Review DOI: 10.6003/jtad.19134r1 Paradoxes in Aesthetic Dermatology

Ümit Türsen,* MD

Address: *Mersin University, School of Medicine, Department of Dermatology, Mersin, Turkey E-mail: [email protected] Corresponding Author: Dr. Ümit Türsen, Mersin University, School of Medicine, Department of Dermatology, Mersin, Turkey

Published: J Turk Acad Dermatol 2019; 13 (4): 19134r1. This article is available from: http://www.jtad.org/2019/4/jtad19134r1.pdf Keywords: Aesthetic Dermatology, Anti Aging, Brimonidine, Laser,Paradoxes

Abstract

Background: Various paradoxical phenomena related to aesthetic dermatology including paradoxes of Q-switched laser-induced tattoo darkening, (IPL) and laser-induced , paradoxical adipose hyperplasia of post-cryolipolysis, paradoxes of androgenetic alopecia, sebaceous glands and aging skin, paradox of acne fulminans associated with isotretinoin treatment, paradoxical rosacea with topical calcineurin inhibitors, paradoxical erythema associated with brimonidine gel, paradoxical masseteric bulging, wrinkles and alopecia associated with botulinum toxins, paraben, lanolin, nail lacquer, exogenous ochronosis paradoxes have been described in the literature. While some of them can be explained logically, the cause for others can only be speculated. Whenever encountered in clinical practice, background knowledge of such paradoxes may be useful to the clinician. As reported previously, when paradoxes are suspected after aesthetic procedures, these therapies should be discontinued and the other alternative procedures are recommended.

Introduction while the and remain unchanged. This paradoxical effect of andro- A “paradox” is defined as a “seemingly absurd gen at different bearing sites is attributed or contradictory statement or proposition to the differentia[1]. Response of the follicular which when investigated may prove to be well dermal papillae to androgen stimulation in founded or true according to Oxford dictio- these sites. In response to androgen stimula- nary[1]. We can call these conditions as the tion, the dermal papillae in the region Janus effect (two faces of aesthetic dermato- secretes IGF1, which has a stimulatory effect logic treatments), Yin/Yang effect or Dual ef- on the hair follicles. On the scalp area, it sec- fects. There are some well-known paradoxes retes TGF-β1 that has an inhibitory effect on in aesthetic dermatology, some of which can the hair follicles. TGF-β1 activity is maximum be explained logically or based on evidence, in the anterior aspect of the scalp, especially while for some, only assumptions or postula- so, over the temples and hence, the develop- tes are put forth. Following are some of such ment of “patterned” [3]. paradoxes in aesthetic dermatology compiled Paradox of Sebaceous glands in aging skin: under caracteristics (Table 1), [1, 12,13,14,1 In the elderly, in spite of decreased output 5]. from sebaceous glands, which is attributed to Paradox of Androgenetic alopecia: At pu- decreased adrenal and gonadal androgen berty, the beard and other secondary sexual synthesis. Their size however, is increased grow, the scalp hair is gradually lost, owing to decreased cell turnover[15].

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Paradox of Aging Skin: In chronologically systemic corticosteroids to combat the early aging skin, the elastic fibers gradually lessen, crisis followed by systemic doxcycline in ad- most likely due to enzymatic degradation of dition of low-dose oral isotretinoin for 3-4 elastin. Together with decreased elastin, the months with the steroids being tapered off skin becomes wrinkled, saggy, and inelastic, gradually. However, isotretinoin must be due to decreased collagen synthesis. Parado- used with caution, as paradoxical induc- xically, the photo-aged skin shows focally in- tion/exacerbation of acne fulminans has creased elastin owing to UV-induced trans been reported[17,18]. criptional activation of the elastin gene and lysozyme-induced reduction in leukocyte Paradoxical topical calcineurin inhibitors elastase activity. Together with heliodermati- (TCIs)-induced rosacea: TCIs are relatively tis, photo-aged skin appears thick, dry, newer topical treatment modalities used for rough, deeply wrinkled, and inelastic owing the treatment of rosacea. However, reports of to the disarrangement of collagen and elastic rosaceiform dermatitis following long-term fibers[16]. usage of these agents have also been docu- mented. Topical immunosuppressive effects of the TCIs leading to overgrowth of Demodex Isotretinoin and acne fulminans: Acne ful- mites in skin together with their inherent va- minans is a severe form of acne with systemic soactive properties possibly act synergisti- features, that may occur in some predisposed cally leading to “iatrogenic rosacea. In this individuals as a hypersensitivity reaction to condition, oral doxycycline, minocycline, clin- Propionibacterium acnes. The treatment of damycin, metronidazole or lymecycline treat- choice is a sequential therapy beginning with ments are recommended[19].

