Guide Biochemistry of Retinoids (Tretinoin vs. Retinol)

[Robynn]

Retinoids are a derivative of Vitamin A
They have a great potent effect on lots of skin issues such as:
- Acne
- Wrinkles
- Hyperpigmentation and more

This is info/guidance on how they should be used

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Retinals ​

Spoiler: Explanation

Retinoids are compounds formed from Vitamin A (Retinol). This is a compound which cant be synthesised through your body. It needs to be gained through diet.

Retinol in your body is catalyzed into Retinaldehyde which is catalysed into Retinoic acid.
The acid formed is the only active form.

Your skin has a method of turning off retinoic acid, this is the CYP26 enzyme family. The enzymes work in the electron transport chains and add a hydroxyl group into inactive metabolites (intermediates or products of photosynthesis) which are glucuronidated, that is the packing up of products to remove them. This is why retinoic acid has a short half life in skin tissue and needs constant reapplication to keep the receptors active.

It also has a negative feedback loop meaning that deviation from the normal amount of retinoic acid causes more CYP26, so the more you apply the more the skin breaks it down.

That is why the method to apply retinoic acid is to do it in concentrated areas instead of high doses and results will take months instead of weak as your skin has to adapt to higher concentrations.

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The reaction pathway ​

Retinoic acid, unlike other tropical ingredients, does not sit on the skin's surface; it enters the outermost layer of the epidermis (the HORNY layer) and eventually travels to the nucleus where it acts as a gene transcription regulator.

Receptors
Retinoic acid binds to two different types of nuclear receptors:

• RARs, they are the primary target for trans-retinoic acid (tretinoin), They are very dominant in the humans epidermis

• RxRs, activated by 9-cis-retinoic acid, and partners with other receptors (RARs)

Mechanism

The absence of ligand - The two nucleur receptors are found on DNA at specific sequences called Retinoic Acid Response Elements. This causes compressors to cause histone modification that prevent transcription of a gene and the production of a protein, so the gene is turned off.

Retinoic acid binds to RAR - ligand-binding domain (LBD) on ligand-binding domain RAR changing the shape of the receptor without breaking any bonds causes:

• Release of coreceptors
• Repositions helix H11 to helix H12 into its active position
• Attracts helper proteins to start transcription and cause gene activation

Gene transcription - Multitude of genes are either reduced in producing proteins or increased in producing proteins. This depends on the gene type, the RAR subtype and the DNA response element architecture.
This is why retinoic acid can have so many effects, it's not a single mechanism.

Genes that improve/change looks activated by retinoic acid:

• Collagen genes
• Growth factor signalling
• Barrier protein synthesis
• Increase intracellular retinoic acid availability

Completely different to surface level skincare it instead reprogrammes your skin cells at their transcription level.

Fresher Skin (Accelerated Cell-Turnover)

The average time it takes for a skin cell to form in the deepest layer of your skin and migrate and shed on the surface is usually 28 days (for a young adult).
With Tretinoin its extremely accelerated and is 14-21 days.
https://jddonline.com/articles/40-y...noin-use-in-review-S1545961613P0638X/?_page=2

This is because retinoic acid upregulated genes involved forming new cells in the epidermis also speeding up the final two stages in the cell cycle.
This means dead skin cells shed faster so your face has a smoother texture, and new skin cells reach the faces surface faster:

• Causing fading of dark spots
• Clogged pores are removed before they can mature, reducing acne
• The outer layer of the epidermis becomes thinner then into a better barrier

All together giving you brighter skin, reduced skin dullness ect.

Collagen synthesis​

This is why some say tretinoin is separate from other tropical ingredients.​

Mechanism​

The receptors in retinoic acid bind to receptors that upregulate transcription of COL1A1 and COL 1A2 (Type 1 collagen) and COL3A1 (Type 3 collagen). Increasing the procollagen mRNA synthesis.
Tretinoin upregulates expression of fibroblast chemotaxis, differentiation into mycofibroblasts and therefore sustained collagen production.

