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The effect of polyamines on hair cycle clock

Authors:
  • International Hair Research Foundation

Abstract and Figures

Polyamines are essential molecules of highly proliferative tissues, where they play a fundamental role in cellular metabolism like RNA and DNA synthesis, control and initiation of translation, growth and cell proliferation, mediators of most of all hormones and growth factors. Many studies have already shown that polyamines, and spermidine in particular, are strongly related to the regular functioning of hair follicle in animals, and that the modification of their synthesis results in significant alterations in the growth and structure of hair fibers. We made a long-term double blind clinical trial placebo controlled and an examination of HF ex vivo by confocal microscopy to understand if the addition of a specific amount of spermidine (as a nutritional supplement) could be efficacy to stop hair loss in chronic telogen effluvium in women underwent hair loss. Our results show the efficacy of this treatment, and we hypothesize the possible mechanism of action of spermidine in hair follicle.
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Research | Dermatol Pract Concept 2017;7(4):5 17
DERMATOLOGY PRACTICAL & CONCEPTUAL
www.derm101.com
A spermidine-based nutritional supplement
prolongs the anagen phase of hair follicles
in humans: a randomized, placebo-
controlled, double-blind study
Fabio Rinaldi1, Barbara Marzani2, Daniela Pinto2, Yuval Ramot3
1 International Hair Research Foundation, Milan, Italy
2 Giuliani S.p.A. R&D, Milan, Italy
3 Department of Dermatology, Hadassah—Hebrew University Medical Center, Jerusalem, Israel
Key words: hair, polyamines, spermidine, anagen, randomized clinical trial
Citation: A spermidine-based nutritional supplement prolongs the anagen phase of hair follicles in humans: a randomized, placebo-
controlled, double-blind study Dermatol Pract Concept 2017;7(4):17-21. DOI: https://doi.org/10.5826/dpc.0704a05
Received: July 26, 2017; Accepted: September 4, 2017; Published: October 31, 2017
Copyright: ©2017 Rinaldi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Giuliani S.p.A., Milan, Italy.
Competing interests: Fabio Rinaldi, MD, serves as a consultant for Giuliani S.p.A. Yuval Ramot, MD, has received travel support from
Giuliani S.p.A. Barbara Marzani, PhD, and Daniela Pinto, PhD, are employed by Giuliani S.p.A.
All authors have contributed significantly to this publication.
Corresponding author: Fabio Rinaldi, MD, International Hair Research Foundation, Viale Bianca Maria 19, 20100 Milan, Italy. Tel: +39-2-
76006089, Fax: +39-2-89059053. E-mail: fabio.rinaldi@studiorinaldi.com
Background: Spermidine has been shown both in vitro and in mice models to have an anagen-pro-
longing effect on hair follicles (HFs).
Objectives: To evaluate the effects of a spermidine-based nutritional supplement on the anagen phase
of HFs in healthy human subjects in a randomized, double-blind, placebo-controlled trial.
Methods: One hundred healthy males and females were randomized to receive a tablet containing a
spermidine-based nutritional supplement or a placebo once daily for 90 days. At the beginning and
the end of the treatment period, 100 HFs were plucked and subjected to microscopic evaluation to
determine the number of anagen V-VI HFs, and immunohistochemical examination was performed
to quantify the Ki-67 and c-Kit levels in the hair bulbs. Pull test was performed after three and six
months.
Results: The spermidine-based nutritional supplement increased the number of anagen V-VI HFs after
three months of treatment, accompanied by increased Ki-67, a marker for cellular proliferation, and
decreased c-Kit, a marker for apoptosis, levels. All results were also significantly better when compared
to the placebo group. The pull test remained negative after six months in all patients receiving the sper-
midine supplement, while 68% of the subjects in the placebo group had a positive pull test.
Conclusions: This preliminary study shows that a spermidine-based nutritional supplement can pro-
long the anagen phase in humans, and therefore might be beneficial for hair loss conditions. Further
studies are needed to evaluate its effects in specific different clinical settings.