Table 1. Paradoxes in Aesthetic Dermatology

Paradoxes Treatments

Paradox of Androgenetic Alopecia Hair transplantation, topical minoxidil, finasteride du- tasteride

Paradox of Sebaceous glands in aging skin Surgery, cryotherapy, electrocoterisation, peeling, lasers

Paradox of Aging Skin Surgery, cryotherapy, electrocoterisation, chemical pee- ling, lasers, topical retinoids, topical sunscreens Paradox of isotretinoin and acne fulminans Systemic corticosteroids and oral antibiotics

Paradoxical topical calcineurin inhibitors (TCIs)-induced Oral doxycycline, minocycline, clindamycin, metronida- rosacea zole or lymecycline Paradoxical Erythema Reaction of Long-term Topical Lasers, topical sunscreens, oxymetazoline cream Brimonidine Gel for the Treatment of Facial Erythema of Rosacea

Paradoxical Q-switched laser-induced tattoo darkening Other lasers like picosecond 532 nm and 1,064 nm laser

Paradoxical hypertrichosis [20]. Other lasers Paradoxical Adipose Hyperplasia After Cryolipolysis Surgical treatment (liposuction or abdominoplasty) or deoxycholic acid injection Paraben, lanolin and nail lacquer paradoxes Therapy should be discontinued

Exogenous ochronosis paradox Other bleaching agents

Paradoxic Masseteric Bulging after BTXA 5-10 U injection over superficial masseter

Paradoxal Wrinkles after forehead BTXA Additional botulinum toxin injection at hyperactivated muscles

Paradoxal Frontal Alopecia after Repeated BTXA Therapy should be discontinued [2,3,4,5,6,7,8,9,10,11,12,1,3,14,15]

