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Journal of Cosmetic and Laser Therapy
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 To link to this article: DOI: 10.1080/14764170500430234 URL: http://dx.doi.org/10.1080/14764170500430234
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Bennett Surgery Center. but medically benign.6). The position statements of the lay press. Physicians training with preceptors in Europe have recently introduced mesotherapy to the USA. An overview of cellulite and adipocyte physiology. Peer-reviewed studies have not evaluated whether these effects translate clinically. St John’s Medical Plaza. has recently become a popular method to purportedly treat the condition. In 1952. buttocks.com (Received 29 September 2005. disrupting connective tissue and augmenting circulation. and endoderm). as well as the American Society for Dermatologic Surgery and American Society of Plastic Surgeons have primarily 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). Bennett Surgery Center. CA 90404. Cellulite. muscle. However. with a literature review and appraisal of compounds commonly used in mesotherapy. Mesotherapy has been traditionally used in Europe for decades as a treatment for musculoskeletal pain (2). Cellulite describes the cutaneous dimpling of the thighs. and the circulatory system. ligament. New York. patients considering mesotherapy for cellulite must be aware that the substances currently being injected to treat this cosmetically disturbing. vasculature. and fat) (1). an increasingly popular. Suite 570. Fax: +1 310 828 6647. Current evidence suggests that structural differences in fat architecture between the sexes account for its appearance. contemporary portrayal of mesotherapy frequently involves injections of phosphatidylcholine and deoxycholate (a bile salt used to solubilize the phosphatidylcholine). accepted 17 October 2005) ISSN 1476-4172 print/ISSN 1476-4180 online # 2005 Taylor & Francis DOI: 10. USA. Experimental studies using individual mesotherapy ingredients for other conditions suggest a number of mechanisms. E-mail: arotunda@hotmail. Santa Monica. CA. Clinical Instructor. Mesotherapy. meso-. including lipolysis. health professionals administering treatments. muscle. Boston. Key words: Mesotherapy. deoxycholate Introduction Of the three embryologic germ layers (ecto-. anti-inflammatory medications. USA. Rotunda. M. and hips that is seen predominately in women. herbs. Dr Michel Pistor first introduced mesotherapy in France as a way to treat disorders affecting the mesoderm (skin. ROTUNDA1. Mesotherapy used for the treatment of cellulite involves numerous. MA. Until further studies are performed. and 3 Private practice. and cellulite (7). alopecia. a method of delivering medication locally with the use of numerous cutaneous injections. lymphedema (3.16). MATHEW M. A review of these compounds for the treatment of adipose tissue is found elsewhere (7. It has also been used to treat cosmetic conditions such as scaring. Moreover. fat. Methods. phosphatidylcholine. Results. traditional European mesotherapy does not incorporate phosphatidylcholine and/or deoxycholate into its formulations (7). Department of Dermatology. 2Massachusetts General Hospital Laser Center. which may theoretically improve cellulite.4).Journal of Cosmetic and Laser Therapy. University of Southern California Keck School of Medicine. Correspondence: A. Harvard Medical School.1080/14764170500430234 . 7: 147–154 Downloaded By: [University of Pittsburgh] At: 23:52 24 July 2007 REVIEW ARTICLE Cellulite: Is there a role for injectables? ADAM M. and dental pain (5. USA. These two ingredients are used for body contouring by local fat ablation and therefore should be differentiated from techniques that attempt to diminish cellulite. AVRAM2 & ALISON SHARPE AVRAM3 1 Department of Dermatology. localized. University of Southern California Keck School of Medicine. Conclusions. photoaging. Santa Monica. The discussion herein is restricted to mesotherapy formulations exclusive of phosphatidylcholine and/ or deoxycholate. NY. the mesoderm develops into connective tissue. USA Abstract Background.Mesotherapy describes a technique 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. intradermal or subcutaneous injections containing combinations of vasodilators. 2005.15. tendon. condition have not been thoroughly evaluated for safety or efficacy.