- Studies have shown that tretinoin treated wounds show an accelerated pathway compared to controls - https://pmc.ncbi.nlm.nih.gov/articles/PMC2699641/ .

- Matrix metalloproteinases are enzymes that degrade collagen (UV exposure is known to upregulate this and damage your skin.)

- However tretinoin suppresses MMP through pathway inhibition turning off the collagen degraders while turning on and speeding up collagen synthesis.

- Moreover at the end of this mechanism tretinoin induces genes/enzymes that are involved in type 1 collagen recycling. This means collagen already in the body is preserved and remodelled and reinforced.

Evidence
The landmark NWJM study (Weiss et al., 1993) showed that 0.1% tretinoin applied for 6 months to sun damaged skin caused increased procollagen formation. Fine wrinkles improved because the dermis becomes thicker and more structurally sound.
https://pubmed.ncbi.nlm.nih.gov/3336176/

So you yourself would see:

• Over 3-6 months your skin appears visibly thicker and thicker and the hollow/sunken appearance you may have due to age begins to reverse.
• And the jawline appears more defined because skin laxity decreases

Pore size Reduction​

Pore size depends on 4 factors:

• Follicular plugging
• Sebum secretion volume
• Collagen support around pores
• Hair follicle caliber

And tretinoin has an effect on ¾ of these:

• Increased prevention of keratin plugs from accumulating inside pores. Causing pores to appear smaller.
• Dermal thickening and improved collagen support around the pores, provides better structure so pore walls become more supported and less stretched.
• Small direct effect on sebum production, oral isotinoin shrinks sebaceous glands but tropical tretinoin does not significantly change the sebum output, so its a pore improvement in primary structural not secretory.

https://pmc.ncbi.nlm.nih.gov/articles/PMC12653878/ - What you would see then is pores less stretched and open.

Hyperpigmentation fading​

• Accelerated cell turnover - as said before the dead skin cells shed faster. Specifically pigmented keratinocytes causing melanosomes to rise to the surface of the skin faster and shed. The dark spots get exfoliated away over time.
• Retinoids interfere with the transfer of melanosomes from melanocytes to keratinocytes, the complex responsible for melanosome trafficking is disrupted, it reduces the number of pigment granules reaching the skin cells.
• Downregulates MITF which is the master regulator of tyrosinase gene expression reducing melanin synthesis.
• Increases permeability of the outermost layer of the epidermis, prompting more distribution of melanin granules preventing dense cluttering that creates dark visible patches.
• Anti-inflammatory effects that mean post-inflammatory hyperpigmentation is suppressed.

Over 3-6 months, sun spots, acne marks and melasma patches wil gradually fade.
Slower than hydroquine but sustainable long term.

Anti-aging ​

Multiple studies have shown:

• Increased epidermal thickness
• Increased dermal collagen width
• Improved elastic fiber structure
• Reduces fine wrinkle depth
• Improved skin roughness
• Prevents further photodamage

No other tropical ingredient has the amount of clinical research and evidence tretinoin has for photoaging reversal.
The mechanism is not cosmetic, its structural regeneration of a damaged dermal matrix. Lessens wrinkles and rebuilds collagen so wrinkles are prevented from forming in the first place.

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Tretinoin vs Retinol​

Tretinoin
Is already retinoic acid, and there is no conversion needed as it binds directly to RARs, so it has a high potency and a high initiation potential

Retinol
Needs to be converted to retinaldehyde then retinoic acid and it has a conversion efficiency in skin of around 5-15%. ​

The potency is lower than tretinoin but it depends on the conversion so therefore has a moderate initiation potential - This is also far easier to get than tretinoin. https://dermoi.com/retinal-vs-retinol-a-scientific-comparison/

This mechanism matters because each enzymatic step loses potency, so due to oxidation, inability and competing pathways the conversion is around 5-15%.
So you would therefore need much higher concentration of retinal to achieve the same biological effects of tretinoin. But also high retinol concentration causes irritation.

