Still hiding from pigment issues? There’s a new deep-science approach. |

Still hiding from pigment issues? There’s a new deep-science approach.

Abnormality in pigment is one of the most common topics readers inquire about on BFT. Most frequently it has to do with hyperpigmentation that results from an inflammatory insult (PIH) or hormonal flux (melasma or “mask of pregnancy”), but many readers have sought information as to how they can lighten or “brighten” their general complexion.

This post provides information about new approaches to managing pigmentation issues, something your hosts have been working on for a considerable time. We will examine this work and the novel multi-prong approaches incorporated into these new and unique products.

For those who wish to learn the basics about pigment issues, we suggest you visit our earlier BFT blogs on the subject.


The management of aesthetically displeasing skin pigmentation is changing. To describe it, we must discuss work performed by the team at Cellese Regenerative Therapeutics over the past couple of years. Regular readers of BFT know that DrJohn and DrGeorge wear day hats as principals of Cellese. 

Pigment Basics Revisited

Melanin is an evolutionary protective pigment whose skin function is as a barrier against ultraviolet (UV) solar radiation. All races have similar numbers of melanin producing cells located within the stratum basalis of the epidermis. Skin color differences result from the pigment content and characteristics of the melanosomes produced by the melanocytes.

Caucasian skin has the smallest amount of pigment and smallest melanosomes; darkly pigmented skin has larger, wider and denser melanosomes. Inflammation from any source, including damage from UV radiation, is a potent stimulus for increased melanin production. Darker Fitzpatrick skin types are more prone to develop aesthetically displeasing hyperpigmentation.

As a general rule, melanosomes produced by melanocytes are expelled and subsumed into nearby keratinocytes. The melanin-laden keratinocytes slowly migrate to the skin surface where they are eventually sloughed off, a process that takes four to six weeks.

Melanogenesis takes place within the melanosomes, catalyzed by the enzyme tyrosinase. Inhibitors of this enzyme have long been mainstay ingredients in depigmenting products, the most well-known of which is hydroquinone. This approach, however, addresses only one of the several processes involved in melanin production, deposition and disposal.

Differences Between Epidermal and Dermal Pigmentation

During embryogenesis, melanocytes are genetically programmed to eventually settle in the lowest region of the epidermis (basal layer), just above the dermal-epidermal junction that separates the epidermis from the dermis. Typically, about one in every ten cells in this layer is a melanocyte, with a ratio of one melanocyte to thirty keratinocytes, which is the predominant cell of the epidermis. Epidermal pigmentation occurs from keratinocyte uptake of melanosomes produced by melanocytes.

As melanocytes (actually the precursor cell, the melanoblast) transit the dermis to the epidermis, some may finally reside within the dermis. Epidermal and dermal melanocytes appear to be biologically different populations. Dermal and epidermal melanocytes participate differently in pigmented lesions. The table below describes the role each layer plays in specific pigmentation scenarios.

Type of Pigmentation Surface (i.e. Epidermal) Deep (i.e. Dermal)
Brown birthmarks, café au lait spots No Yes
Normal tanning Yes No
Prolonged tanning Yes Yes
Freckles Yes No
Age spots No Yes
Melasma Yes Yes
PIH from injuries (burns, cuts, abrasions, etc.) Yes Yes

The illustration below demonstrates the pigment deposition patterns of common skin lesions.

It’s a fact of life that dermal pigment is more difficult to remove than epidermal pigment. Topical products are less able to penetrate to deeper skin layers, although microneedling can be of significant benefit. Pigmented spots that don’t readily respond to topical brightening treatments are likely to involve the dermis.

Multiple Pathways Involved in Melanin Production, Dispersal and Disposal

As was the case when we launched our hair growth products, we approached pigmentation from a deep-science perspective, knowing that melanogenesis is but one part of a complex multi-step pigmentation process. Several other pathways are involved. The steps below can each be addressed to reduce pigmentation.

  1. Inhibit tyrosinase activity and co-factors
  2. Promote tyrosinase degradation
  3. Down regulate gene expression that promotes melanogenesis
  4. Inhibit the pro-melanogenetic effects of UV
  5. Inhibit melanosome transfer from melanocyte to keratinocyte
  6. Increase exfoliation of pigmented keratinocytes
  7. Counter the inflammation stimulus of UV and other stresses

Our Approach

Your hosts have formulated products with active ingredients that influence each of these pathways. A daily-use topical product with all ingredients, and a microneedling solution with those that are physiologically compatible when used in conjunction with 1.0 mm medical needling. The products affect pathways involved in melanogenesis, keratinocyte melanin uptake and cellular exfoliation.