ABSTRACT
18 Research | Dermatol Pract Concept 2017;7(4):5
or acquired diseases affecting the hair shaft; the use of any
topical and/or systemic therapy for hair loss in the previ-
ous three months; regular treatment with corticosteroids,
hormone therapies, anti-androgenic acting products (e.g.,
spironolactone, cimetidine, ketoconazole) or anticoagulants;
infections or other active disease up to three months prior to
beginning the study; organic diseases affecting the kidneys,
liver, cardiovascular system, lungs or the central nervous sys-
tem; diabetes mellitus; alcohol or recreational drug abuse in
the year preceding the start of the study; and clinical history
of sensitivity or allergic reaction. All patients were evaluated
and enrolled to the study in the Rinaldi Dermatologic Clinic,
Milan, Italy.
Study design
This study was a single center, parallel group, double-blinded,
randomized, placebo-controlled trial with 1:1 allocation to
treatment groups. All subjects signed an informed consent
form in accordance with the ICH and Good Clinical Practice
(GCP) Guidelines, prior to undergoing any study related pro-
cedures. Each patient was randomly allocated to either of two
groups (n = 50 in each group): a treatment group receiving a
tablet containing a spermidine-based nutritional supplement,
taken once daily after the main meal, and a placebo group.
The treatment was given for 90 days.
Assessment criteria
All patients were evaluated at three time points: T0 = begin-
ning of the study, T1 = 3 months after the beginning of the
study, and T2 = 6 months after the beginning of the study.
Identification of HF lifecycle phase by means of epilumines-
cence imaging (trichogram to verify normal cycling status,
based on the presence of anagen for at least 80% of hair fol-
licles) was performed at T0 and T1. At both visits, 100 hair
bulbs were plucked from the occipital area of all subjects.
The occipital area was chosen because hair bulbs in this
area are not affected by androgen receptor changes typical
of androgenetic alopecia, thus avoiding enrollment into the
study of subjects suffering from as yet clinically undetect-
able androgenetic alopecia. The plucked hair bulbs were
immersed in saline solution and evaluated microscopically to
select anagen phase V–VI HFs (differentiating from previous
phases and above all from initial catagen phase hair bulbs).
Standardized parameters reported and proposed by Kloepper
et al. were used [19]. The levels of Ki-67, a marker of cel-
lular proliferation, and of c-Kit, a marker of apoptosis, were
determined immunohistochemically on the plucked HFs as
described previously [25]. The extent of hair loss was also
assessed by the hair pull test on T0, T1 and again on T2 to
check for possible onset of physiological telogen effluvium,
typical of the autumn season [26].
Introduction
The polyamines, consisting of putrescine, spermidine and
spermine, are straight chain aliphatic compounds that are
ubiquitously found in living organisms [1,2]. Their levels are
strictly controlled by complex metabolic pathways incor-
porating polyamine biosynthesis, catabolism, and transport
[3,4]. They are essential for the survival and growth of
eukaryotic cells by regulating gene expression and protein
synthesis, affecting a large variety of cellular processes,
including cell growth, differentiation, and regulation [5-7].
The hair follicle (HF), one of the most highly proliferative
organs in mammals, has also been shown to be dependent
on polyamines for its normal growth, function and cycling.
This has been demonstrated in several mouse models, where
changes in polyamine metabolism led to hair loss due to
alteration in the proliferation of the HF keratinocytes [8-18].
Spermidine, the prototypic polyamine in humans, is especially
important for normal hair growth. Indeed, topical administra-
tion of eflornithine, which inhibits ornithine decarboxylase,
the rate-limiting enzyme in the biosynthesis pathway of
polyamines, is used to treat excessive hair growth in females
[17,18]. It has also been shown to decrease the anagen phase
and induce apoptosis in human HFs in vitro [19]. Spermidine
and its metabolically stable analog, N1-methylspermidine,
were demonstrated to prolong anagen and affect epithelial
stem cell functions in human HFs in vitro [5,20,21]. In vivo,
topical application of α-methylspermidine, a stable analogue
of spermidine, enhanced hair growth in telogen phase mice
[22]. Previous preliminary studies have shown the effective-
ness of spermidine-containing nutritional supplements for
the treatment of telogen effluvium [23,24]. However, the
effect of spermidine on the anagen phase in normal subjects
has never been studied in humans. Therefore, we conducted
a randomized, double-blind, placebo-controlled trial on 100
patients, to evaluate the effects of a spermidine-based nutri-
tional supplement on the anagen phase of HFs in healthy
human subjects.