Downloaded By: [University of Pittsburgh] At: 23:52 24 July 2007 Cellulite In order to treat cellulite. safety. Mesotherapy has become as controversial as it is popular. 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. who are motivated by the increasingly competitive market. a characteristic that prevents herniation of fat into the dermis and results in a smooth. melilot). There is a simple clinical correlate to this finding. these findings strongly suggest a hormonal component to its etiology. Although some have proposed vascular (20–24) and inflammatory theories (20. In their seminal paper. by triggering lipolysis in them. forskolin (herbal extract). Obese males rarely display cellulite whereas thin females normally do. 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. Nevertheless. If one pinches the skin of a female posterior thigh. Although the FDA has approved most of the ingredients used in mesotherapy. Taken together. By contrast. In 1978. coumarin. a number of common ingredients (Table I) are advocated at training seminars and are readily available over the Internet. 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. making it vulnerable to criticism by the generally more skeptical medical community.16). theophylline. Advertisements to the public by physicians. enzymes or co-enzymes (7. Rotunda et al. thereby creating an undulating dermal-subcutaneous fat interface and hence the clinical appearance of cellulite. and therefore will not be discussed.26–29). M. caffeine. aminophylline. the ‘mattress phenomenon’ (20). . the force of the pinch will push protrusions of fat deeper into the dermis and produce the clinical appearance of skin dimpling. a characteristic that has since been confirmed by other investigators using similar techniques as well as sonography. An increasing number of compounding pharmacies offer premixed ‘cocktails’ or individually solubilized ingredients that are combined in the syringe prior to injection. hyaluronidase Enhance regional circulation: pentoxyphylline. antibiotics. There is evidence that cellulite is a secondary sexual characteristic in females (18–20).25) to explain the appearance of cellulite. MRI and spectroscopy (26. Because these fibrous septae are oriented perpendicular to the dermis. According to these studies. rather than dimpled cutaneous surface. artichoke a More recent. Table I. the fat lobules they contain easily protrude vertically forming fat herniations into the overlying dermis. Unlike recognized cosmetic treatments such as botulinum toxin and soft tissue fillers. However.29). Although there is not one standardized formulation for cellulite. its constituents are being utilized for unapproved indications and are being administered in a manner whose efficacy. the best evidence supports that there are 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. This is true even in areas of the posterior thigh where cellulite is not clinically present.148 A. herbs (ginko biloba. the smaller fat lobules in males are compartmentalized by septae that are oriented in an oblique fashion. non-traditional. Numerous organizations offer hands-on. a disturbing cosmetic condition for which there is no adequate treatment. It is nearly universal in post-pubertal females and rare in men. the inclusion of these substances in current formulations is meant primarily for localized fat ablation rather than as a treatment of cellulite.a Lipolysis: isoproterenol. Commonly used mesotherapy ingredients for the treatment of cellulite. the authors described genderspecific differences in the structure of subcutaneous fat of men and women. hormones. except in those with androgen deficiencies. a number of physicians have claimed their formulations are proprietary. and pharmacokinetics are unknown. mesotherapy ingredients are phosphatidylcholine solubilized with deoxycholate.28. female fat lobules are larger than those in males and are compartmentalized by fibrous septae that form radial and arch-like structures. Nurnberger and Muller 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). didactic mesotherapy courses for physicians as well as nonphysicians. gender-based structural differences in the organization of female subcutaneous fat that produce the pits and dells characteristic of cellulite (19. Such agents include isoproterenol. i. it is important to understand what physiologic changes produce this phenomenon (17). There is currently no definitive explanation for the physiology of cellulite.e. carnitine Connective tissue dissolution: collagenase. mesotherapy’s efficacy is distinctively ambiguous. is particularly timely.
