advances treatment of celllulite

Treatment of cellulite

Part II. Advances and controversies

Misbah H. Khan, MD,a Frank Victor, MD,a Babar Rao, MD,a and Neil S. Sadick, MDb

Somerset, New Jersey, and New York, New York

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Treatments for localized adiposities range from topical creams to liposuction. Most treatments lack asubstantial proof of efficacy. The unpredictable treatment outcome can be related to the fact that celluliteadipose tissue is physiologically and biochemically different from subcutaneous tissue found elsewhere in thebody. Part II of this two-part series on cellulite reviews the various treatment options that are currentlyavailable for human adipose tissue including, but not limited to, cellulite. It also focuses on newer techniquesthat can be potentially useful in the future for the treatment of cellulite. ( J Am Acad Dermatol 2010;62:373-84.)

Learning objectives: After completing this learning activity, participants should be able to understand thewide range of treatments available for localized adiposities including, but not limited to, cellulite-proneareas, know the differences in their mechanisms of action and be able to make the most appropriatedecision for patient care, and discuss and understand newer treatments for cellulite that are still beinginvestigated along with the physiologic and biochemical basis for their mechanisms of action.

Key words: carboxy therapy; cryolipolysis; endermologie; laser lipolysis; liposuction; mesotherapy;subcision; ultrasonic fat destruction.

Abbreviations used:

AR: adrenoreceptorBAT: brown adipose tissueBMI: body mass indexc-AMP: cyclic adenosine monophosphateEMR: electromagnetic radiationFDA: US Food and Drug AdministrationLED: light-emitting diodeMRI: magnetic resonance imagingNd:YAG: neodymium-doped yttrium aluminium

garnet (laser)PPAR: peroxisome proliferator-activated

receptorsRF: radiofrequencyUCP-1: uncoupling protein-1

The best of the currently available treatmentsfor cellulite have, at most, shown mild im-provements in the appearance of cellulite,

and most of these improvements are not maintainedover time. Studies about cellulite treatments are oftenlimited by small patient groups, the lack of controlgroups, inadequate blinding of investigators, and afailure to test for statistical significance. Therefore,the success of any treatment method for cellulitereduction should be regarded as speculation.Nonetheless, there are interesting treatments avail-able for the reduction of cellulite and localizedhuman adiposities that are commonly used by both

WAT: white adipose tissue

the Departments of Dermatology at Robert-Wood Johnson

niversity Hospital,a University of Medicine and Dentistry New

rsey, Somerset, and Weill Medical College of Cornell University,b

ew York.

ing sources: None.

licts of interest: Dr Sadick and the Sadick Research Group

ork with Syneron on clinical studies of their equipment

eking approval by the US Food and Drug Administration. In

change, Sadick Dermatology receives discounted equipment.

e other authors, editors, and peer reviewers have no relevant

ancial relationships to declare.

int requests: Misbah H. Khan, MD, or Neil S. Sadick, MD, Sadick

ermatology and Sadick Research Group, 911 Park Ave, Ste

, New York, NY 10075. E-mail: khanmisbah6@gmail.

m,[email protected].

-9622/$36.00

10 by the American Academy of Dermatology, Inc.

0.1016/j.jaad.2009.10.041

dermatologists and plastic surgeons (Table I). A briefoverview of these currently available treatments andtheir proposed mechanisms of action are discussedherein. In addition, newer treatment options basedon adipocyte physiology and biochemical behaviorare also discussed as possible avenues for futureresearch in cellulite therapy.

ATTENUATION OF AGGRAVATINGFACTORSKey pointsd Weight loss has a variable effect of cellulite

severity depending upon the clinical grade,withgradeIVcellulitebeingthemostresponsive

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mailto:[email protected],[email protected]:[email protected],[email protected]

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374 Khan et al

d Skin looseness or so-called skin complianceincreases after weight loss, which can ad-versely affect the skin dimpling

Weight lossCellulite occurs in lean women and obese women

and men.1 Weight gain, however, can accentuate the

CAPSULE SUMMARY

d Treatment modalities for cellulite rangefrom topical creams to invasiveprocedures, such as laser-assistedlipolysis and liposuction.

d There is no single treatment of cellulitethat is completely effective.

d Given the complex and multifactorialetiology of cellulite, devices thatcombine radiofrequency, infrared lasers,and suction with massage have recentlygained popularity.

d Future treatment options for cellulitedepend upon our understanding of themolecular basis and hormonal influencesof cellulite adipose tissue.

