Paradoxical Nonscarring Alopecia Following Mesotherapy with Dutasteride: A Case Series

ABSTRACT

Background:

Androgenetic alopecia (AGA) is a disease of polygenic etiology. Androgens play a vital role in the development of patterned hair loss. Dutasteride is an anti-androgen that acts by competitively inhibiting both type 1 and type 2 isoenzymes of 5α reductase. The intradermal deposition of dutasteride has the advantage of negligible systemic absorption. Although dutasteride mesotherapy has not been approved by the Food and Drug Administration, it has been used off-label in the treatment of AGA. Here, we report 4 case series of nonscarring alopecia that developed following a single session of mesotherapy injection.

Materials and Methods:

A total of 15 cases with patterned hair loss were enrolled (13 males and 2 females). The grade of patterned hair loss was between Norwood Hamilton grade 3–6, and in Ludwig pattern between 2 and 3. Once a month intradermal injection of dutasteride mesotherapy was administered in all cases. To standardize the drug administration and for uniform delivery of the drug, 1 cm² grids were created and 2 units at each point was administered at an angle of 60°, a total of 2 ml of 0.01% of dutasteride was administered in each session.

Results:

Mean age of 31.53. The most common adverse effect noted was noncicatricial alopecia was noted in four cases, (3 males and 1 female), followed by pain, itching 1 case each, respectively. The grade of alopecia was AGA grade 5–6, 1 male with Ludwig grade 2 pattern of hair loss and a female with Ludwig grade 2. They developed patchy alopecia involving the mesotherapy site following a single session of dutasteride mesotherapy.

Conclusion:

There is a need for stringent monitoring of manufacturing guidelines of mesotherapeutic cocktails by governing bodies. It should primarily address the optimal concertation of the active ingredients and preservative usage to avoid untoward side effects. The benzyl alcohol and polysiloxane in the cocktail could be the key players having cytotoxic effects, contributing to the development of alopecia. The knowledge of potential adverse effects caused by a drug should always be in the mind of the treating physician.

INTRODUCTION

Androgenetic alopecia (AGA) is the most common form of hair loss. The conversion of testosterone to its more potent form, dihydrotestosterone (DHT) by the enzyme 5-αreductase plays a key role in the development of androgen-mediated hair loss. Dutasteride, is a synthetic 4-azasteroid, a selective and competitive inhibitor of both type-1 and type-2 isoenzymes of 5-α-reductase.[1] It is 3 times more potent in inhibiting 5α-reductase type 2 than finasteride and 100 times more potent in inhibiting type 1 5α-reductase.[2] Theoretically, it carries a higher risk of adverse effects in comparison to finasteride. It reduces serum DHT by more than 90%.[3] To reduce these adverse effects, and as an alternative in individuals with poor tolerance to systemic antiandrogens, mesodermal deposition of a drug depot of dutasteride was suggested. Although mesotherapy is in vogue due to its ease of administration and the nominal skills of the injector, there is a lack of standardised protocol and composition that needs to be delivered.

MATERIALS AND METHODS

In all 15 subjects, monthly intradermal injection of dutasteride was administered. The drug was stored at 4° centigrade by refrigeration. The utilization of the drug was within 24 h of breaking the aluminum seal. To ascertain standardized and uniform drug administration, we followed a grid pattern of mapping the scalp. Here, 1 cm² grids were marked on the treatment area, with a sterile marker pen; beginning from the anterior hairline up to the vertex. With the aid of 31 g needle, a total of 2 ml of 0.01% of dutasteride mesotherapy was administered, by an angle of 60°, bolus of 2 units at each point was administered.

RESULTS

Out of 15 subjects treated, 1 case had Norwood–Hamilton grade 2, 2 cases had grade 3, 4 had grade 4, and 1 had grades 5 and 6, respectively. Two cases of female patterned hair loss of grade 3, 2 had Ludwig pattern 2. One case of diffuse unpatterned hair loss.

Thirteen subjects were on topical minoxidil and 2 subjects were on oral minoxidil of 2.5 mg once at night.

Two subjects had undergone previous hair transplant surgery. One subject had Ehlers-Danlos syndrome. There were no associated comorbidities in the rest of the subjects.

Two completed four sessions of monthly dutasteride, five underwent three sessions, three subjects underwent two sessions, and five of the subjects had a single session, one case was lost for follow-up. A total of four subjects noticed patchy hair loss, among this acute hair fall was noted in cases 1 and 3 (elaborated below). One faced itching and 1 face pain at the injection site.

