CHAPTER 1 - DEFINITION, HISTORY AND NOMENCLATURE

CHAPTER 2 - ONLINE QUESTIONNAIRE FOR CELLULITE CLASSIFICATION

CHAPTER 3 - LIPEDEMA: DESCRIPTION, DIAGNOSIS AND TREATMENT

CHAPTER 4 - ANATOMY OF THE GLUTE REGION APPLIED IN PRACTICE

CHAPTER 5 - GLUTE SHAPING

CHAPTER 6 - INJECTABLE CELLULITE TREATMENTS

CHAPTER 7 - LASER-LIPO: INVASIVE TECHNOLOGY

CHAPTER 8 - OTHER CELLULITE TREATMENTS

CHAPTER 9 - BIOSTIMULATORY EFFECTS OF MICROSPHERE INJECTIONS INTO OVERLYING SKIN STRUCTURES

CHAPTER 10 - INFLUENCE OF HORMONES ON CELLULITE: WITH EMPHASIS ON ADIPONECTIN

CHAPTER 11 - GOLDINCISION®: A MULTIFACTORIAL APPROACH TO THE TREATMENT OF CELLULITE

CHAPTER 12 - STAINS POST-GOLDINCISION®

CHAPTER 13 - ADVERSE EFFECTS AND COMPLICATIONS IN GOLDINCISION®

Cellulite is a complex and multifactorial condition; its etiopathogenesis is still unclear, however it is known that it can be influenced by several predisposing factors – triggers, perpetuators and exacerbators. Lifestyle, hormonal action (especially the estrogen hormone in women), adipose tissue – its disposition, endocrine function and architecture –, as well as changes in blood microcirculation and inflammatory processes, are the main factors involved in cellulite.

Women

Women are the major target of the oft-maligned cellulite. Some women are more bothered, others not so much; a minority of women do not suffer from this condition. Although there are some already well-elucidated factors as to why cellulite more often occurs among women, the fact is that it is enough to be a woman (and consequently to have circulating estrogen) to have cellulite. In addition to the important role of estrogen, the accumulation of fat in the hips, gluts and thighs, as well as the architecture of the female adipose tissue, all contribute to the higher occurrence among women.

Lifestyle

Life habits considered unhealthy are completely associated with the emergence and worsening of cellulite. The excessive intake of food with high fat, salt and preservative content is linked to the development of several metabolic disorders, including hyperinsulinemia – a condition that worsens cellulite. A sedentary lifestyle, in turn, plays a similar role: lack of regular physical activity weakens the muscular layer of blood vessels and causes local hemostasis. This condition leads to hypoxia and ischemia of the adipose tissue, perpetuating and aggravating cellulite.

Alcohol consumption stimulates lipogenesis and causes the dehydration of all body cells, resulting in excessive and inadequate fat storage. Smoking generates a significant increase in free radicals in the body and vasoconstriction of the microcirculatory network. All these factors contribute to the development of cellulite, as well as to its progression and clinical worsening.

Emotional disturbances, such as stress, cause an increase in catecholamines (adrenaline and noradrenaline), which, in high concentrations, stimulate lipogenesis. Some authors classify cellulite as a psychosomatic alteration, suggesting that circulatory and hormonal changes in the hypothalamic centers originate the metabolic alterations. These centers could be affected by frustration, anxiety, depression and stress (PINTO et al., 2002).

Hormones

Female sex hormones play a fundamental role in the genesis of cellulite; they are one of the explanations for the overwhelming occurrence in women. The first signs of alteration in adipose tissue begin at puberty, when there is a physiological increase in estrogen, considered by many authors to be the great villain and initial trigger for the evelopment of cellulite.

The increase in estrogen in the early phase of puberty activates the phase of differentiation of secondary sexual characters. In women, due to the presence of estrogen receptors in adipocytes, these cells replicate and adipose tissue accumulates in typically feminine fat areas – hips, glutes, and thighs.

Estrogen also activates the menstrual cycle and all the cyclic changes arising from it. The worsening of cellulite during menstruation is expected due to fluid retention and weight gain observed in this phase of the month, all especially orchestrated by the physiological increase in the hormone estrogen during this period.