appearance of cellulite.There have been reports ofweight loss and its effects oncellulite. Smalls et al2 re-vealed that weight loss canhave variable effects on cel-lulite grade (Figs 1 and 2). Itcan improve or worsen thecondition for some. Smalls etal2 showed that on average,cellulite severity decreasedfollowing weight loss. Thisis especially true for affectedindividuals who have ahigher body mass index(BMI) and a greater severityof cellulite grading. Theseindividuals experienced im-provement in cellulite sever-ity with significant weightloss. They also found an in-
crease in skin compliance (skin looseness) in all oftheir study participants. Increased skin compliancedid not necessarily have an impact on subjects whosecellulite improved, but it adversely affected theindividuals whose cellulite became worse withweight loss. It is not clear, however, if skin compli-ance plays a significant role in the etiology ofcellulite. Their study also revealed that skin dimplingdid not significantly improve with weight loss, withonly a slight decrease in the depth of dimples. Theyattributed this finding to the fact that skin dimpling iscaused by dermal collagenous septae that do notnecessarily improve with weight loss.
Different regions of the body respond differentlyto weight loss (ie, abdominal vs. femoral). Mauriegeet al3 revealed very interesting findings regardingadipose tissue; their research focused on the re-sponse to a low-calorie diet and the effects thereofon adrenoreceptor (AR) sensitivity on adipocytes ofthe abdominal and femoral regions in both malesand females. Their work showed that there is anoverall significant reduction in fat cell weight in bothsexes by 15% to 20% after an average 10-kg weightloss (P \ .1 and P \ .05). Basal lipolysis, maximallipolytic response to isoproteronol (a b-AR agonist),and dobutamine and procaterol (which are b1- and

b2-AR agonists, respectively) as well as the maximumantilipolytic effects of epinephrine (an a2-AR ago-nist) were similar before and after weight loss.However, both b1- and b2-AR lipolytic sensitivitiesand overall b-AR density were increased in bothgenders after weight loss; this effect was moremarked in the subcutaneous abdominal adipose

tissue as compared to femo-ral adipose tissue (P\.001 to.05). a2-AR antilipolytic sen-sitivity was reduced in adi-pose cells from both regionsin women, but only in ab-dominal adipose cells in men(P\.05), even though a2-ARdensity remained un-changed. In addition, femo-ral adipocytes are larger inwomen than in men. In theirstudy, Mauriege et al3 foundthat this difference loses itssignificance after weight loss,because adipose cell size re-duction was found to be thesame order of magnitude inboth genders.

The result of their work isinteresting from the view-

point of cellulite management. Because we knowthat femoral adipose cells are predominantly a2-ARs,which are antilipolytic (as opposed to abdominaladipocytes, which are b-ARs with high lipolyticresponse to catecholamine stimulation), abdominaladipocytes are the main source of mobilizing energysources during times of calorie deprivation. Ofinterest is the fact that the sensitivity of a2-ARsdecreases during times of fasting. However, theirnumber remains unchanged. Unless weight reduc-tion is a continuous process, femoral adipocytes willregain their size and antilipolytic activity. Furtherstudies need to be performed to investigate theeffects of a low-calorie diet over a long period oftime and what effect that diet will have on femoraladipocyte a2-AR density and sensitivity.

PHYSICAL, MECHANICAL, AND THERMALMETHODSEndermologieKey pointsd There is some evidence that thigh reduction

can be achieved by Endermologie after re-peated treatments over a period of time

d Thigh reduction seen after Endermologietreatments may be influenced by weight loss

Table I. Various treatments of cellulite and their level of evidence as determined from various publishedstudies

Cellulite treatment References Level of evidence*

Weight loss Smalls et al2 and Mauriege et al3 II-B and II-B, respectivelyEndermologie Collis et al4 and Chang et al5 II-A and II-B, respectivelyLiposuction Coleman et al7 IIISubcision Hexsel et al9 IVMesotherapy Hexsel et al11 and Rotunda et al13 II-B and II-B, respectivelyTopical phosphotidylcholine and LED Sasaki et al14 I-ARadiofrequency devices Sadick et al,16,17 Goldman et al,18

and Goldberg et al21II-B, II-A, and II-A, respectively

Ultrasound Moreno-Moraga et al23 II-ALaser-assisted lipolysis Katz et al,26 Geronemous et al,30

and Prado et al28IV, IV, and I-A, respectively

Topical herbs and retinol Li-Balchin et al36 and Kligman et al38 II-A and II-A, respectivelyCarboxy therapy Brandi et al40,41 II-BCryolipolysis Manstein et al52 IV

LED, Light-emitting diode.

*Level IA evidence includes evidence from metaanalysis of randomized controlled trials. Level IB evidence includes evidence from at least

one randomized controlled trial. Level IIA evidence includes evidence from at least one controlled study without randomization. Level IIB

evidence includes evidence from at least one other type of experimental study. Level III evidence includes evidence from nonexperimental

descriptive studies, such as comparative studies, correlation studies, and case control studies Level IV evidence includes evidence from

expert committee reports or opinions or clinical experience of respected authorities, or both.

