more evidence for that idea. I think there might be a simpler explanation though:
This is what Accutane does to the size of one's thyroid:
🙁
Here is the abstract of the study this figure is from:
Background: Isotretinoin is widely used in the treatment of acne. Aims: We investigated the effects of isotretinoin on thyroid function tests and thyroid volume in acne patients. Methods: In this prospective study, a total of 104 acne patients were included. Sixty-six patients were treated with isotretinoin for at least 4 months. Thirty eight patients were included in the control group. The levels of thyroid stimulating hormone, free triiodothyronine, free thyroxine, antithyroglobulin and antithyroid peroxidase antibodies were measured and a thyroid ultrasound was performed in all the subjects before treatment and 4 months after treatment. A “p” value of < 0.05 was considered significant. Results: In the isotretinoin-treated group, thyroid stimulating hormone levels increased significantly during isotretinoin treatment (P = 0.018). Free triiodothyronine, free thyroxine, anti-thyroid peroxidase levels and thyroid volume decreased significantly during treatment (P = 0.016, P= 0.012, P= 0.006, P = 0.020 respectively). Limitations: The major limitation of this study is the lack of follow-up data after the cessation of isotretinoin therapy in acne patients. Conclusion: Patients treated with isotretinoin should be monitored with thyroid function tests.
We also know that hypothyroidism leads to reduced function of sebaceous glands:
Abstract
Sebum excretion rates (SER) were measured before and after treatment in patients with hypothyroidism and thyrotoxicosis. The mean SER in the former was significantly less than that in normal controls but there was no correlation between SER and the severity of the disease as indicated by serum thyroid-stimulating hormone levels. After treatment with L-thyroxine the SER increased but remained subnormal. By contrast the SER was not increased in patients with thyrotoxicosis and it was unaffected by treatment. The human sebaceous gland seems to respond to thyroid hormone mainly in the hypothyroid range.
Hypothyroidism also suppresses sweat gland activity:
The dryness of hypothyroid skin results from decreased eccrine gland secretion. The mechanism for decreased sweating is not clear although the hypothyroid glands are atrophic on histologic examination.
Is this not the best explanation so far for Accutane's effect on sebaceous gland activity? Perhaps I'm reaching a bit but I haven't seen any better explanation.
How many of these symptoms are familiar to those that have taken Accutane:
Direct thyroid hormone action on skin tissues:
HYPOTHYROIDISM
Epidermal Changes
Coarsened, thin, scaly skin
Dermal Changes
Non-pitting edema (myxedema)
Edema (hands, face, eyelids)
Carotenemia
Pallor
Hair and Nail Changes
Dry, brittle, coarse hair
Alopecia
Loss of lateral third of eyebrows
Coarse, dull, thin, brittle nails
Sweat Gland Changes
Dry skin (xerosis)
Decreased sweating
Hmm but isn't hypothyroidism associated with acne? Well, not exactly:
Thyroid hormone action on sebaceous glands is unclear. In hypothyroid states, sebocytes exhibit reduced rates of secretion (SER),10 and TSH and Thyroxine, with co-administration of testosterone, have both been shown to increase sebum secretion.11 Although SER increases with thyroxine, it still remains subnormal.12 Studies have failed to show significant changes in thyroid function parameters in adult acne.7,13 The exact role of thyroid hormone remains unclear but it seems unlikely that it is mediated principally through sebum secretion.
However, thyroid dysfunction is associated with autoimmunity. Accutane has been shown to cause autoimmune conditions:
Abstract
Introduction. Isotretinoin is commonly used to treat cystic acne. Definitive mechanisms of action for isotretinoin are not known though despite many side effects having been documented. Various case reports have noted autoimmune diseases succeeding isotretinoin treatment. Case Report. A 16-year-old female presents with symptoms of tremors, lack of focus, sleeplessness, emotional liability, bulging eyes, loose stools, heat intolerance, and missed menstrual periods. Symptoms manifested shortly after the patient finished a course of oral isotretinoin treatment for acne. Physical exam showed resting tremors, bilateral proptosis, hyperactivity, and rapid speech. A diagnosis of Graves’ Disease was made by correlating symptoms, physical exam findings, ultrasound, and positive family history of autoimmune thyroid disease. Conclusion. Emergence of autoimmune thyroid diseases depends upon genetic predisposition and environmental triggers. Mechanism of action for isotretinoin is not known but the drug may play a role in triggering autoimmunity in genetically susceptible individuals.
https://drhedberg.com/fluoride-melissa-gallico/
This is an interview with the author of this book:
She is very sensitive to fluoride and it is directly associated with the severity of her acne. She is not an isolated case. Importantly, she mentions that she took Accutane in the past. Halogens in general are associated with acne, in particular bromine and fluorine, it seems likely it is more of an allergy issue rather than from direct chemical toxicity of these elements even though they are toxic in themselves. Halogens can interact with iodine though so perhaps when the thyroid is compromised halogens can elicit stronger than normal effects.