Which one to use:​

RETINOL:

• Beginners to retinoids
• Extremely sensitive skin (rosacea, eczema)
• Maintenance after using tretinoin and getting the effects you want
• Easier routines

TRETINOIN:

• Anyone who wants maximum collagen stimulation
• Treating damaged skin, maybe photo damage, deep wrinkles or lots of hyperpigmentation
• Levelling up form retinol
• Anti-aging

You will look worse when you first use tretinoin
The first few weeks they use tretinoin are different to the long term effects which is why some people may give up before gaining results:

Spoiler: Timeline of using Tretinoin

Timeline of using Tretinoin ​

First say around 1-2 weeks

• There will be immediate inflammatory gene expression and blood vessels will dilate causing redness.
• There will also be dryness due to transepidermal water loss
• And your outermost epidermis layer (your visible skin) becomes disrupted causing flaking and peeling.
• Therefore your skin barrier is temporarily disrupted and compromised. Some may think this is an allergic reaction and stop taking it, but it is actually very normal and is expected.

Week 2-4

• More skin turnover and your microcomedones emerge faster than they would naturally.
• Sebaceous follicles that were blocked become expressed causing an infmalitary response
• This can be known as a purge - it looks as if acne is being formed but in reality its pre-existing acne being expelled and this causes more infammarty response
• You would then see breakouts in your face in areas where you normally get acne, but this is a good thing showing that the tretinoin is working.

Week 4-8

• Your skin is now learning to handle the treatment and the outermost layer of the epidermis is now reorganising
• The inflammatory response is now reducing and collagen synthesis pathways are beginning.
• So now you would see slight improvements. Your skin has reduced dryness, less peeling and the purging slows. Skin would start to slightly look smoother.

Week 8-12

• Increased collagen becomes noticeable
• Epidermal tissue thickens
• Hyperpigmentated cells have now mostly been turned over
• Pores seem to becoming smaller
• Your skin would look brighter, smoother and more even - its the start of your fine lines softening too.

Months 3-6

• This is where the results are potent the collagen density has significantly increased
• Wrinkle depth has noticeably reduced as well as hyperpigmentation
• Pore size has definitely reduced and skin texture will have transformed
• These are where the final results are shown.

Most people quit due to the ugly phase where in reality your skin needs time to receive the signals, transcribe new genes, translate new proteins and organise the skin's architecture.
The method to use it is to start with a low concentration such as 0.025%, as higher concentrations may not be better long term.

Spoiler: Frequency

Frequency ​

Week 1-2: 2 nights per week ​

Week 3-4: 3 nights per week ​

Week 5-6: Every other night​

Week 7 and onwards: Nightly​

Spoiler: Technique

Technique​

1. Cleanse with cleanser and wait till skin is completely dry
   • Damp skin increases tretinoin absorption and can cause irritation
2. Add a pea-sized amount for the entire face, too much can again cause irritation.
3. Follow with moisturiser 10-20 minutes after

During early weeks irritation may be severe:

• Apply moisturiser to dry skin
• Wait 10 minted
• Apply tretinoin
• Wait 10 minutes
• Apply moisturiser again

This reduces penetration

Final Notes

• No matter how far through the journey of using tretinoin you must use sunscreen because it makes your skin more photosensitive.
• UV exposure destroys the collagen you are trying to build and causes rebound hyperpigmentation.
• You need to reapply every 2 hours if you are outside to protect the collagen you are building.
• When you use tretinoin, it is your entire routine all you would need is a simple moisturiser, sunscreen and the tretinoin and your results would be better than any extensive routines. This also saves a lot of your money.
• Sorry about a lot of my spelling here

 

[vamp]

bookmarked

 

[pauseboicarti]

dnr use adapalene if beginner upgrade to tret or taz eventually

 

[Robynn]

dnr use adapalene if beginner upgrade to tret or taz eventually

what