J AM ACAD DERMATOLVOLUME 62, NUMBER 3

Khan et al 375

The basis for various massage/suction techniquesused for cellulite treatment rests on the premise thatthe condition is caused by impaired circulation.Endermologie ESI (LPG Systems, Valence, France)or skin kneading is a nonpharmacologic method thatemploys mechanical means to mobilize the subcu-taneous fat in affected areas.4 Despite the high cost ofEndermologie treatment, little evidence exists tosupport its efficacy. Proponents of this process claimthat massage/suction improves the disorganizationof subcutaneous tissue structures and improveslymphatic flow. The procedure is performed twiceweekly, with each session lasting 10 to 45 minutes. A12-week study by Collis et al4 compared healthyindividuals with cellulite treated with Endermologieand/or aminophylline cream (a phosphodiesteraseinhibitor) and found no statistical difference in thighmeasurements between patients. Any subjective im-provement noted by study participants was attrib-uted secondary to weight loss and exercise ratherthan skin kneading. The results of this study werechallenged by the fact that treatment duration wasonly 10 minutes and that improvement should havebeen analyzed by more objective criteria than sub-jective self-assessment alone. Chang et al5 showedpromising results using Endermologie for the treat-ment of thigh circumference reduction. The studygroup exhibited a wide range of body types, initialweights, and final results. Out of 85 patients, 46

patients completed seven sessions of treatment andshowed a mean index reduction in body circumfer-ence of 1.34 cm, while 39 patients who completed 14sessions of treatments showed a mean index reduc-tion in body circumference of 1.83 cm. A decrease inmean body circumference index was seen regardlessof weight loss or gain in study participants. Eventhough evidence exists that Endermologie can re-duce the thigh circumference in a dose- and time-dependent fashion, the long-term efficacy and lon-gevity of these effects is still questionable.Randomized controlled trials need to be conductedwith objective evaluation of response as opposed tosubjects satisfaction, such as the use of noninvasiveimaging techniques to monitor the response ofmassage/suction and the persistent changes thatare claimed as proposed mechanisms of actionover a period of time.

LiposuctionKey pointsd While liposuction can diminish fat deposits

deep in the subcutaneous fat, its effect on thesuperficial components of fat as seen incellulite is often disappointing

d Skin necrosis from devascularization afterextensive undermining is one of the majorlimiting factors

Fig 1. Three-dimensional laser scans from three patients. A, Patient 1 lost 28 pounds andexperienced a decrease in cellulite severity by surface roughness analysis. B, Patient 2 lost 56pounds and had a decrease in cellulite severity. C, Patient 3 lost 69 pounds and had a decreasein overall severity but retained the smaller scale roughness features. The variability in cellulitecan be seen in this figure. (Reprinted with permission.2)

Fig 2. Cellulite dimple fingerprint. The three-dimensional laser scans are shown in the figurefor one subject who lost 48 pounds. Examination of the series of images indicates that thedimple or dimple pattern may be a permanent structure that does not change appreciably, evenwith considerable weight loss. (Reprinted with permission.2)


376 Khan et al

Although lipoplasty has been purported by someto be an excellent method to improve body contour-ing,6 others have reported increased skin dimplingafter liposuction.7 Ultrasonic liposculpturing may bea superior, potentially safer, less destructive tech-nique for cellulite reduction than traditional liposuc-tion.8 Liposuction is still not a recommendedtreatment for cellulite. In part, that may be becausecellulite adipose tissue is very close to the surface ofskin, with only a thin layer of dermis overlying it.

Liposuction performed at a level so close to thesurface of the skin can lead to more complicationsand a poor cosmetic outcome.

SubcisionKey pointsd Subcision can temporarily improve the skin

dimpling seen in cellulite-prone areasd The long-term efficacy of subcision remains

controversial


Khan et al 377

Subcision is an invasive method that is used toimprove cellulite. It palliates skin dimpling by sev-ering the septae that hold the fat lobules. After theinjection of local anesthesia, a 16- or 18-gaugeneedle is inserted into the subcutaneous fat in adirection parallel to the epidermis and the septae aresheared. Hexsel and Mazucco9 investigated subci-sion as a treatment in 232 patients. Only 1% of thestudy subjects were dissatisfied with the results.However, no objective criteria were used to evaluatethe study. It might seem reasonable that if the septaeare responsible for the clinical appearance of cellu-lite, their sectioning should result in improvement inall affected individualsbut this is clearly not theresult of invasive subcision. The pathophysiology ofcellulite is likely more complex than just the orien-tation and configuration of the septae. As mentionedin part I of this article, Pierard et al10 showed thatsome of these septae in high grade cellulite areactually weak hypodermal stretch marks. In theory,sectioning of these fibrous strands might potentiallydestabilize the dermohypodermal junction, therebyfacilitating the adipose tissue herniation.

Phosphotidylcholine and mesotherapyKey pointsd Phosphotidylcholine induces lipolysis via

the activation of cyclic-monophosphate andthe activation of b-ARs

d Gluteofemoral adipocytes have a signifi-cantly lower number of b-ARs as comparedto other localized adiposities

Mesotherapy, a technique that uses the injectionof various substances into the subcutaneous fat todissolve the fat, is another highly popular treatmentfor cellulite.11 However, few studies substantiate thebenefit of this approach. The technique involves aseries of injections delivered into the subcutis. Thesolutions have included compounds like methyl-xanthines, such as caffeine, aminophylline, andtheophylline, etc, which cause lipolysis via phos-phodiesterase inhibition and elevation of cyclicadenosine monophosphate (c-AMP) levels, as wellas hormones, enzymes, herbal extracts, vitamins,and minerals. The one ingredient most consistentlyused is phosphotidylcholine (soybean lecithinextract), which is responsible for lipolysis via theactivation of b-ARs. Rose et al12 showed that amixed septal and lobular panniculitis with abun-dant fat necrosis and serous lipoatrophy is seenafter phosphotidylcholine injection. The lack of aprecise treatment protocol, the unpredictable out-come, and the risk of localized adverse eventsincluding edema, ecchymosis, tender subcutaneous

nodules, infection, urticarial reactions, and irregularskin contourshave discouraged many cliniciansfrom attempting this technique.