The following are the details of nonscarring alopecia developing following dutasteride mesotherapy note in four cases.

Case 1

A 31-year-old male presented with complaints of progressive thinning of hair for 7 years, He was on minoxidil 10% with finasteride 0.1% twice daily for 3 years and oral finasteride 1 mg per day for 6 months. The patient had his wedding scheduled in 4 months, sought better regrowth and desired to omit the adverse effects of oral finasteride. He was diagnosed with Norwood-Hamilton grade 3 patterned hair loss. With considerable improvement in hair density. He was administered mesotherapy with dutasteride 0.01% single session, 2 weeks post meso-session, the patient noticed excessive hair shedding of approximately 500 strands/day, with patchy loss of hair in the frontotemporal area [Figures 1–4].

Figure 1.

Global view, (a) baseline image prior to dutasteride mesotherapy, (b) following 3 weeks of mesotherapy, showing reduced density of frontal area, (c) 2 months following dutasteride injection

Figure 4.

Trichoscopy (Fotofinder GmBH ×20): (a) before, (b) after 1 session of mesotherapy with dutastride 0.01%, showing features of multiple black dots, and yellow dots, few pig tail hairs and increased interfollicular distance

Figure 2.

Baseline image-lateral view, (a) before; (b) after 3 weeks of mesotherapy showing frontotemporal triangular patch of alopecia

Figure 3.

(a) Before dutasteride mesotherapy, (b) 1 month post mesotherapy, (c) 2 months following mesotherapy

This was treated with intralesional steroid 5 mg/ml injection administration and there was regrowth of the patchy hair loss 3 months following the sessions.

Case 2

A 24-year-old female patient with Ehlers-Danlos syndrome type 4 cardiac variant, presented with fine hairs, seeking improved density. There was diffuse thinning of the centroparietal and occipital scalp, trichoscopy showed hair diameter diversity of >20%. Based on clinical and trichoscopic findings, a diagnosis of Ludwig’s grade 2 of female patterned hair loss was made. There was limited improvement in density with topical minoxidil 5%, she was on oral minoxidil 2.5 mg once daily for 5 months. Seeking further improvement in density, made us opt for mesotherapy with 0.01% dutasteride. One month post mesotherapy, there was excessive hair fall and by 2^nd month there was an extreme reduction of hair density, with diffuse alopecia involving the treated site. Trichoscopically, there were multiple black dots and pigtail hair favoring alopecia areata incognoito.

Histological evaluation was carried out which established the trichoscopic findings [Figure 5].

Figure 5.

H and E stain, (a) vertical section ×40: Follicular plugs in dilated infundibula. (b) transverse section ×40: Dermis shows telogen germinal unit mild lympho-histiocytic infiltrate in perivascular areas. Sebaceous gland lobules unaltered. Both terminal and vellus hair were present in the dermis. (c) transverse section ×40 - telogen follicle with perifollicular fibrosis with scant inflammatory infiltrate

Oral tofacitinib 5 mg twice daily was administered and 3 months following treatment, there was recovery of the lost density [Figures 5 and 6].

Figure 6.

Clinical images (a) prior to and (b) postmesotherapy session showing multifocal patches of alopecia

Case 3

A 26-year-old male with advanced stage of AGA (Norwood-Hamilton grade 6), on the medical line of treatment with 10% minoxidil with 0.1% finasteride. He turned down the oral dutasteride owing to the adverse effects.

One session of mesotherapy with 0.01% dutasteride was administered. Following a single session, there were multiple patchy areas of alopecia at the treated site 1 month following the treatment [Figures 6 and 7].

Figure 7.

Trichoscopy images ×20 (a) prior to mesotherapy, (b) empty follicles, increased interfollicular distance pohl-pinkus constrictions increased interfollicular distance

These patches of alopecia were treated with intralesional steroids of 2.5 mg/ml at the affected site. There was partial regrowth following a single session.

Case 4

A 28-year-old male patient with Norwood–Hamilton grade 5, had undergone hair transplant 2 years earlier and was on 5% minoxidil with finasteride twice daily. There was predominant vertex thinning clinically. Mesotherapy with dutasteride 0.01% was administered.

At 1 month following the mesotherapy session, there was deterioration of the vertex density [Figures 8 and 9].

Figure 8.

Baseline clinical images (a) prior to mesotherapy, (b) 1 month post mesotherapy thinning on vertex area, (c) 2 months with only medical line of therapy, progressive thinning over the vertex area

Figure 9.