54). a recent review evaluating mesotherapy has not found any peerreviewed reports in the English literature demonstrating efficacy of this treatment for cellulite (7). The level of cAMP. b3 and a2. body region and degree of adiposity during normal and pathologic circumstances. This unique characteristic is believed to play a key role in determining body fat topography. 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. a characteristic that helps to determine the metabolic rate of adipocytes and. Lipolysis (lipolysis/fatty acid oxidation) and lipogenesis (lipid synthesis) are two critical and basic metabolic functions of adipocytes that occur continuously throughout the life of the cell (30). The three b-ARs transmit a lipolytic signal. which is also triggered by epinephrine. By contrast. Adipose tissue shows significant regional differences in catecholamine responsiveness.16). therefore.40). This characteristic has been attributed. The most potent regulators of lipolysis and TG mobilization in humans are the catecholamines. 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. there is currently no scientific. Caffeine and theophylline are an adenosine antagonist (60). Adenosine exerts its effect on adipocytes via inhibition of AC and the production of cAMP (59). and thyroxine (7. It has been assumed that pharmacologic agents that increase localized lipolysis should tip the balance towards lipid loss.35. Inhibition of lipolysis (antilipolysis) is mediated by a2-AR. Thus. or size. which varies according to gender. In fact. lipolysis should not be confused with apoptosis. b2. In non-pathologic states.47). which are mainly responsible for mediating the catecholamine signal. the process by which adipocytes undergo programmed cell death. theophylline and aminophylline. which are derived from either endocrine or neuronal sources (33). Specifically. and ultimately determines adipocyte volume (30). 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). race and age.48). aminophylline. thereby resulting in the predominance of smaller fat cells. which is constitutively active at baseline. an important second messenger in this pathway. phosphodiesterase (PDE)-inhibitors. the same ligand that stimulates b2-AR action (46. Of these. insulin is the most potent anti-lipolytic hormone in human adipocytes (53.49). the volume. Activated cAMPdependent protein kinase phosphorylates HSL. Of note. whereas a2-AR transmits the antilipolytic signal (32. age. caffeine. gender. 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.Cellulite and injectables theophylline. adipocytes are the only cell type with both agonistic and antagonistic ARs on its surface (36. which in turn activates and increases cAMP phosphodiesterase 3B (32). Understanding the complex system that controls lipolysis is essential if meaningful investigations that explore the potential role of mesotherapy as a treatment for cellulite are to be performed. Interestingly. epinephrine inhibits lipolysis in some anatomic locations (subcutaneous fat) while it stimulates it in others (visceral fat) (36. forskolin. thereby contributing to a greater pool of cAMP and increased basal lipolysis (55). which. which mediates a strong anti-lipolytic and vasodilatory effect in adipose tissue via its own adenosine A1 transmembrane receptor (56–58). It mediates its effect by triggering its own insulin receptor. Downloaded By: [University of Pittsburgh] At: 23:52 24 July 2007 Mesotherapy and cellulite Despite the purported claims. ligand activation of anti-lipolytic a2-ARs suppresses AC. the b2-AR is the major lipolytic subtype with epinephrine acting as the primary ligand (37). b1. of the tissue (34–38). HSL. In addition to catecholamines. in turn.32). a process that ultimately leads to a decrease in HSL activity and reduced lipolysis. Another mechanism for lipolytic control involves adenosine. The balance of lipolysis and lipogenesis varies according to anatomic location. generates a cytosolic pool of cyclic adenosine monophosphate (cAMP) and the subsequent activation of 149 cAMP-dependent protein kinase. When triggered by phosphorylation during lipolysis. ultimately determines the degree of HSL phosphorylation. the rate-limiting enzyme in the liploytic pathway (32. other hormones play an important role in triggering lipolytic or antilipolytic responses that involve cAMP. to the four adrenoreceptor (AR) subtypes. turn off tonic cAMP hydrolysis by PDE. The net degree of lipolysis is determined by the interplay of stimulatory (lipolytic) and inhibitory (anti-lipolytic) pathways. thereby consuming b-AR-mediated increases in cAMP and rapidly reversing HSL activation.39). By contrast. 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). Ligands that bind the stimulatory b-ARs trigger adenylate cyclase (AC). such as common mesotherapy ingredients. in part.48–52). epinephrine and norepinephrine. peer-reviewed investigation in the English literature which demonstrates efficacy of traditional mesotherapy formulations for any medical or cosmetic condition .