The worsening of cellulite is also noted during pregnancy, in which there is a substantial increase in circulating estrogen. A similar situation occurs in estrogen therapies, with the exogenous use of estrogen, as in treatments with oral contraceptives, for instance. The more circulating estrogen, the greater the replication of adipocytes and the greater
accumulation of body fat. The more body fat, the greater the number of estrogen receptors with the possibility of greater adipocyte replication. This vicious estrogen-adipocyte-fat accumulation-estrogen cycle can explain the worsening of cellulite in conditions of hyperandrogenism and body weight gain.

The very low or absent levels of circulating estrogen in men is one of the explanations for the much lower presence of cellulite among the male population. However, this condition can occur in individuals with androgen deficiency, such as Klinefelter syndrome (XXY), in situations of hypogonadism and in patients who use estrogen therapies for prostate cancer.

Although the primary function of adipose tissue is associated with fatty acid metabolism, it also has many endocrine functions. Substances secreted by adipocytes – known as adipocytokines – include leptin; adiponectin; angiotensinogen; resistin; tumor necrosis; factor α receptor (TNF-α); interleukin-6 (IL-6); insulin-like growth factor (IGF-1); lipoprotein lipase (LPL), among others. The secretion of these adipocytokines has paracrine and/or endocrine effects, affecting the metabolism of the connective tissue, which involves endothelial function, inflammation and the deposition of the extracellular matrix itself.

In 2011, Emanuele et al. identified the reduced production and release of adiponectin mRNA in tissues affected by cellulite, compared to adipose regions without it. Adiponectin is an adipocytokine secreted exclusively by adipose tissue and plays a role in improving blood circulation, being a potent vasodilator, anti-inflammatory and antiatherogenic agent. Low levels of this peptide are observed in cases of obesity, diabetes, arterial hypertension and coronary disease, while high concentrations are documented in cases of longevity.

Body fat and sagging skin

Studies show that women with cellulite have greater total or regional body fat than women without this condition. Overweight and obesity are factors that worsen cellulite, however they are not triggering factors. Some studies show that significant weight loss does not necessarily promote clinical improvement in cellulite. An investigation conducted by Smalls et al. (2006) quantitatively examined cellulite in women who underwent major weight loss processes monitored by physicians.

Most of the patients analyzed presented improvements in cellulite with weight loss, but the condition worsened for others. The improvement was associated with significant reductions in weight and thigh fat percentage, baseline Body Mass Index (BMI), and significantly greater baseline severity. Cellulite worsened with considerably lower baseline BMI, smaller reductions in weight accompanied by no change in thigh fat percentage, and marked increases in skin sagging.

Rudolph et al. (2019) recently published a study that investigated sex-specific differences in the architectural arrangement of adipose tissue in the gluteal region and its biomechanical properties. This study has relevant implications when it comes to understanding the pathophysiology of cellulite. With regard to sagging skin and its relationship with cellulite, the thinner the skin, the greater the propensity for the appearance and worsening of this condition. Therefore, it can be concluded that men and women equally show a significant thinning of the dermis thickness of 0.3% per year, regardless of BMI. In other words, the greater the age, the thinner the skin; therefore, the greater the sagging and the more apparent the cellulite.

Adipose tissue

In addition to the endocrine function of adipose tissue and the intimate relationship between body fat accumulation and cellulite, the difference in the architecture of the female and male adipose layer is one of the pillars for understanding this condition. One of the most accepted theories about the etiopathogenesis of cellulite is based on this difference – the Anatomical Theory, published by Nürnberger and Müller in 1978.

If cellulite were merely the expression of excess adipose tissue (as some scholars tried to defend until the 70’s), why, then, would this condition occur almost exclusively among women and only in certain body regions?

It was exactly these questions that two German doctors, Nürnberger and Müller, attempted to answer with their famous publication in 1978, which became the famous Anatomical Theory, which explain the genesis of cellulite based on the peculiarities of the architecture of the female subcutaneous tissue. After a histopathological examination of 180 samples (150 in cadavers and 30 in vivo) of subcutaneous tissue with cellulite, the authors did not find edema and/or fibrosis phenomena – which were the accepted theories by then.