Phosphotidylcholine injections alone have beenused to treat localized fat accumulations in HIVlipodystrophy and lipomas.12 Rotunda et al13 haveidentified sodium deoxycholate, a detergent thatproduces nonspecific destruction of cell membranes,as a major active ingredient in this therapy. Sasakiet al14 used topically applied phosphotidylcholine-based anticellulite gel with low intensity light treat-ment using a light-emitting diode (LED) array atwavelengths of red (660-nm) and near-infrared (950-nm) that is designed to counter the possible mech-anisms that purportedly accentuate the presence ofthigh cellulite. Subjects were randomly treated twicedaily with active gel on one thigh and with placebogel on the other. LED treatments were employedtwice weekly for 15 minutes on both thighs, for atotal of 24 treatments. Eight out of the nine subjectsexperienced significant improvement in the thighstreated with phosphotidylcholine-based anticellulitegel and LED treatments as evident by clinical exam-ination, measurements, and ultrasound evaluationsthat showed a significant reduction in hypodermalthickness. These results also correlated with histo-logic significance. However, at the 18-month evalu-ation period, five of the improved thighs revertedback to their original cellulite grade, and threecontinued to maintain their improved status. Thelimitations of this study were the number of controlsand the population size.

The results of this study are interesting from thestandpoint that low-level light therapy alone failed toshow improvement. But when combined with atopically applied fat dissolving gel, patients showedimprovement in cellulite grade reduction. This raisesquestions regarding themechanismof actionof LED inthe presence of fat dissolving gel; perhaps LED has arole in dermohypodermal remodeling after some fatdissolution, but not otherwise. Future studies areneeded to verify these preliminary findings.

Bipolar and unipolar radiofrequency devicesKey pointsd Unipolar and bipolar radiofrequency devices

are based on the principle of heat generationas a result of water and tissue interactionwithin adipocytes

d Small studies with the available systems haveshown mixed results

Recently, noninvasive devices employing radio-frequency (RF) technology have gained acceptanceand supremacy in the treatment of cellulite. These


378 Khan et al

include the TriActive (Cynosure, Westford, MA) andVelaSmooth (Syneron Medical, Yokneam Illit, Israel).The purpose of integrating RF into cellulite treatmentis to affect the connective tissue septae and fat, bothof which contribute to cellulite. Of the available RFdevices, only VelaSmooth has been approved by theUS Food and Drug Administration (FDA) specificallyfor cellulite treatment. The TriActive laser combines alow-energy diode laser, contact cooling, suction, andmassage. This system has been shown to reducecellulite.15 The VelaSmooth combines infrared light(700-2000 nm), bipolar RF, and suction with me-chanical massage. Like the VelaSmooth, the AlmaAccent RF system (Alma, Buffalo Grove, IL) andThermaCool (Thermage, Hayward, CA) use RF andmaybe useful in the treatment of cellulite.16-18 Boththe Accent and ThermaCool are approved by theFDA for the treatment of wrinkles and rhytides.The ThermaCool is a unipolar RF unit, whilethe Accent system is a combined unipolar andbipolar RF device. Of the two devices, only theAccent system has been evaluated for the treatmentof cellulite.

The precise mechanism by which these combina-tion platforms work is yet to be elucidated. BipolarRF devices are based on the principle of heatgeneration as a result of poor electrical conductance,according to Ohms law:

H = J2r, or heat generation is directly correlatedwith tissue resistance

The heat that is generated is strong enough to causethermal damage to the surrounding adipose tissue andconnective tissue septae. Bipolar RF devices have apenetration depth of [3 mm and allow for bettercontrol and localized adipose tissue alteration.

Unipolar devices use high frequency electromag-netic radiation (EMR). High frequency EMR induceshigh frequency rotational oscillations in water mol-ecules which in turn produces heat (ie, the greaterthe presence of water, the greater the tissue heatgeneration). The depth and breadth of thermaldamage is greater and in a diffuse pattern, with lesscontrol than that provided by bipolar RF devices. Inaddition, low-energy lasers have wound healingproperties, affecting endothelial cells, erythrocytes,and collagen,19 which potentially aids in the healingof localized chronic inflammation, which is stillbelieved to be one of the factors in the etiology ofcellulite. A combination of RF and laser light mayeventuate in enhanced localized fat metabolism,similar to what is seen in mesotherapy.