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Paradoxical Erythema Reaction of Long- and neck. It occurs especially in individuals term Topical Brimonidine Gel for the Tre- with darker skin types (III-VI); with dark, atment of Facial Erythema of Rosacea: In thick hair; and with underlying hormonal 2013 brimonidine tartrate gel 0.33% was conditions. Higher hair density, darker color, approved by the FDA for the treatment of fa- coarseness, or a combination of these at trea- cial erythema of rosacea. Highly selective α- ted sites are risk factors for paradoxical 2 adrenergic agonist, when applied topically hypertrichosis. In this condition, there should it causes peripheral vasoconstriction via a di- be the absence of any other known cause of rect effect on the smooth-muscle sheath of hypertrichosis[7,21 ,22]. superficial cutaneous blood vessels. The Moreno-Arias et al, first described paradoxical blanching effects last 10-12 hours at which hypertrichosis in five of 49 females with point the patient is expected to return to ba- PCOS undergoing IPL treatment for facial hir- seline erythema It was reported a case of fa- sutism. Moreno-Arias and colleagues also de- cial erythema of rosacea that responded to fined paradoxical hypertrichosis as the brimonidine gel with effective blanching for growth of hair in untreated areas in close pro- two years until the patient developed a para- ximity to treated areas[23]. doxical erythema reaction. This is an side ef- fect physicians should be aware of with Hirsch et al, reported the paradoxical effect in continued prescription of brimonidine gel for 14 patients treated with the long-pulse 755- their rosacea patients[13]. nm alexandrite laser. has been observed to appear especially in areas of vel- lus hair growth[21,22]. Paradoxical Q-switched laser-induced tat- Marayiannis et al showed that hair induction too darkening: Paradoxical darkening of the occurred several months after the onset of tattoos, especially the red, white,or flesh- laser treatments and after at toned ones (pink,yellow,tan) occur occasio- least three treatments had been performed. nally. These tattoo pigments often contain This indicates that hair induction is a process ferric oxide (rust-brown) and titanium dioxide that develops over time and that some type of (white). Following laser treatment, these pig- local activation is necessary[24]. ments get reduced to ferrous oxide (black) and blue-colored titanium dioxide respecti- Etiophysiological mechanisms: Inflammation vely. Increased pigmentation may be caused and inflammatory mediators (prostaglandins by deposition of melanin or haemosiderin as and thymosin β4 which promotes angiogene- well as melanocyte stimulation. Hyperpig- sis and wound healing), subtherapeutic ther- mentation was also reported after Q-switched mal injury (more angiogenesis and accelerat YAG laser treatments for congenital pigmen- ion of hair cycling), hyperemia, immobiliza- ted naevus and melasma. Q-switched laser tion and reflex sympathetic stimulation are treatments are contraindicated in patients suspected. The heat-induced inflam matory who have received gold therapy as they in- reaction that occurs in the follicular papilla, duce chrysiasis. Other lasers like picosecond with an increase in the blood flow supply and 532 nm and 1,064 nm lasers are recommen- growth factors for the follicle, might also play ded as treatment[8]. a role. The heat shock may induce follicular stem cell differentiation and growth by in- creasing the level of HSPs like HSP 27 in the Paradoxical Hypertrichosis tissue involved in the regulation of cell growth and differentiation. They believed that a bet- It can occur after all laser/IPL treatments for ter understanding of paradoxical hypertricho- hair removal [20]. Choosing an appropriate sis may also be useful in the treatment of treatment modality, wavelength, and pulse alopecia[22]. width and fluence to deliver the wavelength at, are all imperative for optimal treatment Perifollicular inflammation associated with outcome, as paradoxical hypertrichosis has photoepilation persists for up to 2 weeks. Alt- been observed after laser treatment. Parado- hough feasible, this idea does not explain why xical hypertrichosis has a low incidence (0.6- some follicles react in this way and others do 10%), and most commonly occurs on the face not, because inflammation is not selective