This work attributed cellulite to the combination of two causal factors: excess fat (supporting the idea that there is no cellulite without adiposity) and the anatomical peculiarities of the female subcutaneous tissue. While the examinations of male tissue found fat lobules with collagen fibers arranged obliquely to the surface of the skin, forming a highly interconnected network, the feminine tissue showed collagen
fibers arranged perpendicularly to the surface of the skin, forming a less densely connected network, with voluminous and rectangular fat lobules projecting towards the dermis and forming the characteristic undulation of cellulite.

Architectural differences between male and female subcutaneous tissue continued to be the subject of studies. Querleux et al. analyzed 70 individuals through nuclear magnetic resonance (NMR), using imaging and spectrometry. The study confirmed the difference in the orientation of collagen fibers between men and women, although it did not consider it as extreme as described by Nürnberger and Müller. In 2004, Mirrashed et al., using MRI images, reinforced the herniation of female fat lobules towards the skin as fundamental in the cellulite  process. Furthermore, this study brought to light two important concepts: the first is that a BMI above 30 kg/m2 is not directly related to the appearance of cellulite; the second suggests that the constitutional thinness and looseness of the skin and of the viscoelastic fibers present in the subcutaneous tissue are also pathogenic elements for cellulite.

A multicentric analysis published in 2019 thoroughly investigated the structure and biomechanical resistance of the subcutaneous tissue, focusing on the pathophysiology of cellulite. The study analyzed 20 biopsy samples from the subcutaneous gluteal region (10 from men and 10 from women, all Caucasians, with ages ranging from 36 to 92 years and BMI ranging from 16.70 to 40.80 kg/m2). Although the study case pool was not large, the results were extremely valuable for understanding cellulite. Five different layers were identified until reaching the gluteus maximus muscle: dermis, superficial fat, superficial fascia, deep fat and deep fascia, equally for both sexes. As already known, the fat lobules are enclosed by connective tissue fibers, forming a honeycomb structure. In the female samples, the amount of fat lobules was significantly lower, however these were bulkier and heavier compared to the male subcutaneous tissue.

This study also analyzed the force required for the lobe of fat to break through the fibrous septum and project itself towards the dermis. Septal rupture in male samples required a statistically higher force than in females. This means that the smaller the force required for the septal rupture, the greater the ease of projection of the fat lobe towards the dermis and the greater the propensity for cellulite. With regard to BMI, some points were clarified. The study showed that the higher the BMI, the greater the size and weight of the fat lobules and, therefore, the greater their projection towards the overlying skin.

Quite recently, in 2021, Whipple et al. evaluated the anatomical grounds for the formation of cellulite by means of an ultrasound examination of the undulations themselves. Of 173 cellulites examined, 169 (97.68% of cases) were associated with the presence of a fibrous septum forming the lesion. Querleux et al., in 2002, using NMR images, had already demonstrated that cellulite areas had a high concentration of fibrous septa in the subcutaneous tissue compared to areas without cellulite. The presence of septa contributes to the clinical worsening of the lesions, even among very thin patients. The association of cellulite with fibrous septa is very significant data, especially with regard to the choice of therapeutic method to address this condition. It is known that the only effective treatment for fibrous septa is their rupture through subincisions.

Based on the Anatomical Theory and on all publications about the peculiarities and architectural differences of male and female subcutaneous tissues, one may conclude that cellulite is an imbalance between the forces of containment and extrusion in the subdermal junction. Regardless of BMI and age, women are more prone to cellulite formation due to reduced biomechanical stability in the subcutaneous tissue architecture compared to men. Added to this, the presence of fibrous septa in greater concentration in cellulitic areas contributes to the aggravation of the lesions. Along with the Anatomical Theory, there are two other theories that attempt to clarify the etiopathogenesis of cellulite: the Microcirculatory Theory and the Inflammatory Theory.

The association of cellulite with changes in blood microcirculation was initially proposed by the angiologist Merlen J.F. in 1958; and then once again published by Merlen together with fellow angiologist Curri S.B. in the French journal Phlebologie in 1979. They proposed the nosological classification of cellulite as a microvascular connective tissue disease. They understood it as a dermohypodermosis and an edematous-sclerotic panniculopathy.