To conclude: I hypothesize that Accutane can clear up acne due to induction of hypothyroidism but that it may actually increase susceptibility to allergy induced acne in the long term.
Well Ray Says that vit A uses the same transport as thyroid hormone and that excess vit A can cause hypothyroidsm. He even said people with less than ideal thyroid function should not have more than 5000iu a day.. I wonder why I miss this point when I was following Ray Peat diet.. I had always elevated TSH a lot, but I was taking and eating crazy amounts of vit A anyway lol.. Hopefully with detoxing vit A my TSH will go finally down to 1 max 2..
VAD causes elevated TSH, I bet for that reason a lot of people with thyroid issues have supplemented with retinol when it is actually VA toxicity that is contributing to or causing their elevated TSH...
I also want to understand how vitamin B5 reduces sebum production, it has almost the same affect as accutane, couple days of mega doses and sebum stops. Saw these studies below, showing that 13-cis-retinoic is increased by CoA, and B5 puts CoA production in overdrive. So my thinking here is B5 is helping to produce more 13-cis. B5 could potentially help speed up the depletion of VA? But does high dose B5 also tend toward hypothyroidism?
Synthesis of coenzyme A ester of retinoic acid: Intermediate in vitamin A metabolism
Activation of retinoic acid by coenzyme A for the formation of ethylretinoate
Quote from tim on June 23, 2020, 8:09 amVAD causes elevated TSH, I bet for that reason a lot of people with thyroid issues have supplemented with retinol when it is actually VA toxicity that is contributing to or causing their elevated TSH...
I wonder if people can have vit A toxicity in the liver and deficiency symptoms at the same time like in case of copper. You can have toxic amounts of copper in the liver, brain and other tissues, but all kinds of deficiency symptoms if the liver can't make ceruloplasmin. So if vit A can't be used by the body without RBP it will just sit in the liver.. It is basically vicious circle. The more toxic and damaged liver is from vit A or copper the less systemic proteins like ceruloplasmin, RBP, ferritin etc.. can liver make..
Hi @tim-2,
Thanks for sharing the information and the theory. Sorry in advance for the long-winded response.
A key functional definition of ATA is that it drives stem cell “differentiation”. There are really two phases of the tissue response to ATA. This is well documented in:
Authors: Cheng, Li-Hong, Ito, Yuto; Osaka University, et al.
ISBN 978-1-62100-597-1
From chapter 6: Tretinoin-cyclodextrin Complex in Skin Rejuvenation Therapy
[1] http://www.amazon.com/Retinoic-Acid-Structure-Mechanisms-Microbiology/dp/1621005976
And in a bunch of other studies.
Basically, the first phase is that the stem cells are induced into a state of more rapid replication (and thus differentiation). But, this is just the short term response. The longer term response is ATA induces apoptosis, inflammation, metaplasia, and finally tissue atrophy. This sequence of event is generally well known in dermatology.
Quite interestingly, this closely fits with Wolbach & Howe’s description of tissue response to vitamin A deficiency.
Specific Pathology. — The primary effect of vitamin A deficiency is on epithelial structures. The sequences are atrophy of the epithelium concerned and the substitution for it of a stratified keratinizing epithelium, identical in appearance in all locations, and arising from focal proliferation of basal cells.
- Wolbach, S. B., and Howe, P. R.: Tissue Changes Following
Deprivation of Fat-Soluble A Vitamin, J. Exper. Med. 42: 753 (Dec.) 1925.
So, in the short term, in response to ATA there will be more active stem cells in the sebaceous glands. But, I don’t think that the more abundant stem cells are causing more oil on the skin. Rather, it is that the body is trying to dispose of a lipophilic toxin (VA and ATA) out through the skin. When doing so its ATA that drives the stem cell “differentiation” rates up. But eventually they will die off, become depleted, and once that happens the sebaceous glands will shrink, and stop functioning correctly. So, there’s a widely acknowledged duration paradox to the use of retinoids in dermatology. Works in the short term - but backfires in the long term.
RE: Case Report. A 16-year-old female presents with symptoms of tremors,
Great: They poison a kid with isotretinoin, and then conveniently diagnose her with Graves disease. Somehow they are not able to accept what they’ve just eye witnessed. Therefore, they need to blame it on a “disease” label. No, Graves’ Disease did not cause the autoimmune thyroid disease, and the autoimmune thyroid disease did not cause the Graves’ Disease. A poisoning caused both of them.
