Friday, July 12, 2013

SuppVersity Cellulite Special: The Etiology of Cellulite, Genetical and Behavioural Risk Factors? Physical and Supplemental Treatment Strategies & Their Efficacy

This photo of a 37-year old woman some of you may already have seen Facebook testifies to the success of 12 weeks on 333U/cc retinol cream + high intensity laser pulses (Fink. 2006)
I guess, or should I say, I'd hope (?) that some of you have already been waiting eagerly for the write-up of yesterday's Special Installment of the SuppVersity Science Round-Up on the Super Human Network and all the details and obviously the supps, Carl and I could not squeeze into this 1h+ show.

Before you go over this huge (and this is also why it took me so long to post this) serving of the "Seconds", I do yet highly recommend that you download and listen to the podcast, first. You can grap the MP3, right here.  It's free and if you don't like the ads, just skip forward, but please come to terms with the fact that a daily 2h radio has to be financed one way or another!

Let's dig right into this lumpy-bumby skin condition, now!

Despite the fact that they did not identify the underlying reasons for the development of cellulite correctly, Alquier and Paviot (1920), who described cellulite as a non-inflammatory complex cellular dystrophy of the mesenchymal tissue caused by a disorder of water metabolism, which produced saturation of adjacent tissues by interstitial liquids that was brought about by a reaction to traumatic, topical, infectious or glandular stimuli, already had a pretty decent understanding of the structural characteristics of cellulite (cf. Rossi. 2000).

Figure 1: Overview of the four main stages in the development of cellulite. If you take closer look they actually reflect much of what Alquier & Paviot (1920) already suspected: a disorder in water metabolism and a complex tissue dystrophy, which can yet become inflammatory in the late stages
The fact that cellulite is nothing but the highly visible manifestation of the messed up structural grid that holds the skin (epidermis) and the underlying fat layer in place is also important in view of the fact that up to today, way too many people look at cellulite as if it was something like a transient allergic reactions you could get rid of, once you stop eating things high GI carbs or whatever the contemporary dietary villain may be.

Unfortunately, this is not the case so that Nürnber et al. are not totally off, when they write a a 1978 paper about the ..
“[…] the essential normality and inevitability of [cellulite] in women, the supervention of it in hormonally feminized men, and the near futility of treating the non-disease” (Review by Nürnberger. 1978)
It is, and this is something that was completely missing from the previously cited first description of the “disease”, in fact partly Mother Nature who is to blame for the
  • abnormal hyperpolymerization of the connective tissue,
  • primary alterations in the fatty tissue,
  • microcirculatory alterations
with genetic and hormonal factors determining the basic risk profile and inactivity, a messed up diet, obesity, medication etc. being nothing but corroborating factors.

If you will, the X-chromosome and is myriad downstream effects that make a man a men could even be perceived as a genetic factor – a highly protective one that is.
Figure 2: Relative contribution of perpendicular, tilted and parallel septae to the "structural part" of the dermis (left; Querleux. 2002); comparison female vs. male skin (Rosenbaum. 1998), note: the comparison misses the important parallel structures esp. in the male skin, but I guess it still conveys the basic idea
As you can see in figure 2 (right), the mere fact that the upper most parts of the skin, the Epidermis and the Corium is much thicker in men than in women would already conceal major parts of the pumpy structure in a man. In women, on the other hand, the sclerotic macronodules that form during step four in the etiology of cellulite are highly visible through the “thin skin” of a woman.

Female skin with and without cellulite – what are the differences?

Figure 3: Photos of patients with grade II-IV cellulite. Mind the extreme difference between the contracted and uncontrated state in grade II (top vs. bottom; Rossi. 2002)
In addition to the general sex differences, Querleux et al. (2002) observed that women who suffer from cellulite have a 4x higher fat volume in the dermis, than normal women (note: the total amount of fat in men and women is not significantly different).