Page 3 of 7 (page number not for citation purposes) J Turk Acad Dermatol 2019; 13 (4): 19134r1. http://www.jtad.org/2019/4/jtad19134r1.pdf and thus is not limited to less thermally in- 755-nm alexandrite laser. Willey et al also jured areas. Another hypothesis is that the observed that the 694-nm ruby, 755-nm ale- process of laser epilation may serve to xandrite, 810-nm diode lasers caused hair synchronize the cycling of hairs growing wit- induction. It is unclear whether hair removal hin the laser treatment sites.For example, if with the 1,064-nm Nd:YAG laser is less likely all hairs within a given area are simultaneo- to cause hair stimulation or if it is simply usly in anagen, the overall hair density may used less often, as is the case in their prac- appear to be greater than when hair cycling tice. Paradoxical hair growth has also been is asynchronous[23]. reported when IPL systems are used for other indications such as tattoo and a port-wine stain. It was reported also the postradiothe- Contributing Factors rapy hypertrichosis and low-level radiant ex- 1. Hair thickness: Thicker hair is easier to posure by home-use laser and intense heat, whereas thinner hair, which contains pulsed light devices hypertrichosis[20,21, less chromophore, absorbs light energy less 22,23,24,25]. efficiently and is more difficult to heat. This Treatment Protocols: Therapy is based on explains the failure to epilate fine hairs on two facets: treatment of the already present the face, abdomen, linea alba, and back and induced hair and the prevention of hair in- shoulders in men. duction. Several researchers suggest the 2. Hair color: Melanin is the chromophore continuation of treatments and inclusion of absorbed during photoepilation. As a result, the new hairy areas in the treatment areas, darker hair is more efficiently heated. because induced hair responds to treatment in the same manner as other hair follicles. 3. Depth of treated hair: The optical penetra- After a few treatments, all of the unwanted tion of light may be too superficial to adequa- hair should be gone. Using a shorter-cut fil- tely thermally injure deeply growing anagen ter may also help in this matter, but to pre- hairs. vent the paradoxical effect, the use of higher 4. Underlying undiagnosed hormonal condi- laser fluences is widely emphasized. Willey et tions; PCOS and associated ovarian hyperan- al recommend the placement of cold packs drogenism. surrounding the treatment area during laser therapy to prevent low energies from reac- 5. Hormone supplements hing peripheral follicles. The researchers 6. Medications inducing hypertrichosis; Cor- further recommend making 2 passes with ticosteroids and finasteride. the laser during treatments. Long-pulse 7. The incidence of vigorous laser and IPL 755-nm Alexandrite laser, 18-mm spot size post-treatment side effects; erythema, crus- with an energy setting of 12 to 14 J/cm2 fol- ting, edema, hyperpigmentation lowed by a second pass using 8 to 10 J/cm2 1 minute later. Alternatively, a single treat- 8. Treatment with suboptimal fluences; when ment using one pass followed by a second there is insufficient light energy to destroy single-pass treatment 1 week later may be melanocytes in the matrix of the follicle. tried. Another suggestion is to decrease the 9. Anatomical site/sex: Face and neck of amount of time between laser treatments. women were most likely. Willey et al noted that terminal hair growth most often occurred between the third and 10.Skin types III to VI (as a result of the grea- fourth treatments but also occurred as late ter likelihood of a shift between vellus and as after the tenth treatment. The most cases terminal hair in patients of darker skin of terminal hair growth occurred when treat- types)[7,9]. ment intervals were more than 8 weeks Associated Lasers: Paradoxical hypertricho- apart[25]. Schroeter et al advise that the in- sis, first reported with IPL therapy in 51 of terval between treatments be between 4 and 991 patients. Hirsch et al described it in 14 6 weeks as 3 sessions with the 1,064-nm patients who were treated with a long-pulse Nd:YAG laser, spot size of 10 mm, pulse du-