And, like with so many other disease conditions there’s an endless circular blame game going on. Diabetes is a great example. It’s very widely claimed that diabetes causes cardiovascular disease, macular degeneration, obesity, kidney disease etc. However, all of these other diseases can and do exist outside of the context of diabetes. So, in no way is diabetes required to cause them. Therefore, it is just so much more logical that something else is causing diabetes AND the other diseases to develop, roughly at the same time or independently. A person’s most susceptible tissue is going to fail first. In the case of diabetes it’s the pancreatic stem cells. Something (not just bad luck) is causing that to happen. It’s just after some lag time that more and more organs and tissues succumb to the something else.
Likewise, for thyroid growth (hyperthyroidism) is often followed by thyroid atrophy.
What’s a common characteristic shared by all these diseases? It’s the destruction of stem cells, and the subsequent metaplasia of tissues. Obesity is the odd man out, because the adipose stem cells do not go through the second phase of apoptosis, rather they just perpetually rapidly replicate.
So, rather than a dysfunctional thyroid causing the skin and other issues, we need to look upstream and ask if there is anything else that could have caused both of them independently. That case report you shared is good evidence as to what it really is.
Also, the thyroid can be a more or less direct target of vA toxicity because transthyretin directly binds with the RBP. This fact is rationalised as needed to stop the hormone loss through the kidneys. But, if we didn’t have an overload of the RBPs in circulation then there’d be more free transthyretin/ thyroxine available.
A couple of people have contacted me saying that their TSH levels have improved a lot since adopting a low vA diet.
Thanks for elaborating more Grant.
There is certainly both an epidemic of Hypervitaminosis A as well as thyroid dysfunction and I'm sure there is a lot of overlap. Thyroids are very sensitive to many things, Vitamin A can be prothyroid and antithyroid depending on VA status, I don't expect you to agree with that though. In industrialized nations, VA does tend to be overwhelmingly antithyroid.
One problem I have with the idea that Accutane works through destruction of sebaceous gland function is that if it was that toxic I would think that it would actually kill! If it was that cytotoxic I'd expect to see much more bodily damage.
I think it is less likely with VA than with copper but I think that a lot of third world VAD may be similar to what you described. Many cases may be because of zinc and other deficiencies despite having some liver reserves. Low serum retinol in western countries is rare so I doubt there is much of what you describe happening in these countries.
I think you said that high dose B5 can cause hair loss or was that biotin? If it's B5 then it's probably worth investigating hypothyroid effects from megadoses. I think working out B5's mechanism will help us understand a lot.
B5 could potentially help speed up the depletion of VA?
It could speed up the conversion of retinol to retinoic acid like riboflavin does but I don't think that's a good thing. Excretion is obviously good but accelerating metabolism in the steps before excretion isn't necessarily so if the steps after the accelerated step but before excretion are bottlenecked.
Our study demonstrates that 13-cis RA markedly decreases sebaceous gland size by 8 weeks of treatment, and a trend toward this reduction is apparent at 1 week. This is consistent with the observations that sebum secretion can be markedly reduced by 13-cis RA as early as 2 weeks.13,14 However, the sebaceous gland architecture returns to pre-treatment levels as early as 2 months after cessation of therapy and the rate of return is faster with the lower doses of isotretinoin.15 Despite this observation, for unknown reasons, isotretinoin induces permanent remission of acne in a majority of cases.
This is odd, they are saying sebum production quickly returns to normal but acne does not usually return. Can Accutane users confirm this please?
Quote from tim on June 23, 2020, 11:17 pmOur study demonstrates that 13-cis RA markedly decreases sebaceous gland size by 8 weeks of treatment, and a trend toward this reduction is apparent at 1 week. This is consistent with the observations that sebum secretion can be markedly reduced by 13-cis RA as early as 2 weeks.13,14 However, the sebaceous gland architecture returns to pre-treatment levels as early as 2 months after cessation of therapy and the rate of return is faster with the lower doses of isotretinoin.15 Despite this observation, for unknown reasons, isotretinoin induces permanent remission of acne in a majority of cases.
This is odd, they are saying sebum production quickly returns to normal but acne does not usually return. Can Accutane users confirm this please?
For me sebum production returned in higher production and acne worsened after taking it. Some people get debilitating issues after taking only one pill that last indefinitely, some after taking full 6 month courses, and some people seem to not notice issue(but I suspect these are people that are not in tuned with their bodies).