In the largest study of VelaSmooth to date, Sadickand Mulholland16 evaluated 35 patients who

completed either eight or 16 treatments withVelaSmooth. A dermatologist blinded to the studygroup evaluated the photographs and found 40%improvement on average.

A more recent study of VelaSmooth found astatistically significant decrease in thigh circumfer-ence at 4 weeks, but no immediate change or apersistent decrease at 8 weeks postprocedure.17

Visual improvement of \50% was noted in themajority of subjects. Thirty-one percent of the sub-jects experienced bruising.

Goldman et al18 compared the efficacy of treat-ment of cellulite using two novel modalities:TriActive and VelaSmooth. Patients were treatedtwice weekly for 6 weeks with either VelaSmoothor TriActive. They calculated a 28% versus a 30%improvement rate, respectively, in the upper thighcircumference measurements, while a 56% versus a37% improvement rate was observed, respectively,in lower thigh circumference measurements. Theresults were statistically significant (P [ .05).Incidence and extent of bruising was higher forVelaSmooth than in TriActive system, which maybeattributed to mechanical manipulation.

Alvarez et al20 used animal models to revealinteresting results regarding the effects of RF treat-ment on dermal cellularity and collagen formation.They employed six sessions of RF treatment on thebacks of guinea pigs (1 session/week) and tookbiopsy specimens both after each session and 2months after the last treatment. They found relevantchanges in the papillary dermis that underwent anexpansion related to edema and vascular congestion.These changes were followed by an increase incellularity and an accumulation of intercellular sub-stances. Subsequently, an increase in collagen, elas-tic fibers, and mucopolysacchrides was observed.These changes led to increased dermal thickness andcollagen content.

Goldberg et al21 used an Accent unipolar RF devicefor cellulite treatment. Their study included subjectswith higher grade cellulite on the upper thighs. Theywere treated every other week for a total of sixtreatments. Results obtained 6 months after the lasttreatment showed an average 2.45-cm reduction inthigh circumference with minimal side effects. Nochanges inposttreatmentmagnetic resonance imagingscans were observed, and no lipid abnormalities wereseen. They attribute their longer-lasting effects to theformation of dermal fibrosis with subclinical scarringin the papillary and reticular dermis and increasedcontraction between the dermis and Camper fascia,which has been previously reported in ultrasoundimaging studies.22 The presence of thickened dermal


Khan et al 379

fibrous bands might temporarily improve the appear-ance of cellulite. However, the long-term efficacy ofthis treatment modality still needs to be investigated.

UltrasoundKey pointsd Ultrasound waves can induce adipocyte de-

struction by various mechanisms such ascavitation and thermal damage

d Although ultrasound can be a useful adjunctto other treatments used for cellulite, itsefficacy as the sole treatment lacks substan-tial evidence

It is too early to determine whether noninvasiveultrasound may have a cellulite application. TheUltraShape (UltraShape, San Ramon, CA) is a non-FDA approved device that has been recently shownto decrease subcutaneous adipose tissue thickness.In a conducive setting, ultrasonic energy affectstissue destruction through three mechanisms: cavi-tation, micromechanical disruption, and thermaldamage. Noninvasive ultrasound works either bythermal or micromechanical effects on the tissue at acertain depth. In a study conducted by Moreno-Moraga et al23 of 30 subjects (who maintained con-stant weight during the study period), the researchersfound a mean decrease of 2.3 cm in local fat depositsafter three treatments.24 Although this finding isstatistically significant, it is not known whetherultrasound treatment is effective in changing thearchitectural component of cellulite to cause lastingeffects. Further studies of this device are needed.

Lasers for fat removal: Possible role in thetreatment of celluliteKey pointsd Laser-assisted liposuction has become very

popular among surgeons and dermatologistsas a preferred treatment for localizedadiposities

d Laser-assisted lipoplasty might be a betteroption for small surface areas

d Its efficacy and superiority over traditionallarge-volume liposuction is questionable andrequires further blinded controlled studies

The advantages of laser-assisted lipid destructionover the traditional tumescent liposuction havemade headlines since the approval of the neodym-ium-doped yttrium aluminium garnet (Nd:YAG) laserfor fat removal.

The Nd:YAG (1064-nm) laser (Smartlipo;Cynosure, Westford, MA) targets selected areas offat for destruction in addition to simultaneously

tightening the skin.25,26 This technology is less inva-sive compared to conventional liposuction. It em-ploys a 300-m fiber in a 1-mm diameter cannula thatis threaded under the skin, in comparison to the 3- to5-mm cannulae used in traditional liposuction.

The ultrashort, high-peak power of the laserpulses generates a photoacoustic effect that selec-tively disintegrates adipocyte membranes, resultingin discharge of the cellular contents with minimalrisk of tissue charring. The laser also coagulatestissue to promote collagen tightening and hemosta-sis.27 The thermolysis of the laser will ablate fattissue, which can then be aspirated by either syringesuction or peristaltic pump. Although laser-assistedliposuction has gained a tremendous amount ofinterest among surgeons and dermatologists, itsefficacy and superiority over traditional liposuctionhas been questioned. Prado et al28 found no majorclinical differences for suction-assisted lipoplastyversus laser-assisted lipoplasty. They also foundincreased levels of free fatty acids in the blood afterlaser lipoplasty. However, Goldman et al29 and Kimand Geronemus30 did not show any significantchanges in serum lipid profile.

