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Journal of Cosmetic and Laser

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formerly Journal of Cutaneous Laser Therapy
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Cellulite: Is there a role for injectables?
Adam M. Rotunda a; Mathew M. Avram b; Alison Sharpe Avram c
a
Department of Dermatology, University of Southern California Keck School of
Medicine, Bennett Surgery Center, Santa Monica, CA
b
Massachusetts General Hospital Laser Center, Harvard Medical School, Boston,
MA
c
Private practice, New York, NY

Online Publication Date: 01 December 2005

To cite this Article: Rotunda, Adam M., Avram, Mathew M. and Avram, Alison
Sharpe (2005) 'Cellulite: Is there a role for injectables?', Journal of Cosmetic and Laser Therapy, 7:3, 147 - 154
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REVIEW ARTICLE

Cellulite: Is there a role for injectables?

ADAM M. ROTUNDA1, MATHEW M. AVRAM2 & ALISON SHARPE AVRAM3

1
Department of Dermatology, University of Southern California Keck School of Medicine, Bennett Surgery Center, Santa
Monica, CA, USA, 2Massachusetts General Hospital Laser Center, Harvard Medical School, Boston, MA, USA, and
3
Private practice, New York, NY, USA

Abstract
Background. Cellulite describes the cutaneous dimpling of the thighs, buttocks, and hips that is seen predominately in
women. Current evidence suggests that structural differences in fat architecture between the sexes account for its
appearance. Mesotherapy, a method of delivering medication locally with the use of numerous cutaneous injections, has
recently become a popular method to purportedly treat the condition.
Methods. An overview of cellulite and adipocyte physiology, with a literature review and appraisal of compounds commonly
used in mesotherapy.
Results. Experimental studies using individual mesotherapy ingredients for other conditions suggest a number of
mechanisms, including lipolysis, disrupting connective tissue and augmenting circulation, which may theoretically improve
cellulite. Peer-reviewed studies have not evaluated whether these effects translate clinically.
Conclusions. Until further studies are performed, patients considering mesotherapy for cellulite must be aware that the
substances currently being injected to treat this cosmetically disturbing, but medically benign, condition have not been
thoroughly evaluated for safety or efficacy.

Key words: Mesotherapy, fat, Cellulite, phosphatidylcholine, deoxycholate

Introduction American Society of Plastic Surgeons have primarily

Of the three embryologic germ layers (ecto-, meso-,
and endoderm), the mesoderm develops into con-
nective tissue, muscle, and the circulatory system. In
1952, Dr Michel Pistor first introduced mesotherapy
in France as a way to treat disorders affecting the
mesoderm (skin, muscle, tendon, ligament, vascu-
lature, and fat) (1).Mesotherapy describes a techni-
que by which mixtures of medications and other
compounds are injected directly into a diseased area
so that systemic effects of oral or intravenous
medications can be avoided. Mesotherapy has been
traditionally used in Europe for decades as a
treatment for musculoskeletal pain (2), lymphedema
(3,4), and dental pain (5,6). It has also been used to
treat cosmetic conditions such as scaring, alopecia,
photoaging, and cellulite (7).
Physicians training with preceptors in Europe
have recently introduced mesotherapy to the USA.
The position statements of the lay press, health
professionals administering treatments, as well as the
American Society for Dermatologic Surgery and
focused on describing mesotherapy as a novel
treatment for cellulite and collections of localized
fat rather than as a treatment for medical conditions
(7–14). Moreover, an increasingly popular, contem-
porary portrayal of mesotherapy frequently involves
injections of phosphatidylcholine and deoxycholate
(a bile salt used to solubilize the phosphatidylcho-
line). However, traditional European mesotherapy
does not incorporate phosphatidylcholine and/or
deoxycholate into its formulations (7). These two
ingredients are used for body contouring by local fat
ablation and therefore should be differentiated from
techniques that attempt to diminish cellulite. The
discussion herein is restricted to mesotherapy
formulations exclusive of phosphatidylcholine and/
or deoxycholate. A review of these compounds for
the treatment of adipose tissue is found elsewhere
(7,15,16).
Mesotherapy used for the treatment of cellulite
involves numerous, localized, intradermal or sub-
cutaneous injections containing combinations of
vasodilators, anti-inflammatory medications, herbs,