Active ingredients and mechanisms of action in daily-use topical:

Active Ingredients and mechanisms of action in microneedling topical:

Clinical Study

Products were tested in a 90-day randomized study of thirty-one participants aged 30 to 70 years of age of both genders with Fitzpatrick skin types I to V. Using a zero to five-point scoring system, a skincare specialist analyzed before and after high-resolution photos with different wavelengths of light. Using the same scoring system, each participant also completed subjective questionnaires at the beginning and end of the trial. Photo analysis and questionnaires confirmed significant and safe brightening and improved appearance of undesired facial pigmentation, regardless of its cause.  Participant satisfaction was extremely high. No adverse events were reported during the study.


Slow & Steady

Treatment of abnormalities of facial pigmentation requires a slow steady approach as overzealous treatment can have devastating consequences. As an example, experience with higher doses of hydroquinone has repeatedly shown it is possible to end up with pigment abnormalities that are significantly worse than the original problem. The most severe pigment problems occur in people with skin that is especially prone to darkening, higher Fitzpatrick skin types. Gradual cautious lightening is preferable to inadvertent injury that can be counterproductive and worsen the problem.

The products tested function to affect the seven pathways of skin pigmentation: -melanocyte stimulation and control, melanin synthesis and production, melanin uptake and dispersal, and cellular exfoliation – using multiple gentle yet effective physiologic “nudges.”

Additional information will soon be available at




Ebanks J, Wickett R , Boissy RMechanisms Regulating Skin Pigmentation: The Rise and Fall of Complexion Coloration. Int J Mol Sci. 2009 Sep; 10(9): 4066–4087.

Arndt, K.A. and Fitzpatrick, T.B.Topical use of hydroquinone as a depigmenting agent.JAMA 194(9), 965967 (1965).

Ando H, et al. Melanosomes Are Transferred from Melanocytes to Keratinocytes through the Process of Packaging, Release, Uptake and Dispersion. Journal of Investigative Dermatology. Volume 132, Issue 4, April 2012, 1222-1229

Serre C, Busuttil V, Botto JM. Intrinsic and extrinsic regulation of human skin melanogenesis and pigmentation.  Int J Cosmet Sci. 2018 Aug;40(4):328-347.

Pillaiyar T, Namasivayam V, Manickam M, Jung SHl Inhibitors of Melanogenesis: An Updated Review. J Med Chem. 2018 Sep 13;61(17):7395-7418.

Bissett DL et al. Reduction in the appearance of facial hyperpigmentation by topical N-acetyl glucosamine. J Cosmet Dermatol 2007 Mar.6(1):20-6

Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci. 2014 Aug; 19(8): 753-757

Yun WJ et alEpidermal growth factor and epidermal growth factor signaling attenuate laser-induced melanogenesis. Dermatol Surg. 2013 Dec; 39(12): 1903-11

Yokota T, Nishio H, Kubota Y, Izogushi M,  The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res. 1998 Dec; 11(6) 355-61







  1. Maya N says:

    I have been using AnteAge cleanser, serum, and accelerator for about a month now. I am loving the improvement in tone, texture, fine lines, and PIH, but I have noticed small bumps/pimples popping up all over my face that I cannot attribute to anything else – diet, hormones, etc. I am not using any other products except for my usual makeup (which is rare these days as I’m trapped at home) and occasionally a glycolic face wash. It’s frustrating because the products do seem to be helping my fine lines and pigment issues, but then I am getting these small little bumps that are offsetting the aesthetic benefits. The bumps are not true whiteheads… they don’t even appear to be clogged pores… they’re almost like very very tiny blisters?! Is this a natural side effect? The good news is that even if I pick at them (which I know I shouldn’t), they do seem to heal very quickly.

    Thanks so much. I love the product otherwise but just am not sure what’s going on with the bumps or if this is common within the first month or so of use.

    • drgeorge says:

      A few people have minor issues when they first begin using our products, especially people who have not used products with true active ingredients. And our Serum/Accelerator products have more actives than any other brand of which we are aware. The increased rate of cellular proliferation and turnover takes a period of time for your skin to establish a new “set point”. As that occurs, the phenomenon you are experiencing can occur. Don’t fret, it will resolve. A reasonable approach may be to gently “scrub” the skin with an exfoliative cleanser or even a very mildly abrasive glove. Older layers of skin will accelerate the rate at which the slough off and the problem should resolve.

      FYI, To get the same number of active ingredients typically requires purchase of many different kinds of products. Several years ago DrGeorge was interviewed by a Los Angeles television program interested in our approach to hi-science skincare. They priced the many different actives, not including the bone marrow stem cell conditioned media, and came up with a total that approached $1000!

  2. mike says:

    I’m looking into ordering the AnteAGE home microneedling kit with 0.25 mm roller. I’m a 32-year-old male with a history of acne and some light to moderate scarring, which have improved significantly over the years. What are your thoughts on using this roller for the purpose of product penetration and collagen production? How frequently is it suggested to use your microneedling kit? I am currently using tazorac .01% concentration. What would be the appropriate regime for using micronneedling and tazorac? Also, what is your professional opinion on using a microneedling pen for home use?