Significant increase in FFA oxidation over physiologic levels at rest and during exercise after ingestion of caffeine (100–103). FFA: free fatty acid. Raises cAMP by: inhibiting PDE (79).83). and in vivo (34. Downloaded By: [University of Pittsburgh] At: 23:52 24 July 2007 Ingredient Isoproterenol Proposed mechanism Increases lipolysis. aminophylline increases cAMP (78). Also augments cAMP by antagonizing adenosine (76. Hyaluronidase Coumarin (benzopyrone) Disruption of dermal connective tissue thought to produce surface irregularities Augments circulation (84. theophylline increases cAMP (75). 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). Modest (5% with respect to initial levels) but statistically significant reduction of arm lymphedema in patients treated with oral coumarinic extract of melilotus (120). placebo-controlled study (89). in part due to preventing FFA accumulation (83). stimulation of tissue macrophages. Caffeine Thyroxine Carnitine Collagenase Dissolution of fibrous bands and septae that are thought to influence surface dimpling (26–28). Augments circulation.150 A. which is a potent vasorelaxant.121). a hydrophilic polysaccharide found in human skin. increasing catecholamine release (epinephrine) by the sympathetic nervous system (80).91–94) after local isoproterenol infusion. Carnitine increases delivery rate of long-chain FFAs into mitochondria for b-oxidation (82. thereby raising cAMP (74). Improves circulation.106). Improves erythrocyte deformability and reduces blood viscosity in vitro (90). Use of coumarin combined with physical therapy reduces limb lymphedema more than either treatment alone (118). Addition of theophylline with human fat increases lipolysis in vitro (98) and in vivo (75). Forskolin(extracted from the herb Coleus forskohlii) Theophylline Aminophylline Augments lipolysis in adipocytes exposed to aminophylline in vitro (78.111). potent vasodilator. which is also a soft tissue cosmetic filler. Increases lipolysis. Collagenase is the major collagenolytic enzyme responsible for collagen damage in photoaging (110.77). However. 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). diterpenes. Directly activates AC independent of ARs.99). increases proteolysis and reduces excess protein (86. Ginko biloba also acts as a vasomodulator (89). Ginko extracts enhance peripheral and cerebral circulation (88. M. Clinical reduction after collagenase injection into human lipomas (112). Increases lipolysis.87). However. inhibits platelet activating factor and decreases platelet aggregation (88. Proposed mechanism and the experimental basis for using the common mesotherapy ingredients for cellulite. Reduces volume of chronic high-protein edema. AR: adrenoreceptor. Augments lipid oxidation (82. is degraded by hyaluronidase in vitro (113) and in vivo (114). mean skin blood flow significantly reduced in subjects receiving oral ginkgo extract in a recent randomized. Regional forearm blood flow significantly increased in double-blinded placebo-controlled study with patients receiving 6 weeks of an oral ginko biloba extract (122). double-blind. PDE: phosphodiesterase. As a selective b-AR agonist. Artichoke extract Hyperthyroidism leads to enhanced local response of adipose tissue to norepinephrine levels in vivo (104.83). As a non-selective PDE inhibitor. and antagonizing adenosine (60). Experimental support Concentration-dependent increase in FFA and/or glycerol release in human adipocytes in vitro (73). Increases lipolysis. In vitro collagenase digestion is a common technique for adipocyte isolation that does not adversely affect cell survival (107–109). Reduces reperfusion injury in vivo by preserving endothelial cell vasorelaxation in rabbits (123). Natural source of coumarins (119). Augments circulation. An active constituent. As a PDE inhibitor. A fifty-study meta-analysis of oral and topical coumarin demonstrates significant reduction in symptoms of limb edema (117). AC: adenylate cyclase. 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.85). Rotunda et al. Table II. Increases lipolysis. cAMP: cyclic adenosine monophosphate. no evidence that oral carnitine supplementation improves exercise performance or weight loss in humans (82. Oral and intravenous L-carnitine demonstrates cardioprotective effects after myocardial infarction. NO: nitric oxide. . the local in situ effects are transient and occur at much lower concentrations than those in circulation (95). Augments circulation. Hyaluronic acid.89). Augments lipolysis (81). Melilot (Melilotus officianalis or sweet clover) Ginko biloba Pentoxyphylline Augments circulation.105). No effect on skin flap survival in animals receiving oral pentoxifylline (124) but parenteral pentoxifylline plus topical nitroglycerin positively influence flap survival (125). isoproterenol stimulates b-AR and increases cAMP (73).