Laser-assisted lipoplasty may be best suited forsmaller surface areas. Of concern is the fact thatthermal energy, when used for therapeutic purposes,always has the potential for and risk of scarring.Lasers delivered via cannulas can also cause endhits of burns. The results are promising, but addi-tional work needs to be performed.

Based on the theory of selective photothermoly-sis,31 laser light in the range of far infrared can be usedto selectively target fat. Fat can be selectively coagu-lated or destroyed using lasers in the far infraredspectrum. Anderson et al32 reported that the 1210-nmand 1720-nm laser wavelengths were able to selec-tively heat adipose tissue; however, no devices asso-ciated with these wavelengths are commerciallyavailable. In addition, at the time that this article waswritten, no studies of these devices in the treatment ofcellulite have been published. Selective laser irradia-tion of fat at these wavelengths may be an importantbreakthrough in the treatment of cellulite.

ODey et al33 showed fatty tissue ablation using ahigh-powered diode laser (l = 940 nm) using fat cellsharvested from the anteromedial thigh in vitro. Theirstudy showed that l = 940 nm achieves an increasedabsorption of both fatty tissue and water whilemaintaining a penetration depth of several millime-ters. Water in the connective tissue septae might beresponsible for some of the side effects, such ascarbonization and enhanced collateral damage lead-ing to the vaporization of fat cells. These results arepreliminary, yet encouraging.


380 Khan et al

Pharmacologic agentsKey pointsd Several pharmacologic agents available for

the treatment of cellulite lack scientific evi-dence of long-term efficacy

d It is unlikely that topically applied pharma-cologic agents can alter the fundamentalarchitectural alterations that exist in cellu-lite-prone areas

d Topically applied retinoic acid for 6 monthscan enhance dermal collagen productionand improve the strength of the hypodermalseptae

d Carboxy therapy can induce lipolysis be-cause of its positive effect of physiologicoxidative lipolytic process

d Peroxisome proliferator-activated receptorsare a recently discovered family of nucleartranscription factors that are shown to en-hance skin tightening and induce the uncou-pling protein-1 on adipocytes

CatecholaminesNumerous pharmacologic agents are used to treat

cellulite. These include methylxanthines, retinoids,lactic acid, and herbal agents.34 Despite the plethoraof topical treatments available at the dermatologyoffice, pharmacies, spas and boutiques, and over theInternet, there are no large scale studies showing theeffectiveness of any of these therapies. Only twoagentsaminophylline and retinoidshave beencritically evaluated. Aminophylline stimulates b2-AR activity and causes a localized lipolytic effect.Collis et al4 evaluated the effectiveness of topicalaminophylline gel in combination with 10% glycolicacid and concluded that this therapy fails to improvecellulite. Even though it has been hypothesized thattopically applied aminophylline can penetratethrough the dermis to cause significant lipolysis,this has not been scientifically proven. As statedpreviously, the majority of ARs in the femoral areaare a-ARs rather than b2-ARs, which upon stimula-tion with nonselective catecholamine will have anantilipolytic effect. Nonetheless, these treatments arestill used, and patients have reported subjectiveimprovement.

Herbal productsThe herbal product Cellasene (Medestea

Internazionale, Torino, Italy) contains gingko bi-loba, sweet clover, seaweed, grape seed oil, leci-thins, and evening primrose oil has been marketedinternationally as a miracle cure for cellulite.35 Aparallel, placebo controlled clinical study comparingthe effects of Cellasene with those of a control cream

on the appearance of cellulite in 24 women between25 and 45 years of age failed to reveal significantchanges after a 2-month course.36 Of note, seven ofthe 11 women using the study cream gained weight.It is important to note that many of the ingredients inpurported topical treatments for cellulite are notknown, and therefore the risk for adverse effectsmay be increased. In one study, there were 232ingredients in the 32 different cellulite creamsexaminedthese ingredients were predominantlybotanicals, emollients, and caffeine.37 One-fourth ofthese materials were noted to cause allergicreactions.

Retinoic acid and its effect on cellulite adiposetissue

Topically applied retinol 0.3% over a period of 6months or more has been shown to improve cellu-lite.38,39 These effects may be related to the knowneffects of retinoids (increasing dermal collagenthickness and improving the contour of elasticfibers). Studies have also shown an increase in factorXIIIaepositive dendrocytes. Retinol itself can act asan antiadipogenic agent by inhibiting the differenti-ation of human adipocyte precursor cells.