Patients and Methods
Subjects
A total of 100 healthy men and women were recruited into
the study after giving written consent. The participants were
randomized into the treatment group (31 men and 19 women,
36.08 years of age on average, age range 23-50) or placebo
group (36 men and 14 women, 35.6 years of age on average,
age range 22-48). All participants in the study had unremark-
able dietary and lifestyle habits. Exclusion criteria included
initial signs of androgenetic alopecia demonstrated by min-
iaturization of the hair shaft as observed in the occipital
region; a family history of androgenetic alopecia; congenital
Research | Dermatol Pract Concept 2017;7(4):5 19
by decreased levels of the apoptosis marker, c-Kit (Table2).
At the same time, in the placebo group, Ki-67 levels were
decreased and c-Kit levels increased. There was a statistically
significant difference between the spermidine-treated group
and the placebo group.
Pull test
At baseline, all subjects had a negative pull test (Table 3).
There was a gradual increase in the number of subjects that
had a positive pull test in the placebo group, with 14 subjects
at T1 (28%), and 34 subjects at T2 (68%) having a positive
test (Table 3). This was in contrast to the subjects in the
spermidine-treated group, where only one subject was found
to have a positive test at T1 (Table 3), and none at T2. The
difference between the groups was statistically significant at
both time points.
Discussion
Our results provide preliminary evidence that a spermidine-
based nutritional supplement, when given orally once daily
for 90 days, can promote anagen prolongation, and reverse
the transition between anagen to catagen and to telogen. Part
Student’s t test was used for comparing the number of
anagen hair bulbs and Ki-67 and c-Kit levels at baseline and
at T1, and the change from baseline was compared between
groups using the paired t-test. Comparison of the pull test
results between T1 and T2 was performed using the Chi-
square test or Fisher’s exact test. The statistical analyses were
performed on all subjects enrolled (n=100) by means of a
two-tailed test and on a significance level of 0.05 (p-value).
Results
Number of anagen V-VI hair bulbs
The number of anagen hair bulbs increased in the spermi-
dine treatment group between T0 and T1 (more than 50%
increase), while in the placebo group there was a significant
decrease in the number of anagen hair bulbs of approximately
20% (Table 1). There was a highly statistically significant dif-
ference in the change in anagen hair bulb number between the
spermidine-treated group and the placebo group (p<0.0001).
Ki-67 and c-Kit assessments
Treatment with spermidine increased the levels of the prolifer-
ation marker Ki-67 after 3 months of treatment, accompanied
TABLE 1. Number of anagen phase V-VI hair bulbs
Placebo
Mean (s.d.)
N=50
Spermidine
Mean (s.d.)
N=50
P value
(between treatment
groups, Student’s t-test)
T0 25.54 (4.05) 24.64 (4.45) 0.29 (n.s.)
T1 20.24 (3.14) 37.44 (3.84)
Absolute change between T1 and T0 -5.3 (2.3)* 12.8 (6.87)* <0.0001
*p<0.0001 within treatment group, change from T0, paired t-test.
n.s. non signicant; s.d. standard deviation.
TABLE 2. Expression of Ki-67 and c-Kit
Placebo
Mean (s.d.)
N=50
Spermidine
Mean (s.d.)
N=50
P value
(between treatment
groups, Student’s t-test)
Ki-67
T0 91.58 (8.83) 90.08 (12.12) 0.48 (n.s.)