(a) Baseline clinical image showing anisotrichosis, (b) 1 month following dutasteride mesotherapy showing increased interfollicular distance, predominant single follicular units with increased intermediate to vellus hairs

DISCUSSION

Mesotherapy was first introduced by French physician Pistor.[4] It consists of intradermal deposition of the drug that aids in sustained and slow release of the active ingredient. Although drugs such as minoxidil and finasteride have been Food and Drug Administration approved in the treatment of patterned hair loss, their use as a mesotherapeutic agent has not yet been approved.[5] The use of mesotherapy is used as an off-label technique to administer the active ingredient.

In this study, the mesotherapy cocktail composed of dutasteride 0.01%, benzyl alcohol 0.1%, polysiloxane 2%, pH of 7, and chlorobutyl stopper. Dutasteride, a hydrophobic drug, requires dissolution.

The use of benzyl alcohol as the solvent and polysiloxane in the cocktail, as both have been associated with irritation and inflammatory reactions. Specifically, low-molecular-weight linear polydimethyl siloxane, termed hexamethyldisiloxane has been reported to induce inflammatory conditions and necrosis in the sites of subcutaneous injections.[6] We propose that the use of preservative benzyl alcohol, and polysiloxane could been attributing factors causing cytotoxicity,[6,7] eventually culminating in alopecia.

The pharmaceutical preparations usually have additives that interacts with the active drug component, other additives, and packaging materials. These interactions, which can cause drug–additive interactions, additive–additive interactions, package–additive interactions, and also drug degradation.[8] There are only two reports of alopecia development following dutasteride mesotherapy.[8,9] Reguero Del Cura et al. attributed ethyl alcohol, the preservative as a causative factor for hair loss. The possible pathomechanism includes cell apoptosis accompanied by reactive oxygen species overproduction, autophagy activation, and increased nuclear translocation of nuclear factor kappa B.[8] El-Komy et al. suggested other factors like delayed cutaneous reaction or an acute reaction to manufacturing changes in the injected solution composition.[9] They observed the presence of perivascular and perifollicular inflammatory infiltrate comprising lymphohistiocytes, which was also noted in our case (case 2).

The administration of mesotherapeutic agents has been associated with some adverse effects. These can range from mild and transient, such as burning sensation, erythema, headaches, to severe and long-lasting, including injection site infections, granulomatous foreign-body reactions, fat necrosis, nonscaring/scarring alopecias, scalp abscess, and angioedema suggested by Busanello EB et al.[10]

In our study, the most common adverse effects were the manifestation of noncicatricial alopecia in four cases, with excessive hair fall noted in cases 1 and 2 enlisted in Table 1. Other reported side effects such as pain and itching in two subjects. Similarly, Moftah et al. reported pain and itching in 82.6% and 3.5% of patients, respectively on 126 female subjects receiving dutasteride-containing mesotherapy, reported pain and itching in 82.6% and 3.5% of patients respectively.[11]

Table 1.

The enrolled cases and adverse effects noted following dutasteride mesotherapy

Age/sex	Diagnosis	Number of sessions	Post-HT	Topical minoxidil	Oral minoxidil	Adverse effects
32 year/male	AGA G4	4	No	10% BD	No	Nil
24 year/male	AGA G3	4	No	10% BD	No	Nil
28 year/male	AGA G5	3	No	5% BD	No	Nil
27/male	AGA G4	3	No	10% BD	No	Nil
40 year/male	LP 2	3	No	10% BD	No	Nil
28/male	AGA G6	3	HT - 2022	5% BD	No	Deterioration of vertex noted after 3 sessions
34/male	LP 2	3	HT - 2022	10% BD	2.5 mg OD - 7/23	Nil
31/male	AGA G3	2	No	10% BD	No	Patchy hair loss
33 year/male	AGA G4	2	9 years back	5% OD	No	Nil
54/female	FPHL 3	2	No	5% OD	No	Pain at the injection site - lasting for 3 days
26/male	AGA G5	1	No	5% BD	No	Patchy hair loss
35/male	AGA G4	1	No	5% BD	No	Nil
32/male	AGA G2	1	No	5% OD	No	Developed itching at injection site
24/female	FPHL 3	1	No	No	Minoxidil 2.5 mg OD	EDS Diffuse alopecia
25/male	DUPA	1	No	10% BD	No	Lost to follow-up

FPHL - Female patterned hair loss; AGA - Androgenetic alopecia; DUPA - Diffuse unpatterned hair loss; EDS - Ehler Danlos’s syndrome; OD - Once daily; BD - Twice daily; HT - Hair transplant; LP - Ludwig’s pattern