Binazzi contributed to the strength and popularity of this theory after histologically evaluating a series of samples and identifying variations in adipocyte size and shape, dermal edema, lymphatic vessel dilation, and hyperfollicular keratosis. Under normal conditions, in the capillaries, the arterial system joins the venous system in such a way that the blood is never free in the tissues. In the connecting area, the vessels allow the interstitial liquid (which surrounds all the cells of the body) to be filtered. What is left of this liquid is collected by the lymphatic vessels, in a process known as lymphatic drainage.

In the subcutaneous tissue with cellulite, due to alterations in the arteriolar pre-capillary sphincters and the deposit of glycosaminoglycans in the wall of the dermal capillaries and between the collagen fibers, microcirculation is hampered. This is followed by an increase in pressure in the capillaries, which also results in an increase in the permeability of the capillaries as well as of the venules and, finally, the retention of liquid in the dermis.

According to the Microcirculatory Theory, inadequate lymphatic drainage, allowing fluid retention in the dermal interstitium, is the first alteration in the etiopathogenesis of cellulite. The dermis becomes permanently infiltrated by interstitial fluid and its residues, leading to a state of edema. The edema compresses the capillaries, thus hampering venous return. This accentuates stasis and vascular permeability, worsening the edema. Thus, a vicious circle is established in which “cellulite causes cellulite itself”.

The Microcirculatory and Inflammatory Theories intertwine in some points. It so happens that the deposit of glycosaminoglycans on the capillary wall, a situation that hinders blood and lymphatic microcirculation, also triggers the release of pro-inflammatory cytokines and the recruitment of inflammatory cells to the cellulite site.

The first publications on cellulite, in the 1920s, already described it as an inflammatory skin disease. However, it was more recently that the Inflammatory theory gained emphasis – with a better understanding of inflammatory diseases themselves, as well as the inflammatory nature of multiple conditions and situations, such as, for example, plurimetabolic syndrome, some cancers, or even a diet based on junk food.

The publication by Gruber and Huber, in 1999, sounded an alarm in the medical community, especially among gynecologists, regarding the need for these specialists to adopt multidisciplinary approaches, especially with regard to hormonal action. It was shown that ovarian hormones are involved in the genesis or worsening of several diseases (autoimmune, vascular, dyslipidemic, etc.), including cellulite. In 2005, Draelos Z. et al. reinforced the relationship between ovarian hormones and inflammation, demonstrating that the chronic inflammatory process in women results from the activation of estrogen and the deposit of glycosaminoglycans by dermal fibroblasts.

In the Inflammatory Theory, estrogen plays a key role in the etiopathogenesis of cellulite. Estrogen is considered the initial trigger of this process and the protagonist in the evolution, perpetuation and worsening of lesions. Since adipocytes are full of estrogen receptors, this hormone performs a lipogenic action on adipose tissue, activating adipocyte replication and fat accumulation in the hips, glutes and thighs. The greater the accumulation of fat, the greater the amount of estrogen receptors and the greater the action of this hormone in the adipose tissue itself. Estrogen also exerts a hydrophilic action on this tissue, leading to the accumulation of interstitial fluid, an edema which, in turn, triggers the entire cascade of microvascular changes in the etiopathogenesis of cellulite. In both actions of estrogen on adipose tissue – lipogenic and hydrophilic –, there is a vicious cycle in which “cellulite causes cellulite itself”.

A study published in 2020 identified muse cells (multilineage of differentiated stress-resistant cells) in tissue affected by cellulite. Muse cells are pluripotent, stress-tolerant mesenchymal stem cells with a special ability to regenerate. According to Conti et al. (2020), this regenerative capacity plays an important role in the modification of adipose tissue and is considered the first step in the cascade of events involved in the etiopathogenesis of cellulite.