Correspondence: A. M. Rotunda, Clinical Instructor, Department of Dermatology, University of Southern California Keck School of Medicine, Bennett
Surgery Center, St John’s Medical Plaza, Suite 570, Santa Monica, CA 90404, USA. Fax: +1 310 828 6647. E-mail: arotunda@hotmail.com

(Received 29 September 2005; accepted 17 October 2005)

ISSN 1476-4172 print/ISSN 1476-4180 online # 2005 Taylor & Francis
DOI: 10.1080/14764170500430234
 148 A. M. Rotunda et al.
hormones, antibiotics, enzymes or co-enzymes
(7,16). An increasing number of compounding
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pharmacies offer premixed ‘cocktails’ or individually
solubilized ingredients that are combined in the
syringe prior to injection. Although there is not one
standardized formulation for cellulite, a number of
common ingredients (Table I) are advocated at
training seminars and are readily available over the
Internet. Nevertheless, a number of physicians have
claimed their formulations are proprietary.
Mesotherapy has become as controversial as it is
popular. Unlike recognized cosmetic treatments
such as botulinum toxin and soft tissue fillers,
mesotherapy’s efficacy is distinctively ambiguous,
making it vulnerable to criticism by the generally
more skeptical medical community. Although the
FDA has approved most of the ingredients used in
mesotherapy, its constituents are being utilized for
unapproved indications and are being administered
in a manner whose efficacy, safety, and pharmaco-
kinetics are unknown.
Numerous organizations offer hands-on, didactic
mesotherapy courses for physicians as well as non-
physicians. Advertisements to the public by physi-
cians, who are motivated by the increasingly
competitive market, create the illusion that
mesotherapy is an imported European panacea for
a number of cosmetic and medical conditions. A
critical evaluation of mesotherapy’s efficacy or
potential efficacy for the treatment of cellulite, a
disturbing cosmetic condition for which there is no
adequate treatment, is particularly timely.
Cellulite
In order to treat cellulite, it is important to under-
stand what physiologic changes produce this phe-
nomenon (17). There is currently no definitive
explanation for the physiology of cellulite. There is
evidence that cellulite is a secondary sexual char-
acteristic in females (18–20). It is nearly universal in
post-pubertal females and rare in men, except in
those with androgen deficiencies. Obese males rarely
display cellulite whereas thin females normally do.
Taken together, these findings strongly suggest a
hormonal component to its etiology. Although some
have proposed vascular (20–24) and inflammatory
theories (20,25) to explain the appearance of
cellulite, the best evidence supports that there are
Table I. Commonly used mesotherapy ingredients for the treatment of cellulite.a
Lipolysis: isoproterenol, forskolin (herbal extract), theophylline, aminophylline, caffeine, carnitine
Connective tissue dissolution: collagenase, hyaluronidase
Enhance regional circulation: pentoxyphylline, coumarin, herbs (ginko biloba, melilot), artichoke
a
More recent, non-traditional, mesotherapy ingredients are phosphatidylcholine solubilized with deoxycholate. However, the inclusion of
these substances in current formulations is meant primarily for localized fat ablation rather than as a treatment of cellulite, and therefore will
not be discussed.
gender-based structural differences in the organiza-
tion of female subcutaneous fat that produce the pits
and dells characteristic of cellulite (19,26–29).
In 1978, Nürnberger and Müller developed the
‘anatomic’ hypothesis of cellulite based on their
examination of 180 deep biopsies from the thighs
and buttocks of live patients and cadavers (19). In
their seminal paper, the authors described gender-
specific differences in the structure of subcutaneous
fat of men and women, a characteristic that has since
been confirmed by other investigators using similar
techniques as well as sonography, MRI and spectro-
scopy (26,28,29). According to these studies, female
fat lobules are larger than those in males and are
compartmentalized by fibrous septae that form
radial and arch-like structures. Because these fibrous
septae are oriented perpendicular to the dermis, the
fat lobules they contain easily protrude vertically
forming fat herniations into the overlying dermis,
thereby creating an undulating dermal-subcutaneous
fat interface and hence the clinical appearance of
cellulite. By contrast, the smaller fat lobules in males
are compartmentalized by septae that are oriented in
an oblique fashion, a characteristic that prevents
herniation of fat into the dermis and results in a
smooth, rather than dimpled cutaneous surface.
There is a simple clinical correlate to this finding.
If one pinches the skin of a female posterior thigh,
the force of the pinch will push protrusions of fat
deeper into the dermis and produce the clinical
appearance of skin dimpling, i.e. the ‘mattress
phenomenon’ (20). This is true even in areas of
the posterior thigh where cellulite is not clinically
present. Pinching the skin of male posterior thighs is
far less likely to produce the mattress phenomenon
due to the difference in organization of fat tissue
septae.
Adipocyte physiology: potential mechanisms
for cellulite reduction
It has been theorized that agents that reduce adipose
tissue mass in affected areas may diminish the
appearance of cellulite. An interest in mesotherapy
as a treatment for cellulite has evolved primarily
because several formulations are thought to produce
a localized reduction in fat cell (adipocyte) size,
and hence adipose tissue mass, by triggering lipo-
lysis in them. Such agents include isoproterenol,