These adverse effects are more common in patients with a known history of hypersensitivity reactions to ingredients, preexisting scalp pathology like congenital nevus or prior surgical trauma near the injection site, may be predisposed to a higher risk. Additional risk factors include drug–drug interactions, and possible product contaminations.[12]

In a study by Sobhy et al., the cumulative dose of dutasteride for the pure dutasteride group was 0.675–0.9 mg and for the dutasteride cocktail (dutasteride 5 mg, dexapanthenol 500 mg, biotin 20 mg, and pyridoxine 200 mg) was 6.75–9 mg.[11] However, in our subjects, the maximum dose of administered dutasteride was 0.01% of 2 ml dutasteride which was adequate to cause nonscarring alopecia. Table 2 emphasizes the studies showing adverse effects due to mesotherapy with dutasteride.[13]

Table 2.

Studies on mesotherapy with dutasteride and reported adverse effect

Studies	Concertation, comparision of dutasteride cocktail	Combination therapy	Drug administration regimen	Adverse effects	Cause of adverse effect
Saceda- D et al.[14] RCT	0.005% (dutasteride 5 mg, D-panthenol 500 mg, biotin 20 mg and pyridoxine 200 mg in a final volume of 10 mL)	-	Sessions: 7 Frequency: Weeks 0, 1, 2, 3, 5, 7, 11	Injection site pain - 6/14 (42.9%), headache - 2/14 (14.3%), scalp tightness - 1/14 (7.1%)	NR
Moftah et al.,[11] 2013 (n=86; female) Non-RCT	0.05% dutasteride 0.5 mg, biotin 20 mg, pyridoxin 200 mg, D-panthenol 500 mg, 2 mL		Sessions: 12 Frequency: Weeks 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16	Tolerable pain - 71/86 (82.6%), headache - 19/86 (22.1%), itching - 3/86 (3.5%)
El-Komy M,[9] 2017 (n=3) Case series	2 mL dutasteride 0.005% (mesologica) and 3 mL of IGF-1, BFGF, VEGF, copper tripeptide-1, multi-vitamins, amino acids and minerals	-	Case 1 - NR Case 2 - monthly sessions-for 1 year Case 3-3 sessions	Case 1: Pain and patchy alopecia Case 2: Painful, crusted patch of alopecia Case 3: Two linear erythematous atrophic scars with almost complete hair loss
Reguero del Cura,[8] 2022 (n=2, 1 male, 1 female) Case series	10 mL of dutasteride 0.05% in 4 mL of ethanol, 5995 mL of propylene glycol > >final concentration of 0.025% achieved by diluting 2% of mepivacaine, total of 3 mL/session	-	Case 1 - single session Case 2-2 sessions	Case 1 (female) - focal patchy alopecia at the injection site Case 2 (male) - several bald atrophic alopecia patches at injection sites	Hypothesised ethanol, the preservative to be the likely cause
Magdaleno-Tapial,[15] 2020 Case report	Dutasteride in alcohol and propylene glycol		Single session	Marked facial swelling and erythema, angioedema-like contact dermatitis	Confirmed patch test revealed positive reactions to dutasteride and propylene glycol in formulations
Melo, 2022[16] (n=14, male - 4, female - 10) Case series	Dutasteride+lignocane		Once in 3 months	Frontal edema	secondary to topical minoxidil/dutasteride/large volume of anesthesia infiltration

IGF-1 - Insulin-like growth factor-1; BFGF - Basic fibroblast growth factor; VEGF - Vascular endothelial growth factor

The centers governing the manufacturing guideline and the use of permissible limits of preservatives need to be standardized. Optimal usage of each active substance, with the solvents that are safer and lack cytotoxic properties needs to be established. The lack of standardisation of composition, interval between sessions and ideal concentration of dutasteride and other active ingredients in mesotherapy cocktail, presence of unidentified cytotoxic agents that needs addressal to avoid future development of undesired side effects.

CONCLUSION

The definitive factors causing the adverse effects secondary to dutasteride mesotherapy have been attributed to the preservative or due to the dutasteride itself. There may be other factors at play that need further evaluation. It is imperative to make a risk/benefit assessment based on the pattern of hair loss and duration of hair loss. Awareness of alopecia secondary to mesotherapy with dutasteride can avoid clouding of diagnosis with conditions like alopecia areata. Further investigation and in-depth analyses are required to identify the subset of patients who are at potential risk, thereby defying the future incidence of these untoward effects.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.