It goes without saying that this increase in volume would actually require an increase in strength or the number of stabilizing elements in the flexible structure that holds the fat, liquids and other components of the skin in place.In conjunction with the increased interstitial pressure that is a result of the microcirculatory alterations and the defect in collagen synthesis this increase in fat volume is however more than the comparatively unorganized fibrous structure of the female skin can hold.

If you think of the skin as three-dimensional grid that is filled with balls and lacks the structural components that separate the balls in the 1st row from those in the 2nd, 3rd, … etc. row, it should be obvious that any endogenously (interstitial pressure) or exogenously applied pressure (from within = muscle; or from outside = pinching) will push the balls or rather fat cells against the top-layer that's covering the grid (the uppermost parts of the skin) and cause pumps to appear at the surface.

A very similar mechanism is responsible for the appearance of the bumps and the valleys you see through the thin layer that’s covering the underlying fluid and fat-filled part of the dermis in women with cellulite.

Cold, not valsodilated & "lumpy-bumpy"

The presence of the sclerotic perpendicular macronodules in-between the pumps and dentures, only contribute to the nasty appearance and do little to maintain the structural integrity of the tissue that’s actually supposed to be pervaded by numerous small & flexible, randomly but highly crosslinked septae that keep the fat cells in place.

Figure 4: I assume you would not have needed this thermograph to tell me that cellulite ain't exactly hot ;-)
If you look at the thermograph to the right of this paragraph you will also notice that the metabolic activity of the tissue is similarly irregular and (don’t get fooled by the colors) overall much lower in women with cellulite compared to their “healthy” counterparts.

This is both a contributing factor, as well as a results of the decreased micro-circulation in the dermis (see cold green areas) and contributes to the increased water retention in the skin. The latter will increase the pressure and worsen the condition… it is a self-perpetuating viscous cycle, yet one that opens therapeutic doors not to reverse, but at least to halt the progress of the ongoing dystrophic processes.

Estrogen drives cellulite development

And while we are going to deal with the "therapeutic" options in just a minute, let's briefly recapitulate, what I said about the causes / confounding factors during yesterday's show (listen to the podcast for details):
  • genes and sex - simply being a women predisposes you to develop cellulite; I know it's not fair, but that's how it is; the same goes for the genes: if your mother and grandmother had it, chances are you will develop it, as well 
  • Figure 5: The influence of estrogen on the pathophysiology of cellulite (Rossi. 2002); easy to see, estrogen is the motor of cellulite development
    high estrogen, low progesterone (e.g. puberty, pregnancy, birth control, PMS; partial revision in menopause possible) - estrogen (E2) increases the accumulation of fat, spec. in the areas that are typically affected by cellulite, it renders the fibroblasts more hydrophobic and predisposes to water retention and edema, it increases the permeability and thus the leakage from the cells and promotes the formation of sclerotic tissue (figure 5)
  • insulin resistance / diabetes - does not only accelerate fat gain (at least as long as there is still some insulin around), but will also increase the production of glycosaminoglycans which will draw even more water into the tissue (Lotti. 1990)
  • obesity (and obesogenic diets) - the faster the fat accumulates and the larger the cells become the greater the demand on the structural components of the dermis and the more likely it will give in and the bumps and start to appear (remember: cellulite is not about having too much body fat, if it is acquired slowly and you are not genetically pre-dispositioned to cellulite you can accumulate quite an amount of fat without developing cellulite)
  • hypothyroidism - thyroid hormone increases hyaluronic acid and chondroitin sulphate production, low levels will thus hamper the formation and renewal of the structural parts of the dermis
  • stress / corticosteroids - if you are not taking exogenous corticosteroids like prednisone, stress and high corticosteroid levels are actually identical and have similar effects as low thyroid hormone (by the way, stress, even "eu-stress" such as exercise, will also have thyroid hormone levels plummet; learn more)
  • lack of exercise - decreased vasodilation, increased weight gain, increased water retention, increased risk of diabetes... I don't have to enumerate all of them, right?
  • low potassium, zinc, copper and selenium intake - while the former will help your body regulate the water balance, zinc and copper are important for the formation of the net that keeps the fat in place and have, just as selenium anti-oxidant properties as part of Copper/Zinc Superoxide Dismutase
  • smoking and boozing - both will promote the decline in micro-circulation
Now that you know what you cannot change and / or should not do, let's take a look at what you can do as far as physical treatments and supplements / drugs are concerned.