theophylline, aminophylline, caffeine, forskolin, and
thyroxine (7,16). Understanding the complex sys-
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tem that controls lipolysis is essential if meaningful
investigations that explore the potential role of
mesotherapy as a treatment for cellulite are to be
performed.
Lipolysis (lipolysis/fatty acid oxidation) and lipo-
genesis (lipid synthesis) are two critical and basic
metabolic functions of adipocytes that occur con-
tinuously throughout the life of the cell (30).
Specifically, lipolysis represents the process by which
intracellular triacylglycerol (TG) is hydrolyzed or
degraded into free fatty acids (FFAs) and glycerol
which are then released into the circulation (31,32).
The balance of lipolysis and lipogenesis varies
according to anatomic location, gender, race and
age, and ultimately determines adipocyte volume
(30). It has been assumed that pharmacologic agents
that increase localized lipolysis should tip the
balance towards lipid loss, thereby resulting in the
predominance of smaller fat cells. Of note, lipolysis
should not be confused with apoptosis, the process
by which adipocytes undergo programmed cell
death.
The most potent regulators of lipolysis and TG
mobilization in humans are the catecholamines,
epinephrine and norepinephrine, which are derived
from either endocrine or neuronal sources (33).
Adipose tissue shows significant regional differences
in catecholamine responsiveness, which varies
according to gender, age, body region and degree
of adiposity during normal and pathologic circum-
stances, a characteristic that helps to determine the
metabolic rate of adipocytes and, therefore, the
volume, or size, of the tissue (34–38). This
characteristic has been attributed, in part, to the
four adrenoreceptor (AR) subtypes, b1, b2, b3 and
a2, which are mainly responsible for mediating the
catecholamine signal. The three b-ARs transmit a
lipolytic signal, whereas a2-AR transmits the anti-
lipolytic signal (32,35,39). The net degree of
lipolysis is determined by the interplay of stimulatory
(lipolytic) and inhibitory (anti-lipolytic) pathways.
The binding of hormones and other physiological
effectors to ARs triggers a cascade of events that
ultimately leads to activation or inhibition of
hormone-sensitive lipase (HSL), the rate-limiting
enzyme in the liploytic pathway (32,40). When
triggered by phosphorylation during lipolysis, HSL,
which is constitutively active at baseline, travels from
its location in the cytosol to the TG stores in the
lipid droplet where it can then mediate its lipolytic
effect (41–45). The level of cAMP, an important
second messenger in this pathway, ultimately deter-
mines the degree of HSL phosphorylation.
Ligands that bind the stimulatory b-ARs trigger
adenylate cyclase (AC), which, in turn, generates a
cytosolic pool of cyclic adenosine monopho-
sphate (cAMP) and the subsequent activation of
Cellulite and injectables 149
cAMP-dependent protein kinase. Activated cAMP-
dependent protein kinase phosphorylates HSL. By
contrast, ligand activation of anti-lipolytic a2-ARs
suppresses AC, a process that ultimately leads to a
decrease in HSL activity and reduced lipolysis. In
non-pathologic states, the b2-AR is the major
lipolytic subtype with epinephrine acting as the
primary ligand (37). Inhibition of lipolysis (anti-
lipolysis) is mediated by a2-AR, which is also
triggered by epinephrine, the same ligand that
stimulates b2-AR action (46,47). A balance in favor
of epinephrine-mediated lipolysis or anti-lipolysis is
determined by regional variations in b-lipolytic and
a-anti-lipolytic AR ratios as well as by regional