    • drgeorge says:

      The home microneedling kit and 0.25 mm dermaroller can be of significant benefit to improve appearance. The 0.25 mm needle length is long enough to enhance product penetration but not long enough to do significant trauma to the dermis. Medical needling uses needles 0.5 mm and longer and results in pinpoint bleeding in most people. Longer needles are needed for thicker areas of skin on the face and elsewhere, especially if the intent is to reduce scarring or the appearance of striae. Pigmentation also requires longer needles. The AnteAGE kit includes Microneedling Solution, the penetration of which is enhanced with even shallow needling. Some of the ingredients have published proof of enhanced collagenesis so one can expect improved appearance with regular use. Two or three times a week is typical.

      Tazorac is the brand name for tazarotene, a retinoid (vit A derivative) prescribed as a treatment for acne and psoriasis. Tazorac creme is used to help reduce fine facial wrinkles and certain types of pigmentation. Concentrations approved by the FDA include 0.001%, 0.005% and 0.01%. We see no contraindication for applying with 0.25 mm needling although as a general rule, especially with deeper needly treatments, we recommend products that contain only physiologic ingredients i.e. those found naturally in the skin such as is contained in the AnteAGE brand. Do be observant for any evidience of allergy or sensitivity reactions, however, until you are certain there are no obvious negative effects. Let us know how it goes.

      The question of home use of a microneedling pen has too many issues to give you a recommendation. Pen quality, needle length and material, method of keeping equipment hygenic and clean, and possibility of cross-contamination if used by more than one person are all considerations that must be addressed. We’ll stay agnostic on this one. Needling pens are the domain of licensed estheticians (shallow needling only). Medical needling is performed by nurse practitioners, physicians and properly supervised nurses.

  3. Issa says:

    I have a question regarding your opinion on the (relatively) new and increasingly popular injection treatment called “Profhilo”, a mix of high and low molecular weight hyaluronic acid. After reading articles here on bft I’m skeptical! Would love your input!

    • drgeorge says:

      This product is new to us. The company website has limited information but impressive before and after photos. Be aware, however, that photos in the marketing of skin care products have been known to be altered. If these are accurate depictions, the results look good. Profhilo is a “combo” product of low and hi molecular weight HA that is “stabilized” so its degradation is gradual. Thus far, we have not located published studies with this product but would love to see what has been done in terms of clinical studies.

  4. Julia says:

    This is in regard to the AnteAGE Brightening Microneedling Solution. I remember you saying that only limited physiologic ingredients can be used with a derma-roller and acids are not safe. Is tranexamic acid an exception to this rule? Also what would be a more efficient use of this Brightening solution – one use per week with 0.5mm needle or or 2-3 uses per week with a shorter 0.25-0.3mm needle? Would this solution make any difference for someone who already used tranexamic acid topically every day, for example an AnteAge Brightener? Also do you know what is the actual % of tranexamic acid in Brightener and Solution?

    • drgeorge says:

      Acids are chemical substances that donate protons (a hydrogen atom without its electron) and vary in potency from very strong to very weak. Potency refers to the tendency, powerful or weak, for the proton to dissociate from the parent molecule. Strong acids include hydrochloric and nitric acids; there are a total of 7 strong acids. All others are considered weak. Our body is literally filled with weak acids. Amino acids, fatty acids, ascorbic acid, lactic acid, and hyaluronic acid are just a few examples. Tranexamic acid is a weak acid. No effect on our products from a chemical standpoint.

      Tranexamic acid injections are used for surgical and obstetrical conditions to help control and reduce blood loss. It is given intravenously in doses up to 20 grams. It is exceedingly safe, and the extremely tiny amounts in our products, by comparison, are not a problem whatsoever.

  5. M. says:

    How often can microneedling with 1.0 mm needles and AnteAge Brightening solution be performed to achieve the results seen on Instagram? I noticed that that one solution bottle can be split into two uses. If microneedling is done only once a month, won’t the remaining half of solution go bad during those 4 weeks?

    • drgeorge says:

      Good questions. Using a 1.0 mm needle creates enough tissue trauma that the resultant healing cascade will take about a month to complete. Likewise, using the Brightening Microneedling Solution initiates changes in the pigmentation pathways (multiple) that take time. For those reasons we think about four weeks is a reasonable interval. All of our products are produced using preservative systems that are time tested and globally accepted and include ingredients that are also used to preserve vaccines and other injectable substances. We are not aware of any issues with our microneedlig products when used in interval fashion. Placing in the refrigerator between treatments is a sound idea. We recommend it.