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ration of 30 ms, and energy fluence of 30 Paraben paradox: Many individuals who are J/cm2[26]. allergic (patch test positive) to parabens can continue using cosmetics containing them on Paradoxical Adipose Hyperplasia (PAH) normal skin without developing any dermati- After Cryolipolysis tis. But react to such topical medications Although cryolipolysis has a low incidence of when applied over compromised skin like ve- side effects, 33 cases of PAH have been repor- nous ulcers[4]. ted (0.0051-0.14%). The adipose tissue at the Mechanism: Parabens are metabolized by the treatment site is reported to increase in mass esterases in epidermis and also paraben-re- to a degree that is clearly visible at the mac- sistant microbial strains hydrolyze parabens roscopic scale. MRI data revealed growth of to hydroxybenzoic acid. In defective skin, pa- the cryolipolysis-treated tissue, while H&E rabens will not metabolise by esterases and staining revealed decreased adipocyte organi- also paraben resistant bacteria will hydrolyze zation, septal thickening around fat globules, parabens to alllergic compounds[4]. and an increase in vascularity in the cryoli- polysis-treated tissue. The methodology takes Lanolin paradox: Lanolin is mostly used in advantage of the observation that lipid-rich topical medications, emollients, and cosme- cells are more susceptible to cryoinjury. Typi- tics. Lanolin-sensitive patients often are cal treatment time is 1 hour, during which patch test negative to pure lanolin, which may the temperature of the tissue roll decreases to be due to a low concentration of allergens and about 0°C. Crystallization of cytoplasmic li- also the fact that when used “as is,” pure la- pids within the adipocytes initiates a cascade nolin is a weak sensitizer[5]. of events, characterized by adipocyte apopto- Nail lacquers paradox: Contact allergy to nail sis, panniculitis, and eventual loss of adipocy- lacquers is common. Tosylamide/formal- tes. FDA initially approved cryolipolysis for dehyde resins are mostly used in lacquers. Al- the noninvasive reduction in focal adiposity of lergic contact dermatitis to these resins may the flanks in 2008 and later for the abdomen occur on any part that are accessible to the in 2011, for submental or chin fat area in nails (commonly the eyelids, face, neck, and 2015. Side-effects include temporary eryt- occasionally the thighs and genitalia) and pa- hema, edema, mild pain. Transient decrease radoxically in many, no signs of dermatitis in sensation is seen in two-thirds of patients, are seen at the periungal region[14]. which can persists for up to 8 weeks[6,27]. Exogenous ochronosis paradox: It is a loca- Factors mediating susceptibility: Incidence of lized paradoxical hyperpigmentation of the PAH has been higher in male gender, and in skin due to prolonged use of bleaching agents patients of Hispanic descent[27]. containing hydroquinone and phenolic com- pounds. Topical hydroquinone may inhibit Etiology: The negative suction process of the homogentisic acid oxidase in the dermis, with cryolipolysis instrument may stimulate adi- the result of a local accumulation of homo- pocyte proliferation. Suction with inadequate gentisic acid that polymerizes to form ochro- cooling may lead to hypoxia and stimulate re- notic pigment. The ochronotic coloration most parative rebound adipose hypertrophy and commonly results from the prolonged use of septal thickening. PAH may be due to this fib- certain topical agents like hydroquinones, but rosis of the adipose tissue, in which the ext- it also occurs with the use of antimalarials racellular matrix is expanding. Some adipo and products containing resorcinol, phenolic cytes may be “naturally selected” for survival compounds, mercury, or picric acid[10]. due to their inherent tolerance to cryolipoly- Paradoxic Masseteric Bulging after Botuli- sis. Cryolipolysis leads to activation of pree- num toxin (BTXA) Injection: Paradoxical xisting adipocytes via recruitment of resident masseteric bulging occurs in rare cases after or circulating stem cell population[6,27]. BTXA injections into the masseter (0.49 %). Treatment: Cryolipolysis therapy should be The deep inferior tendon can prevent the discontinued. Surgical treatment (liposuction toxin from spreading into the entire superfi- or abdominoplasty) is recommended. Deoxyc- cial masseter during the BTXA injection pro- holic acid injection also can work[6,27]. cedure and also superficial masseter muscle