variations in AR ligand-binding affinities (36,48).
Thus, epinephrine inhibits lipolysis in some ana-
tomic locations (subcutaneous fat) while it stimu-
lates it in others (visceral fat) (36,48–52).
Interestingly, adipocytes are the only cell type with
both agonistic and antagonistic ARs on its surface
(36,49). This unique characteristic is believed to
play a key role in determining body fat topography.
In addition to catecholamines, other hormones
play an important role in triggering lipolytic or anti-
lipolytic responses that involve cAMP. Of these,
insulin is the most potent anti-lipolytic hormone in
human adipocytes (53,54). It mediates its effect by
triggering its own insulin receptor, which in turn
activates and increases cAMP phosphodiesterase 3B
(32). Constitutively active cAMP phosphodiesterase
3B is part of an anti-lipolytic counter-regulatory
system in which cAMP is hydrolyzed or degraded to
5’-AMP as soon as it is formed by AC, thereby
consuming b-AR-mediated increases in cAMP and
rapidly reversing HSL activation. By contrast,
phosphodiesterase (PDE)-inhibitors, such as com-
mon mesotherapy ingredients, theophylline and
aminophylline, turn off tonic cAMP hydrolysis by
PDE, thereby contributing to a greater pool of
cAMP and increased basal lipolysis (55).
Another mechanism for lipolytic control involves
adenosine, which mediates a strong anti-lipolytic
and vasodilatory effect in adipose tissue via its own
adenosine A1 transmembrane receptor (56–58).
Adenosine exerts its effect on adipocytes via
inhibition of AC and the production of cAMP
(59). Caffeine and theophylline are an adenosine
antagonist (60).
Mesotherapy and cellulite
Despite the purported claims, a recent review
evaluating mesotherapy has not found any peer-
reviewed reports in the English literature demon-
strating efficacy of this treatment for cellulite (7). In
fact, there is currently no scientific, peer-reviewed
investigation in the English literature which demon-
strates efficacy of traditional mesotherapy formula-
tions for any medical or cosmetic condition
 150 A. M. Rotunda et al.
Table II. Proposed mechanism and the experimental basis for using the common mesotherapy ingredients for cellulite.
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Ingredient Proposed mechanism
Isoproterenol Increases lipolysis. As a selective
b-AR agonist, isoproterenol
stimulates b-AR and increases cAMP
(73).
Forskolin(extracted Increases lipolysis. Directly activates
from the herb Coleus AC independent of ARs, thereby
forskohlii) raising cAMP (74).
Theophylline Increases lipolysis. As a non-selective
PDE inhibitor, theophylline increases
cAMP (75). Also augments cAMP
by antagonizing adenosine (76,77).
Improves circulation; potent
vasodilator.
Aminophylline Increases lipolysis. As a PDE
inhibitor, aminophylline increases
cAMP (78).
Caffeine Increases lipolysis. Raises cAMP by:
inhibiting PDE (79), increasing
catecholamine release (epinephrine)
by the sympathetic nervous system
(80), and antagonizing adenosine
(60).
Thyroxine Augments lipolysis (81).
Carnitine Augments lipid oxidation (82,83).
Collagenase Dissolution of fibrous bands and
septae that are thought to influence
surface dimpling (26–28).
Hyaluronidase Disruption of dermal connective
tissue thought to produce surface
irregularities
Coumarin Augments circulation (84,85).
(benzopyrone) Reduces volume of chronic
high-protein edema; stimulation of
tissue macrophages; increases
proteolysis and reduces excess protein
(86,87).
Melilot (Melilotus Augments circulation.
officianalis or sweet
clover)
Ginko biloba Augments circulation. An active
constituent, diterpenes, inhibits
platelet activating factor and