  6. Peter says:

    I’m 24 years old and over the past 5 years, I’ve struggled with mild hyperpigmentation. I self-treated with several OTC products with little to no improvement. After 2 years of failing, I saw my dermatologist who prescribed 4% hydroquinone. I have followed the instructions for 2 months and see no improvement. When the days shorten in the fall so there is less sunlight, she plans to treat me with IPL (intense pulsed light.) In the meantime, she prescribed .05% tretinoin once a week for a month, then twice a week. I noticed my very fine smile lines were gone, the texture of the skin got smoother and my hyperpigmentation improved slightly. But my forehead lines got deeper, and new wrinkles developed under my eyes.

    I contacted my dermatologist and she told me my skin was not moisturized properly. I don’t agree. My skin barrier was intact with no signs of dehydration or irritation. I moisturize my skin three times a day. After 1 month my new wrinkles got much worse and even my husband noticed them. I decided to stop the tretinoin immediately and went to my dermatologist. She also noticed my new wrinkles. She mentioned that Retin A can’t produce wrinkles but, in her practice, she saw a couple of patients who had the same issues as me. I’m extremely sad…. sometimes I don’t even look in the mirror to avoid looking at it. Does tretinoin have this side effect or it’s all in my head ?

    • drgeorge says:

      Part of the wrinkling phenomenon you describe can simply be related to aging. By the early to mid-’30s, nearly everyone starts to notice lines and wrinkles on their face and neck. Wrinkles develop with increasing age, exposure to ultraviolet light, smoking, and repeated facial expressions. Genetics also play a role. You can help by protecting your skin from the sun, use products with “built-in” sunscreens, moisturize regularly, don’t smoke, and eat a healthy diet.

      Tretinoin can cause side-effects, but the development of wrinkles is not something commonly seen. (A PubMed search this morning did not return evidence of tretinoin causing wrinkles.) Expected during early treatment is burning, itching, stinging, scaling, or redness of the skin. Darkening and lightening of the skin can also be seen.

      • Peter says:

        I agree that my wrinkles may be caused by aging but before starting Retin A, I had very fine lines under my eyes and now (I counted them), I have 5 wrinkles near the right eye and 6 near the left eye. I never had those prior to using Retin A. I avoided sun, used sunscreen, moisturize and I dont smoke. My diet had always been healthy. Something accelerated the proces of developing wrinkles and the only thing that change was including tretinoin in my skincare.

        • drgeorge says:

          Something called an “N or one” study may help sort this out. (It may not, also.) An N of one study is one classic method of conducting a medical study. A condition or disease is treated with a substance to see if an improvement occurs. The treatment is then discontinued to see if the condition or disease severity returns. If it does, then the substance is validated as the reason for the improvement. In your case, it’s a little different. Stop using Retin A and observe if there are changes in your skin. If “yes”, you have your answer. If “no”, something else is going on. That something else is difficult to identify. Let us know how it goes.

  7. Monica says:

    I recently started using Anteage Serum and Accelerator a couple of months ago. Pleased with the results. I am African-American interested in evening skin tone and texture. I have gone back in BFT looking to see how Anteage and NIOD Cais 2:1 might complement each other. I found a response that appears to discourage GHK-Cu but not GHK. I had planned to use my Anteage, wait an hour, then apply NIOD Cu. Would it be best to not use the product (unopened yet) and lean more towards GHK like Matrixyl as a layer on top of my Anteage (non MD)?

    • drgeorge says:

      Good news! No need to add Matrixyl to your regimen. Matrixyl 3000 is an ingredient in the serum. You’re already using it.

  8. Tim says:

    Anteage is a core part of my skincare routine and I’ve seen great results with it. For .25mm microneedling 2-3x a week, is it okay immediately afterwards to apply my usual topicals (Anteage Serum, Anteage Brightener, Vitamin C serum and tretinoin .05%)?

    Also, what is the benefit of using the microchanneling solution instead?

    • drgeorge says:

      .25mm microneedling is helpful in promoting enhanced penetration of active ingredients but does not qualify as “medical” microneedling which is .5mm or greater and typically results in pinpoint bleeding, indicating penetration into viable, living dermis. The likelihood of active ingredients, and all other ingredients for that matter, gaining entrance into the dermis is more and more likely the deeper one goes. Likewise, the chance of inciting an allergic or other type of untoward reaction is greater. It is for this reason, we have long recommended only physiologic naturally occurring substances found within skin be applied after deeper needling. For the more shallow needling, the odds of promoting a nasty reaction is reduced. As you know, we produce a variety of microneedling products which are formulated for immediate application with microneedling. For all the others, it is probably a good idea to do a “test area” to see if there is a reaction. For medical microneedling, we have always recommended several hours, and usually overnight, before putting on products specifically formulated for topical application to intact skin.

Leave a Comment