Page 5 of 7 (page number not for citation purposes) J Turk Acad Dermatol 2019; 13 (4): 19134r1. http://www.jtad.org/2019/4/jtad19134r1.pdf fiber overactivity. In the treatment, 5-10 U in- reased neurological stimulation of jection over superficial masseter is recom- function due to blockage of the function of au- mended, if not abated after 1-2 weeks[11]. tosomic fibers[28,29,30,31,32]. Paradoxal Wrinkles after forehead BTXA In- Conclusion jection: Site specific side effects associated Whenever encountered in clinical practice, botulinum toxin injection for forehead hori- background knowledge of such paradoxes zontal lines includes paradoxal exaggeration may be useful to the clinician. As reported of wrinkles. The new appearance of a notice- previously, when paradoxes are suspected able glabellar protrusion and also, a new deep after aesthetic procedures, these therapies wrinkle on one side of the forehead just above should be discontinued and the other alter- the have been reported. For the tre- native procedures are recommended. atment of forehead horizontal lines, the injec- tion points should always be 4-5 cm above References the orbital rim. As a result, paralysis of the 1. Oxford dictionaries. Last accessed on 2013 Jan 20. frontalis is limited to the upper part of the Available from: http://oxforddictionaries.com/defini- frontalis and compensatory hyperactivation of tion/english/paradox. the lower part of frontalis muscle can be pos- 2. Adya KA, Inamadar AC, Palit A. Paradoxes in derma- sible in the lateral part of forehead. Therefore, tology. Indian Dermatol Online J 2013; 4:133-142. especially in people frequently using the fron- PMID: 23741675 talis muscle to raise their eyebrows or eyelids, 3. Inui S, Itami S. Androgen actions on the human hair exaggeration of previously unidentifiable follicle: perspectives. Exp Dermatol 2013; 22: 168- wrinkles can take place at the border between 171. PMID: 23016593 the paralyzed frontalis muscle and non-pa- 4. Fisher AA. Esoteric contact dermatitis. part II: the pa- raben paradox. Cutis 1996; 57: 135-138.PMID: ralyzed frontalis muscle. In the medial part of 8882007 the forehead, the hyperactivation of glabellar 5. Wolf R. The lanolin paradox. Dermatology 1996; 192: muscles can be possible because of similar 198-202. PMID: 8726630 reasons. This hyperactivation of glabellar 6. Ward CE, Li JY, Friedman PM. ATX-101 (Deoxycholic muscles with weakness of the frontalis Acid Injection) for Paradoxical Adipose Hyperplasia muscle may cause the protruding of glabellar Secondary to Cryolipolysis. Dermatol Surg 2018; 44: area. The exaggeration of forehead lines after 752-754. PMID: 29053536 botulinum toxin treatment can improve spon- 7. Honeybrook A, Crossing T, Bernstein E, Bloom J, Wo- taneously without any further treatment. For odward J. Long-term outcome of a patient with para- the compliance and satisfaction of patients, doxical hypertrichosis after laser epilation. J Cosmet Laser Ther 2018; 20: 179-183. PMID: 29020484 additional botulinum toxin injection at hype- ractivated muscles can be performed12. 8. Bae YS, Alabdulrazzaq H, Brauer J, Geronemus R. Successful treatment of paradoxical darkening. La- Paradoxal Frontal Alopecia after Repeated sers Surg Med 2016; 48: 471-473. PMID: 26833886 BTXA Injections for Forehead Wrinkles: It was 9. Lolis MS, Marmur ES. Paradoxical effects of hair re- reported the cases of 5 females who developed moval systems: a review. J Cosmet Dermatol 2006; 5: regression of the frontal hairline after several 274-276. PMID: 17716243 treatments with BTXA for forehead wrinkles. 10. Gandhi V, Verma P, Naik G. Exogenous ochronosis The authors called this phenomenon as botu- After Prolonged Use of Topical Hydroquinone (2%) in a 50-Year-Old Indian Female. Indian J Dermatol lin induced frontal alopecia (BIFA). Wabbels 2012; 57: 394-395. PMID: 23112363 and Stanzel reported a patient with eyebrow 11. Lee HJ, Kang IW, Seo KK, et al. The Anatomical Basis alopecia following repeated injections of BTXA of Paradoxical Masseteric Bulging after Botulinum for blepharospasm. There are 3 studies that Neurotoxin Type A Injection. Toxins (Basel) 2016: 30; evaluated the effectiveness of BTXA injections 9. PMID: 28042813 for the treatment of and an- 12. Kang SM, Feneran A, Kim JK, et al. Exaggeration of drogenetic alopecia with almost poor results. wrinkles after botulinum toxin injection for forehead Possible explanations include changes in the horizontal lines. Ann Dermatol 2011; 23: 217-221. PMID: 21747624 levels of molecules that may be involved in regulating the hair cycle, i.e. substance P and 13. Lowe E, Lim S. Paradoxical Erythema Reaction of Long-term Topical Brimonidine Gel for the Treatment calcitonin gene-related peptide and other sig- of Facial Erythema of Rosacea. J Drugs Dermatol naling molecules and receptors, and/or dec- 2016; 15: 763-765. PMID: 27272086

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