Currently available physical "treatment" options

I highly encourage you to also listen to the podcast, as I am going to keep this short in view of the fact that Carl went through all the items, anyway:
  • Iontophoresis: Applies a galvanic current on the surface of the skin to depolarize it and alllow drugs pass through the dermis; it is also used to increase the vasomotor action (vasoconstriction, followed by vasodilation) of which practitioners of this method believe that it may have a positive effect on the compromised metabolism in cellulite skin
  • Acoustic wave therapy / ultrasound: Uses high frequency vibrations, which have a thermic and vasodilator effect; is also used as an adjunct to "hammer" drugs into the skin; there is some evidence that it can provoke lipolysis and is thus used during liposculpture procedures. Russe-Wifingseder et al. reported only recently that the use of ultrasaund that acts only on the subcutaneous tissue produced "improvement in number and depth of dimples, skin firmness and texture, in shape and in reduction of circumference" (Russe-Wifingseder. 2013) in placebo-controlled trial.
  • Thermotherapy: The heat is suppose to increase vasodilation. Experts say that its effectiveness is questionable, as some reports suggest that it did actually aggravated cellulite, maybe in consequent protein denaturation due to the high temperature. 
  • Pressotherapy / Massage therapy: Either done by hand or with a pneumatic massager, the intention is to help the skin to release the liquid that's accumulating in the tissue and activate the venous return; it is also used to to treat lymphatic, venous or mixed oedema of the limbs, so that you can expect cosmetic effects of unknown (probably short ;-) duration
  • Lymphatic drainage: While it has been used since 1936, the pumping movements using gentle and rhythmic pressures will stimulate the lymphatic flux, but have no proven and above all persistent effect on cellulite
  • Laser therapy Low‐level, dual‐beam laser energy, as well as high intensity pulsed laser that are commonly used for "body-contouring" have been reported in several studies to "help" with cellulite. Most of those do yet only report reductions in subcutaneous fat and results like "increased well-being" among the particpants.
  • Elecrolipophyresis: Unlike with the #1 on the list the electric current is not applied to the surface of the skin, but rather to several pairs of thin (0.3 mm) long (5–15 cm) needles which are connected to a low frequency current generator. This generates an electromagnetic field which is supposed to modify the interstitial tissue and aid in the circulatory drainage, as well as lipolytic processes. High quality evidence for its usefulness is absent.
  • Mesotherapy – This is the well known injections of "solvents" into the adipose tissues. While there are various protocols available most involve phosphatidylcholine. What they all have in common is a highly questionable safety profile and the fact that they yield very ambiguous (mainly negative in peer-reviewed studies) results. Aside from that, dissolving the fat cells within an already corrupted structure is not exactly what I would deem helpful...
Before we go on to the supplements, let me briefly mention that a meta-analysis of cosmetic products marketed for cellulite reduction did show an overall effect, with respect to the thigh circumference (-0.46cm, analysis of 21 original papers; cf. Turati. 2013), while there was no consistent improvement in the nasty look of the skin.

Supplements & drugs for cellulite prevention (and reduction!?)