Carboxy therapyCarboxy therapy is a treatment in which carbon

dioxide is injected into the subcutaneous tissue. Thistreatment purports to affect fat cells and circula-tion.40 Brandi et al41 showed increased skin elasticityup to 55.5% when combined with liposuction for thetreatment of cellulite on lateral thighs. A proposedmechanism may be related to a hypercapnia-in-duced rise in capillary blood flow, a drop in cutane-ous oxygen consumption, or a right shift of theoxygen-dissociation curve (Bohr effect). This effectmight account for the positive affect on the physio-logic oxidative lipolytic process.41

Peroxisome proliferator-activated receptoragonists and their effect on cellulite

Peroxisome proliferator-activated receptors(PPARs) are a recently discovered family of nucleartranscription factors,42,43 and three PPAR receptortypes (PPAR-a, PPAR-b, and PPAR-g) have beencharacterized. PPARs bind to the peroxisome pro-liferator response element within the promoter re-gion of the DNA in the target gene in the form ofheterodimers with the retinoid X receptor (RXR). AllPPARs are found in adipocytes. Petroselinic acid andconjugated linoleic acid have been reported aspotent PPAR-a activators, improving epidermal dif-ferentiation, reducing inflammation, increasing ex-tracellular matrix components, and eliciting skin


Khan et al 381

tightening. They are also known to induce uncou-pling protein-1 (UCP-1) levels. Like retinoids, theyalso deliver pleotropic benefits. In vitro studies haveshown that conjugated linoleic acid can prevent lipidaccumulation in adipocytes.

ADVANCES AND NEWER APPROACHES INTHE TREATMENT OF CELLULITEKey pointsd Perilipin A protein, located on adipocytes, con-

trols adipogenesis and adipolysiseffects thatare mediated via estrogen-receptor relatedreceptorea and PPAR-a, respectively

d Characterization of cellulite adipose tissue(white vs brown) is essential in order to betterunderstand the cellulite physiology and toexplore newer treatment options

d Selective cryolysis is a new technique thatmight have potential for cellulite treatment

Perilipin A, estrogen-related receptorea, andPPAR-g in adipocyte regulation

Perilipin A is one of the most abundant proteins ofadipocytes; it regulates adipogenesis and adipolysis.The process is regulated through phosphorylation bythe catecholamine c-AMP/protein kinase A cas-cade.44 Expression of perilipin-A is markedly ele-vated during adipocyte differentiation. It has beenproven that PPAR-g is responsible for this regula-tion.45 PPAR-g is the master regulator of adipogene-sis, but the orchestrated actions of many othertranscriptional factors are also important for the fulldevelopment and maintenance of adipocytes.Estrogen-related receptorea (ERR-a) is likely to beone of such transcriptional factors, based on itselevated expression during adipogenesis and thelean phenotype of ERR-a null mice.46 Perilipin A islocated on the lipid droplet surfaces in adipocytesand steroidogenic cells. It plays a major role in boththe accumulation and mobilization of lipids in adi-pocytes. At a basal rate, this protein protects thestored triglyceride core in the lipid droplet from theattack of lipases. Once phosphorylated by proteinkinase A upon stimulation by catecholamines, peril-ipin allows or even recruits lipases to access lipiddroplets, resulting in active lipolysis. Perilipin gene isa target of ERR-a, which under basal conditionspromotes adipogenesis. In addition, ERR-a is presentin white adipose tissue, a major lipid storagedepot of the human body. This might explainthe high affinity of gluteal and femoral receptorsto circulating estrogen and high rate of adipogen-esis and considerably lower rates of adipolysisunder normal conditions. The perilipin gene isalso a target for PPAR-g; the stimulation of which

leads to inhibitory effects on adipogenesis andpromoting lipolysis.47 Therefore, the control ofadipocyte differentiation varies greatly among dif-ferent body sites, and a complex network oftranscriptional factors controls energy metabolism.Other newly discovered hormones, such as grehlinand PYY-36, might have a role in controllinghunger at the level of satiety center in the hypo-thalamus and central obesity. However, their rolein the pathophysiology of cellulite still remains tobe shown.

Conversion of white adipose tissue to brownadipose tissue and vice versa

Because of the antilipogenic properties of reti-noic acid agonists and PPAR receptor agonists,along with their unique ability to induce UCP-1,they have become targets in the search for the cureof cellulite.

Although evidence to support their use both inhumans and in vivo is still lacking, there have beeninteresting reports of the use of these agonists toconvert white adipose tissue (WAT) to brown adi-pose tissue (BAT) in vitro mainly via the induction ofUCP-1. An in vitro study by Alvarez et al48 investi-gated the effects of various retinoic acid receptors(RARs) on the induction and expression of UCP-1.UCP-1 is exclusively found in BAT. Their workconcluded that cotransfection of murine expressionvectors for the different RAR and RXR subtypesindicates that RAR-a and RAR-b, as well as RXR-a,are the major retinoid receptor subtypes that arecapable of mediating the responsiveness of UCP-1 toretinoids. The effects of retinoids on UCP-1 transcrip-tion involve both RAR- and RXR-dependent signalingpathways. The responsiveness of BAT to retinoids invivo relies on a complex combination of the capacityof RAR and RXR subtypes to mediate UCP-1 inductionand their distinct expression in the differentiatedbrown adipocytes.