According to the hypothesis raised by this study, muse cells, after estrogen stimulation, activate the entire biochemical cascade of prostaglandin production, cyclooxygenase expression and metalloproteinase and elastase stimulation. These inflammatory cytokines stimulate fibroblasts, which, in turn, increase the formation and deposit of fibrotic collagen in the adipose tissue septa, thus aggravating the case of cellulite. This is yet another vicious circle (cellulite – muse cells – estrogen – inflammatory cascade – fibroblasts – fibrotic collagen – cellulite), in which “cellulite causing cellulite itself”.

The conclusion, after an extensive literature review, is that cellulite is a dystrophic process of the adipose tissue, resulting from multiple interconnected factors, which act by multiple mechanisms on various target elements within adipose tissue itself. There is no one theory that trumps all others. What is clearly concluded is that all published theories complement each other and are involved in the etiopathogenesis of cellulite. However, there are still questions on what the initial trigger of the process would be. What could be the first event in the cellulite formation cascade? Would this first step be the same for all women? Why do some women have cellulite while others don’t?

Alquier L. Ce qu’est la cellulite: comment la traiter? Monde Méd, 1949, déc. 59 (960): 344. (Revue classée au dossier cellulite).
Amore R, Amuso D, Leonardi V, Sbarbati A, Conti G, Albini M, Leva F, Terranova F, Guida A, Gkritzalas K, Gavashely L, Velichenko R. Treatment of Dimpling from Cellulite. Plast Reconstr Surg Glob Open. 2018 May 18;6(5):e1771.
Bass LS, Kaminer MS. Insights Into the Pathophysiology of Cellulite: A Review. Dermatol Surg. 2020 Oct;46 Suppl 1(1):S77-S85.
Bass LS, Kaminer MS. Insights Into the Pathophysiology of Cellulite: A Review. Dermatol Surg. 2020 Oct;46 Suppl 1(1):S77-S85.
Christman MP, Belkin D, Geronemus RG, Brauer JA. An Anatomical Approach to Evaluating and Treating Cellulite.
J Drugs Dermatol. 2017 Jan 1;16(1):58-61.
Conti G, Zingaretti N, Amuso D, Dai Prè E, Brandi J, Cecconi, D, Manfredi M, Marengo E, Boschi F, Riccio M, Amore R, Iorio EL, Busato A, De Francesco F, Riccio V, Parodi PC, Vaienti L, Sbarbati A. Proteomic and Ultrastructural Analysis of Cellulite-New Findings on an Old Topic. Int J Mol Sci. 2020 Mar 18;21(6):2077.
Curri SB, Merlen J.F. Microvascular disorders of adipose tissue. J. MalVasc. 1986; 11, 303–309.
de la Casa Almeida M, Suarez Serrano C. Rebollo Roldán J, Jiménez Rejano JJ. Cellulite’s aetiology: a review. J EurAcad Dermatol Venereol. 2013 Mar;27(3):273-8.
Draelos Z. The disease of cellulite. J. Cosmet. Dermatol. 2005, 4, 221–222.
Emanuele E, Minoretti P, Altabas K, Gaeta E, Altabas V. Adiponectin expression in subcutaneous adipose tissue is reduced in women with cellulite. Int J Dermatol. 2011 Apr;50(4):412-6.
Ghigi R. Le corps féminin entre science et culpabilisation. Autour d’une histoire de la cellulite. Travail, genre et sociétés, vol. 12, n. 2, 2004, p. 55-75.
Godoy JM, de Godoy Mde F. Evaluation of the prevalence of concomitant idiopathic cyclic edema and cellulite. Int J Med Sci. 2011;8(6):453-5. doi: 10.7150/ijms.8.453. Epub 2011 Aug 2.
Gruber DM, Huber JC. Gender-specific medicine: the new profile of gynecology. Gynecol. Endocrinol. 1999, 13, 1-6. Lageze P. Sciatique et infiltrate cellilalgique, Thèse Med., Lyon, 1929.