As mentioned on the show, most of the supplements in the following list are going to help mitigate some of the symptoms, reduce the fat load (literally) on the weak structure of improve the micro-circulation. Aside from retinol and maybe silicon, of which esp. the former appears to have a direct effect on what's going on beneath the surface of the skin, most don't hold much promise for getting rid of the underlying problems.
  • Suggested read: "Brown Algae Extract Reduces Body Fat Without Dieting or Exercise. Ecklonia Cava Polyphenols Help Shed Weight Even in The Presence of a Slight Caloric Surplus." | read more...
    Supplements to burn the fat - Methylxanthines (theobromine, theophylline, aminophylline, caffeine), which act through phosphodiesterase inhibition, isoproterenol and adrenaline which are beta-adrenergic agonists, and yohimbine, piperoxan, phentolamine and dihydroergotamine which are alpha-antagonists and will "encourage" the fat cells in this "stubborn fat area" to release more of the fat that's stored in them -- just pick the next best fat-burner from your local supplement story invent something that will have it pass through the stratum corneum and you got your "topical fat burner", of which I can only repeat that it will not get rid of the bumps - if anything it will reduce the severity.

    In view of the importance of Co-enzyme A in this process, adequate vitamin B5 and cysteine, which are used for its synthesis and maybe even carnitine, which helps to transport and burn the fat that's actually released from the fat traps on your thighs can enhance the effects of the previously mentioned agents. This is important because free fatty acids may saturate the system, leading to negative feedback of lipolysis (Di Salvo. 1995).

  • Suggested read: "How Working Out Changes the Morphology of Your Body Fat" | read more...
    Supplements to increase micro-circulation: Ivy and Indian chestnut extracts, ginkgo biloba and rutin, maybe pycegnol and the pharmacological agent Pentoxifylline, which is a drug commonly sold by Aventis under the brand name Trental it improves microcirculatory perfusion through its effect on haemorrheological factors, including erythrocyte shape, platelet aggregation and plasma fibrinogen concentration. While Pentoxifylline has been used to treat chronic venous insufficiency, stasis ulcers in controlled studies, its efficacy wrt to cellulite has not been proven.
  • Antioxidant and immune modulatory supplements: Vitis Vinifera, borage oil, fucus. The latter is a common type of brown algae, that will also enhance the metabolism and reduce the oedema and intestinal inflammation.  

  • Asiatic centella extract aka guta cola: The main reason this is a standalone is the frequency with which it is mentioned in the literature. Centella has a vegetable origin and consists of asiaticosideo (40%), madecassic acid (30%) and Asiatic acid (30%), triterpenic derivatives which act in vitro on fibroblasts, stimulating collagen and mucopolysaccharide synthesis.

    Chronic overtraining is no solution and the stress could in fact cause your to your cellulite problems. In addition, it is also the cause of chronic injuries, which persist even, when you finally realized that your own ambition is about to ruin your health (learn more).
    It has been used in the past both topically and systemically, and reported benefits of the oral administration route must probably be ascribed to its beneficial effects on the micro-circulation. According to Hausen (1993) it does neither lead to cutaneous hypersensitivity, nor does it have a toxic effect, when it is ingested.

    In a histopathological, double-blind study by Hachem & Borgoin from the late seventies it the administration of 60 mg of dry Asiatic centella extract orally once a day for 90 days brought about a significant reduction in the diameter of adipocytes in both the deltaoid and gluteofemoral regions in the patients who received centella compared to those who received placebo. Interestingly, this reduction was more apparent on the gluteofemoral region and went in hand with a decrease in interadipocyte fibrosis. 

    If it were not for the missing placebo control in most of the hitherto published studies, this could actually be a supplement worth trying.