decreases platelet aggregation (88,89).
Ginko biloba also acts as a
vasomodulator (89).
Pentoxyphylline Augments circulation. Improves
erythrocyte deformability and
reduces blood viscosity in vitro (90).
Artichoke extract Augments circulation.
AC: adenylate cyclase; AR: adrenoreceptor; cAMP: cyclic adenosine monophosphate; FFA: free fatty acid; NO: nitric oxide; PDE:
phosphodiesterase.
Experimental support
Concentration-dependent increase in FFA and/or glycerol release in
human adipocytes in vitro (73), and in vivo (34,91–94) after local
isoproterenol infusion; the local in situ effects are transient and occur at
much lower concentrations than those in circulation (95).
Pretreatment exposure of adipose tissue with forskolin with subsequent
addition of isoproterenol in situ results in higher glycerol output than
with isoproterenol alone (96) and increases in glycerol release in vitro
(97).
Addition of theophylline with human fat increases lipolysis in vitro (98)
and in vivo (75).
Augments lipolysis in adipocytes exposed to aminophylline in vitro
(78,99).
Significant increase in FFA oxidation over physiologic levels at rest and
during exercise after ingestion of caffeine (100–103).
Hyperthyroidism leads to enhanced local response of adipose tissue to
norepinephrine levels in vivo (104,105).
Carnitine increases delivery rate of long-chain FFAs into mitochondria
for b-oxidation (82,83). However, no evidence that oral carnitine
supplementation improves exercise performance or weight loss in
humans (82,106). Oral and intravenous L-carnitine demonstrates
cardioprotective effects after myocardial infarction, in part due to
preventing FFA accumulation (83).
In vitro collagenase digestion is a common technique for adipocyte
isolation that does not adversely affect cell survival (107–109).
Collagenase is the major collagenolytic enzyme responsible for collagen
damage in photoaging (110,111). Clinical reduction after collagenase
injection into human lipomas (112).
Hyaluronic acid, a hydrophilic polysaccharide found in human skin,
which is also a soft tissue cosmetic filler, is degraded by hyaluronidase in
vitro (113) and in vivo (114).
Placebo-controlled clinical trials using oral coumarin for chronic
lymphedema after breast cancer surgery have shown both reduction (115)
and no effect (116) on limb circumference. A fifty-study meta-analysis of
oral and topical coumarin demonstrates significant reduction in
symptoms of limb edema (117). Use of coumarin combined with physical
therapy reduces limb lymphedema more than either treatment alone
(118).
Natural source of coumarins (119). Modest (5% with respect to initial
levels) but statistically significant reduction of arm lymphedema in
patients treated with oral coumarinic extract of melilotus (120).
Ginko extracts enhance peripheral and cerebral circulation (88,121).
Regional forearm blood flow significantly increased in double-blinded
placebo-controlled study with patients receiving 6 weeks of an oral ginko
biloba extract (122). However, mean skin blood flow significantly
reduced in subjects receiving oral ginkgo extract in a recent randomized,
double-blind, placebo-controlled study (89).
Reduces reperfusion injury in vivo by preserving endothelial cell vaso-
relaxation in rabbits (123). No effect on skin flap survival in animals
receiving oral pentoxifylline (124) but parenteral pentoxifylline plus
topical nitroglycerin positively influence flap survival (125).
Incubation of aortic rings and endothelial cells in vitro with artichoke leaf
extract enhances endothelial cell NO synthase (126) and directly
potentiates release of NO (127), which is a potent vasorelaxant.