it may be argued that agents such as collagenase and hyaluronidase are reasonably appropriate in mesotherapy cellulite treatments. Iotti E. Although several of the commonly used ingredients have a theoretical potential to produce localized lipolysis and/or disrupt connective tissue. Donini I. Downloaded By: [University of Pittsburgh] At: 23:52 24 July 2007 . This technique utilizes dialysis probes implanted in subcutaneous fat for continuous monitoring of interstitial or extracellular metabolites. Nevertheless. in some cases. it is conjecture whether this treatment is effective. Second. coumarin.10:539–42. As noted earlier.62). the vasodilator (buflomedil) and homeopathic (carnitine and melilotus) treatments did not produce any effect (63). 1988. It is also important to reiterate that lipolysis does not produce a permanent effect. Mesotherapy in the treatment of lymphedema: histologic and ultrastructural observations. cellulite is thought to result primarily from underlying connective tissue anatomy. During several studies in which effects of the catecholamine isoproterenol was measured over several hours using microdialysis. can affect the appearance of cellulite. such as apoptosis. and. A lasting effect on fat cell volume by mesotherapy-mediated adrenergic stimulation or inhibition of PDE/adenosine pathways has not been proven. urticaria pigmentosa (68). however.71). the role of pentoxyphylline. in all likelihood. it is unknown whether these effects translate clinically. it is unknown whether these effects are clinically significant. Most of the published literature regarding mesotherapy describe adverse events. and hyperpigmentation (72). which was recently presented at the American Society of Plastic Surgery Annual Meeting. Therefore. which initially increased. 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 adenosine in vitro and in vivo). lipolysis triggers an acute metabolic response that is. may even make it worse (128). Marinoni E. and a number of circulation-enhancing herbs for cellulite is tenuous at best. What is mesotherapy? Chir Dent Fr. Mesotherapy with naproxin sodium in musculoskeletal diseases. this notion relies upon several assumptions. et al. this theoretical assumption has yet to be proven through clinical trials.95). Tachyphylaxia to catecholamines has been attributed to desensitization of the AR system (129). 1976. 1982. Although it is acknowledged that increased adiposity due to weight gain may make cellulite more evident and that weight loss may help improve its appearance (19. These treatments may expose patients to unforeseen risks as they seek the elusive ‘cure’ for a cosmetically disturbing but medically benign condition. patients considering mesotherapy for cellulite must be aware that the substances being injected have not been thoroughly evaluated for safety or efficacy. drug eruptions (70.28). In accord with the proposition that effective cellulite treatments should be directed towards chemically or physically weakening connective tissue (26). Rather. the often-repeated speculation that promoting ‘lymphatic drainage’ and increasing local circulation to attenuate cellulite has not been established. 2. 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). transient. demonstrated significant waist and thigh reductions restricted to patients receiving subcutaneous injections of a phosphatidylcholine formulation. It is important to note that liposuction. it assumes that localized lipolysis in the subcutaneous fat. including mycobacterial infection (64–66). a rationale to remain cautiously optimistic. A double-blinded clinical trial evaluating ‘mesoplasty’. Conclusion Until clinical studies are performed that validate the use of mesotherapy ingredients for cellulite. subcutaneous nodules (69). which should theoretically reduce the size of adipocytes in this area. after exposure to pharmacological agents.16. returned to or approximated the basal rate despite repeated injections of increasing catecholamine doses (91. koebnerization of psoriasis (67). such as glycerol (a sensitive marker for lipolysis). For agents that augment lipolysis and disrupt connective tissue. References 1. First. the most effective method for removing fat and disrupting subcutaneous connective tissue. Riv Eur Sci Med Farmacol.26. rather than from an excess of adipose tissue reserves (19.95).61. Thus.30:25–34. De Anna D. Objective data such as this confirms the theoretical potential of some ingredients to produce localized lipid breakdown. A number of published studies have examined the effect of lipolytic agents on human adipose tissue in vivo using microdialysis (91.21). There is.46: 59–60.Cellulite and injectables (7. fat destruction alone does not ameliorate the structural reasons that produce cellulite. has minimal effect on improving the appearance of cellulite. 3. Carella G. Pistor M. Until further studies are performed. both thin and obese females display cellulite. gross changes from 151 infusion of isolated or combinations of lipolytic agents have not been reported. Finally. Yet again. Chir Patol Sper. Reports of these reactions may increase over time if physician and non-physicians unfamiliar with cutaneous anatomy and proper injection technique embrace this modality as a therapy for cellulite. The role of impaired lymphatic drainage as a cause of cellulite is speculative. Guazzetti R. the degree of lipolysis.
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