  • Suggested read: "Evidence From the Metabolic Ward: 1.6-2.4g/kg Protein Turn Short Term Weight Loss Intervention into a Fat Loss Diet" 2x-3x higher than RDA protein intakes work equally well for men and women, to get and stay lean and lose fat and build / maintain muscle - it does not always take supplements, you see (learn more)?
    Sillicium: While you probably never thought about it, sillicium (organic) is present in celery, peppers, carrots, potatoes, unrefined grains and cereals and beets, all sorts of veggies and fruits, basically everything that growth on earth that has silica in it. The maximum daily recommended dose is 10.5 mg Si/day; and being a structural element of the connective tissue, it is actually not surprising that studies (mostly in vitro or rodent, unfortunately) have demonstrated that silanols (groups of hydrogen and sillicium compounds, similar to the hydrocarbides) provoke the formation of bridges between the hydroxylated amino acids of the elastic fibres and collagen fibres protecting them from non-enzymatic glycolysation and decreasing their degradation rate.

    Sillicum also acts as a coenzyme during interstitial matrix macromolecule synthesis. As such it helps reorganize structural glycoproteins and proteoglycans by stimulating polar amino acid grouping and normalizing hydrophilic capacity. Both effects which would obviously be highly desirable for someone suffering from a compromised dermal glycoprotein matrix. 

    In view of the fact that it has also been reported to increase microcirculation by modifying venous capillary and lymphatic permeability and has even been shown to stimulates cAMP synthesis as well as triglyceride hydrolysis and thus promote the release of fatty acids from the stored fat cells, it appears to be the perfect nutrient for any woman suffering from cellulite... in view of this fact it is surprising that I could not find a single reputable study proving its effects (note: I did not find one showing the opposite either) 

Actually, the next and last item on the list would be retinol,  but instead of just adding it to the bottom I want to briefly recapitulate that it was a 12-week treatment with weekly applications of intense pulsed light (the equipment used was a Quadra Q4 IPL) with a wavelength of 585-nm and nightly applications of a compounded retinyl-based cream (330 U/cc) that was applied after the ladies had used some aceton to remove the protecive layer of the skin 5x / week (Fink. 2006).

Some more details on the retinol / retinyl palmitat studies

In that it is interesting to note that the scientists picked retinyl palmitate not just for its better safety profile (compared to all-trans-retinoic acid) but also due to its short half-life, its well-known ability to stimulate type I collagen, and its ability to resist air oxidation.
Figure 6: Increase in blood flow in 20 women with moderate cellulite of the thighs treated twice daily on one side for 6 months with a 0.3% stabilized retinol cream while the opposite side was treated with the vehicle (Kligman. 1999)
In a previous study by Kligman et al. (1999) a similar cream containing 0.3% stabilized retinol did lead to marked increases in the blood flow as well as the synthesis of glycosaminoglycans and collagen in a group of 20 women with moderate cellulite on the thighs. Moreover, ...
"[t]here was also a marked reduction in the density of hypoechogenic areas on the retinol sides, from 53% to 18% of black pixels on image analysis. Blood flow measurements were unchanged on the vehicle sides but increased significantly on the retinol sides. Thickness measurements by ultrasound scan were unchanged on the vehicle sides but increased significantly on the retinol sides, from 1.44 to 1.60 mm." (Kligman. 1999)
In their study, Fink et al. observed responses in both the patients who received the combination treatment with the pulsed laser and retinol, as well as in those who received only the laser therapy; and with 60% (9) of their patients having a ≥ 50% improvement in cellulite at 3 months that lasted for 7 of the women up to the 8-months follow up, the overall results are pretty impressive.

Visible not just measurable improvements most likely due to vitamin A

Before and after pictures of the second, 50 year old patient in the vitamin A + pulsed laser study (Fink. 2006)
As I already mentioned on the show, though, the actual reason I picked this study to anchor the show were the two before and after pictures. The first set of which (see top of the page) is the one I already published on the SuppVersity Facebook Wall as a sneak preview, the other one that was taken from a 50 year-old patient (see image to the right) shows similar improvements. Due to the fact that she started out with a higher grade of cellulite, the end-result is yet not as astonishing as the one of the 37 year-old women you "know" already. Both women were in the combined treatment group and in all honesty, I personally consider the retinol the more promising therapeutic agent of the two.