(7,16,61,62). A double-blinded clinical trial evalu-
ating ‘mesoplasty’, which was recently presented at
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the American Society of Plastic Surgery Annual
Meeting, demonstrated significant waist and thigh
reductions restricted to patients receiving subcuta-
neous injections of a phosphatidylcholine formula-
tion; the vasodilator (buflomedil) and homeopathic
(carnitine and melilotus) treatments did not produce
any effect (63). Most of the published literature
regarding mesotherapy describe adverse events,
including mycobacterial infection (64–66), koebner-
ization of psoriasis (67), urticaria pigmentosa (68),
subcutaneous nodules (69), drug eruptions (70,71),
and hyperpigmentation (72). Reports of these
reactions may increase over time if physician and
non-physicians unfamiliar with cutaneous anatomy
and proper injection technique embrace this mod-
ality as a therapy for cellulite.
There is, however, a rationale to remain cautiously
optimistic. A significant amount of experimental
data using individual components of mesotherapy
for non-cosmetic conditions suggests that these
agents may have the potential ability to improve
cellulite (Table II). For agents that augment lipo-
lysis and disrupt connective tissue, this notion relies
upon several assumptions. First, it assumes that
localized lipolysis in the subcutaneous fat, which
should theoretically reduce the size of adipocytes in
this area, can affect the appearance of cellulite.
Although it is acknowledged that increased adiposity
due to weight gain may make cellulite more evident
and that weight loss may help improve its appear-
ance (19,21), cellulite is thought to result primarily
from underlying connective tissue anatomy, rather
than from an excess of adipose tissue reserves
(19,26,28). As noted earlier, both thin and obese
females display cellulite. It is important to note that
liposuction, the most effective method for removing
fat and disrupting subcutaneous connective tissue,
has minimal effect on improving the appearance of
cellulite, and, in some cases, may even make it worse
(128). Thus, fat destruction alone does not amelio-
rate the structural reasons that produce cellulite.
Second, although some of the ingredients in
mesotherapy formulations individually may enhance
adipocyte lipolysis (by stimulating b-ARs or by
inhibiting anti-lipolysis by blocking PDE or adeno-
sine in vitro and in vivo), it is unknown whether
these effects are clinically significant. A number of
published studies have examined the effect of
lipolytic agents on human adipose tissue in vivo
using microdialysis (91,95). This technique utilizes
dialysis probes implanted in subcutaneous fat for
continuous monitoring of interstitial or extracellular
metabolites, such as glycerol (a sensitive marker for
lipolysis), after exposure to pharmacological agents.
Objective data such as this confirms the theoretical
potential of some ingredients to produce localized
lipid breakdown. Nevertheless, gross changes from
Cellulite and injectables 151
infusion of isolated or combinations of lipolytic
agents have not been reported.
It is also important to reiterate that lipolysis does
not produce a permanent effect, such as apoptosis.
Rather, lipolysis triggers an acute metabolic response
that is, in all likelihood, transient. During several
studies in which effects of the catecholamine
isoproterenol was measured over several hours using
microdialysis, the degree of lipolysis, which initially
increased, returned to or approximated the basal rate
despite repeated injections of increasing catechola-
mine doses (91,95). Tachyphylaxia to catechola-
mines has been attributed to desensitization of the
AR system (129). A lasting effect on fat cell volume
by mesotherapy-mediated adrenergic stimulation or
inhibition of PDE/adenosine pathways has not been
proven.
In accord with the proposition that effective
cellulite treatments should be directed towards
chemically or physically weakening connective tissue
(26), it may be argued that agents such as
collagenase and hyaluronidase are reasonably appro-
priate in mesotherapy cellulite treatments. Yet again,
this theoretical assumption has yet to be proven
through clinical trials.
Finally, the often-repeated speculation that pro-
moting ‘lymphatic drainage’ and increasing local
circulation to attenuate cellulite has not been
established. The role of impaired lymphatic drainage
as a cause of cellulite is speculative. Therefore, the
role of pentoxyphylline, coumarin, and a number of
circulation-enhancing herbs for cellulite is tenuous
at best.
Conclusion
Until clinical studies are performed that validate the
use of mesotherapy ingredients for cellulite, it is
conjecture whether this treatment is effective.
Although several of the commonly used ingredients
have a theoretical potential to produce localized
lipolysis and/or disrupt connective tissue, it is
unknown whether these effects translate clinically.
Until further studies are performed, patients con-
sidering mesotherapy for cellulite must be aware that
the substances being injected have not been thor-
oughly evaluated for safety or efficacy. These
treatments may expose patients to unforeseen risks
as they seek the elusive ‘cure’ for a cosmetically
disturbing but medically benign condition.
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