Laroche G, Vacher H. Cellulite et troubles endocriniens. Gaz. Med. Fr., 1935, (12):523-532.
Layt C. A Study of a Novel Controlled Focal Septa Release Method for Improving Cellulite. Plast Reconstr Surg Glob Open. 2022 Apr 8;10(4):e4237.
Littré E, Robin, Ch. Dictionnaire de médecine, de chirurgie, de pharmacie, de l’art vetérinaire et des sciences qui s’y rapportent, 13.ed. Paris, Baillière et Fils, 1873.
Merlen JF. La cellulite. Entité Clinique et mecésisme pathogènique. Cone. Med., 10 mai 1958, 80, n.19, 2311-2317.
Merlen JF, Curri, B. et al. La cellulite, affection microvasculo conjonctive. Phlébologie, 1968, 32(3):279.
Merlen JF, Curri SB. Anatomico-pathological causes of cellulite. J. MalVasc. 1984, 9, 53–54.
Nürnberger F. Practically important diseases of the subcutaneous fatty tissue (including so-called cellulite). Med. Welt. 1981, 32, 682–688.
Nürnberger F, Müller G. So-called cellulite: an invented disease. J. Dermatol. Surg. Oncol. 1978, 4, 221–229.
Paschoal LHC, Cunha MG. Fisiopatologia e Atualização Terapêutica da Lipodistrofia Ginoide Celulite. 2.ed. Revisada e ampliada. 2012, DiLivros.
Paviot J. Cellulagie. J. Méd. Lyon, 1929, 10.
Paviot J. Les cellulites, leurs rapports avec les troubles hépatodigestifs, leurs terrains, J. Méd. Lyon, 1926, 7.
Pérez Atamoros FM, Alcalá Pérez D, Asz Sigall D, Ávila, Romay AA, Barba Gastelum JA, de la Peña Salcedo JA, Escalante Salgado PE, Gallardo Palacios GJ, Guerrero-Gonzalez GA, Morales De la Cerda R, Ponce Olivera RM, Rossano Soriano F, Solís Tinoco E, Welsh Hernández EC. Evidence-based treatment for gynoid lipodystrophy: A review of the recent literature. J Cosmet Dermatol. 2018 Dec;;17(6):977- 983.
Quatresooz P, Xhauflaire-Uhoda E, Piérard-Franchimont C. and Piérard GE. Cellulite histopathology and related mechanobiology. International Journal of Cosmetic Science, 28: 207-210, 2006.
Rossi ABR, Vergnanini AL (2000). Cellulite: a review. Journal of the European Academy of Dermatology and Venereology, 14: 251-262.
Rudolph C, Hladik C, Hamade H, Frank K, Kaminer MS, Hexsel D, Gotkin RH, Sadick NS, Green JB, Cotofana S. Structural Gender Dimorphism and the Biomechanics of the Gluteal Subcutaneous Tissue: Implications for the Pathophysiology of Cellulite. Plast Reconstr Surg. 2019 Apr;143(4):1077-1086.
Scherwitz C, Braun-Falco O. So-called cellulite. J Dermatol Surg Oncol. 1978 Mar;4(3):230-4.
Schonvvetter Bianca, Soares Juliana Laudicéia Marques, Bagatin Ediléia. Longitudinal evaluation of manual lymphatic drainage for the treatment of gynoid lipodystrophy. An. Bras. Dermatol. 2014 Oct;; 89(5): 712-718.
Smalls LK, Hicks M, Passeretti D, Gersin K, Kitzmiller WJ, Bakhsh A, et al. R. Effect of Weight Loss on Cellulite: Gynoid Lypodystrophy. Plast Reconstr Surg. 2006;118:510-6.
Terranova F, Berardesca E, Maibach H. Cellulite: nature and aetiopathogenesis. Int J Cosmet Sci. 2006 Jun;28(3):157-67.
Tokarska K, Tokarski S, Woźniacka A, Sysa-Jędrzejowska A, Bogaczewicz J. Cellulite: a cosmetic or systemic issue? Contemporary views on the etiopathogenesis of cellulite. Postepy Dermatol Alergol. 2018 Oct;35(5):442-446. doi: 10.5114/ada.2018.77235. Epub 2018 Jul 19. PMID: 30429699; PMCID: PMC6232550.
Whipple LA, Fournier CT, Heiman AJ, Awad AA, Roth MZ, Cotofana S, Ricci JA. The Anatomical Basis of Cellulite Dimple Formation: An Ultrasound-Based Examination. Plast Reconstr Surg. 2021 Sep 1;148(3):375e-381e.