As I told Carl on the show it cannot be excluded that the combination of tissue breakdown from the laser and the "collagen-anabolic" effects of retinol are perfect synergists. Similarly, it is difficult to say, whether the use of aceton only rendered the 2x/day application that was used in the Kligman study unnecessary or whether it was the removal of the stratum corneum that made the treatment so effective.

Bottom line: I would hope to see ongoing research in particular with regards to topical based retinol treatments for cellulite. And if respective results are published outside of the bazillion of small scale "studies" that come with the endless (and endlessly hilarious) amount of patents for all sorts of snake oil, I can guarantee that they will be part of the regular SuppVersity news (NO, I am not going to write another special, I am exhausted any you can keep all typos and worse mistakes for yourself ;-)


References:

  • Di Salvo RM. Controlling the appearance of cellulite: surveying the cellulite reduction effectiveness of xanthines, silanes, CoA, 1-carnitine and herbal extracts. Cosm Toil 1995; 110: 50–59.
  • Fink JS, Mermelstein H, Thomas A, Trow R. Use of intense pulsed light and a retinyl-based cream as a potential treatment for cellulite: a pilot study. J Cosmet Dermatol. 2006 Sep;5(3):254-62.
  • Hachem A, Borgoin JY. Étude anatomo – clinique des effets de l’extrait titré de centella asiatica dans la lipodystrophie localisée. La Méd Prat 1979; 12(4): 17–21.
  • Hausen BM. Centella asiatica (indian pennywort), an effective therapeutic but a weak Sensitizer. Contact Dermatitis. 1993; 29(4): 175–179. 
  • Kligman AM, Pagnoni A, Stoudemayer T. Topical retinol improves cellulite. Journal of Dermatological Treatment. 1999; 10: 119–25
  • Lotti T, Ghersetich I, Grappone C, Dini G. Proteoglycans in so-called cellulite. Int J Dermatol. 1990 May;29(4):272-4.
  • Querleux B, Cornillon C, Jolivet O, Bittoun J. Anatomy and physiology of subcutaneous adipose tissue by in vivo magnetic resonance imaging and spectroscopy: relationships with sex and presence of cellulite. Skin Res Technol. 2002 May;8(2):118-24.
  • Rosenbaum M, Prieto V, Hellmer J, Boschmann M, Krueger J, Leibel RL, Ship AG. An exploratory investigation of the morphology and biochemistry of cellulite. Plast Reconstr Surg. 1998 Jun;101(7):1934-9.
  • Rossi AB, Vergnanini AL. Cellulite: a review. J Eur Acad Dermatol Venereol. 2000 Jul;14(4):251-62.
  • Russe-Wilflingseder K, Russe E, Vester JC, Haller G, Novak P, Krotz A. Placebo controlled, prospectively randomized, double-blinded study for the investigation of the effectiveness and safety of the acoustic wave therapy (AWT(®)) for cellulite treatment. J Cosmet Laser Ther. 2013 Jun;15(3):155-62.
  • Turati F, Pelucchi C, Marzatico F, Ferraroni M, Decarli A, Gallus S, La Vecchia C, Galeone C. Efficacy of cosmetic products in cellulite reduction: systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2013 Jun 14.

16 comments:

  1. So if one wanted to get a vitamin A cream how many mgs/g would it be to equal the 333u/cc?

    ReplyDelete
    Replies
    1. you can check the IUs over at wikipedia => http://en.wikipedia.org/wiki/International_unit

      here it says "1 IU is the biological equivalent of 0.3 μg retinol", now you have 330IU, i.e. ~100µg or 0.1mg per cc

      hope that helps

      Delete
    2. It does, thx. I looked on line to see the conversation but I was getting too many different tabulations.

      Is there a suggestion on what could be applied prior to the suggested cream to enhance the absorption?

      Delete
  2. Hello Doc!
    What about Silicium for wrinkles?

    ReplyDelete
  3. This comment has been removed by the author.

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