Other interesting studies by Tiraby et al49,50 haveidentified a PPAR-g coactivator 1a (PGC-1a), whichis expressed in higher levels in BAT than in WAT. Itsexpression is increased in response to cold and b-ARstimulation, leading to higher levels of UCP-1 inconjunction with RXR-a and an increase in mito-chondriogenesis. These changes ultimately promotethe conversion of WAT to BAT. This might be a newparadigm for further research into the treatment ofcellulite.

Selective cryolysisCryolysis is an interesting concept that might have

future applications in the reduction of cellulite andlocalized adiposities. There is evidence that adipose


382 Khan et al

tissue is selectively sensitive to cold injury, such aspopsicle panniculitis.51 The most likely mecha-nism hypothesized when popsicle panniculitis wasfirst described is that crystallization of cytoplasmiclipids in adipocytes occurs at temperatures wellabove the freezing point of tissue water. The poten-tial for tissue-specific cold injury was first investi-gated and recently reported by Anderson et al52 in ananimal model. Black Yucatan pigs were exposed totemperatures of 20, -1, -3, -5, and -7 8C for 10 minutesusing the Zeltiq prototype device (Zeltiq Aesthetics,Pleasanton, CA). At 3.5 months of follow-up, sometreated areas showed grossly obvious loss of severalmillimeters of subcutaneous fat. The investigatorsdid not find any significant change in serum lipidvalues. In this study, inflammation and adiposetissue loss were well correlated. Both proceededfor many weeks after a single, local exposure to cold,reaching an apparent maximum at 4 weeks after andresolving about 3 months after cold exposure. In itsearly inflammatory phase, panniculitis may furtherdamage adipocytes. In its later phase, however,phagocytosis appears to account for removal ofadipocytes and loss of fat tissue.

Many important details about selective cryolysisremain to be studied. Most importantly, there is notenough information available in the published liter-ature regarding the mechanisms of adipocyte injuryin adult humans when subzero temperatures areapplied to the surface of skin. In addition, selectivecryolysis might be challenged by the fact that humanfat is rich in unsaturated fatty acids with a muchlower freezing point as opposed to pig fat, which isrich in saturated fatty acids with a rather highermelting point.

The precise nature of the fatty acids and otherlipids of cellulite fat have yet to be defined. Selectivecryolysis is a newer, noninvasive treatment optionfor localized adiposities. Its role in the treatment ofcellulite is still under investigation.

Excessive localized adipose tissue is one of themain etiologies of cellulite. In addition, the depth,breadth, and extent of cellulite vary from one part ofthe body to another in a rather unpredictablemanner. Skin surface cooling with either a flat or asuction device might offer some advantage forliposculpting similar to other noninvasive treatmentmodalities, such as ultrasound and radiofrequencydevices. Well controlled comparison trials areneeded to better define the superiority of one treat-ment over another.

CONCLUSIONCellulite is an architectural disorder caused by

multifactorial etiologies. Despite a large number of

treatments availableall of which claim to worksomehowfew actually do work, and many workwith unpredictable results.24 Limited therapeuticoptions are available that can alter the genetic factorsresponsible for dermohypodermal heteromorphismamong both affected and unaffected individuals. Theconnective tissue septae that traverse and subdividethe hypodermis serve as suspenders that hold theadipose tissue. Theoretically, if the volume of herni-ated adipose tissue in the hypodermis can be re-duced in a selective, predictable, controlled, and safemanner, it might clinically improve cellulite. Inaddition, increasing the dermal thickness can alsopotentially strengthen the dermohypodermal junc-tion, thereby reducing adipose tissue herniation. Theconfiguration of fat found in the cellulite (WAT vsBAT) by receptor analysis of the adipocytes in thegluteofemoral area needs to be better identifiedusing techniques such as polymerase chain reaction.Understanding the mechanisms governing the ac-quisition and persistence of white and brown adi-pocytes can have novel implications in terms of thepathophysiology and therapeutic strategies used inthe future for the management of cellulite.

Recently introduced noninvasive cryolysis mighthave promising results in the reduction of subcuta-neous fat, at least temporarily. Its role in the treat-ment of cellulite adipose tissue as a noninvasivemodality remains to be explored.

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Treatment of cellulitePart II. Advances and controversiesAttenuation of Aggravating FactorsWeight lossPhysical, Mechanical, and Thermal MethodsEndermologieLiposuctionSubcisionPhosphotidylcholine and mesotherapyBipolar and unipolar radiofrequency devicesUltrasoundLasers for fat removal: Possible role in the treatment of cellulitePharmacologic agentsCatecholaminesHerbal productsRetinoic acid and its effect on cellulite adipose tissueCarboxy therapyPeroxisome proliferator-activated receptor agonists and their effect on celluliteAdvances and Newer Approaches in the Treatment of CellulitePerilipin A, estrogen-related receptor-alpha, and PPAR-gamma in adipocyte regulationConversion of white adipose tissue to brown adipose tissue and vice versaSelective cryolysisConclusionReferences

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