T1 86.63 (7.66) 102.77 (10.75)
Absolute change between T1 and T0 -4.96 (6.76)* 12.69 (8.1)* <0.0001
c-Kit
T0 9.19 (1.08) 9.67 (1.12) 0.03
T1 10.99 (1.14) 7.52 (1.22)
Absolute change between T1 and T0 1.8 (1.07)* -2.16 (1.24)* <0.0001
*p<0.0001 within treatment group, change from T0, paired t-test.
n.s. non signicant; s.d. standard deviation.
20 Research | Dermatol Pract Concept 2017;7(4):5
the last administration of the pill, as demonstrated by the
negative pull test in the treatment group. These preliminary
results can serve as a proof of principle to the fact that oral
spermidine can exert functional effects on human HFs and
further strengthen previous results that showed its effective-
ness for the treatment of telogen effluvium [23,24]. The pos-
sible beneficial effects of this compound for telogen effluvium
and other hair disorders, such as pattern hair loss, need to be
further confirmed in larger controlled studies.
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TABLE 3. Pull test results
T0 T1 T2
Placebo
N (%)
Spermidine N
(%)
Placebo
N (%)
Spermidine N
(%)
Placebo
N (%)
Spermidine
N (%)
- 50 50 36 (72) 49 (98)* 16 (32) 50 (100)#
+- - 14 (28) 1 (2)* 19 (38) -
++ - - - - 12 (24) -
+++ - - - - 3 (6) -
*p<0.0001 by Fisher’s exact test; #p<0.0001 by Chi-Square test
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... In vivo, topical application of α-methylspermidine, a stable analogue of spermidine, enhanced hair growth in telogen phase mice [22]. Previous preliminary studies have shown the effectiveness of spermidine-containing nutritional supplements for the treatment of telogen effluvium [23,24]. However, the effect of spermidine on the anagen phase in normal subjects has never been studied in humans. ...
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Background: Spermidine has been shown both in vitro and in mice models to have an anagen-prolonging effect on hair follicles (HFs). Objectives: To evaluate the effects of a spermidine-based nutritional supplement on the anagen phase of HFs in healthy human subjects in a randomized, double-blind, placebo-controlled trial. Methods: One hundred healthy males and females were randomized to receive a tablet containing a spermidine-based nutritional supplement or a placebo once daily for 90 days. At the beginning and the end of the treatment period, 100 HFs were plucked and subjected to microscopic evaluation to determine the number of anagen V-VI HFs, and immunohistochemical examination was performed to quantify the Ki-67 and c-Kit levels in the hair bulbs. Pull test was performed after three and six months. Results: The spermidine-based nutritional supplement increased the number of anagen V-VI HFs after three months of treatment, accompanied by increased Ki-67, a marker for cellular proliferation, and decreased c-Kit, a marker for apoptosis, levels. All results were also significantly better when compared to the placebo group. The pull test remained negative after six months in all patients receiving the spermidine supplement, while 68% of the subjects in the placebo group had a positive pull test. Conclusions: This preliminary study shows that a spermidine-based nutritional supplement can prolong the anagen phase in humans, and therefore might be beneficial for hair loss conditions. Further studies are needed to evaluate its effects in specific different clinical settings.
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Recent developments in research methods and techniques, such as whole-exome and -genome sequencing, have substantially improved our understanding of genetic conditions. Special progress has been made in the field of genotrichoses, or hereditary hair diseases, a field that has been obscure for many years. The underlying genes for many of the monogenic hair diseases are now known. Additionally, complex analyses of large cohorts of patients have given us the first clues to the genes associated with polygenic hair disorders, such as androgenetic alopecia and alopecia areata. Thanks to these major findings, the sophisticated regulation of the morphogenesis, development and growth of hair follicles has begun to be revealed, and new players in this delicate molecular interplay have been exposed.
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Spermidine (Spd), the prototypic polyamine, has been shown to be essential for hair follicle (HF) growth. However, Spd can be readily converted into other polyamines, and is physiologically unstable. Therefore, to assess its individual functions on HFs, we used the metabolically stable Spd analog N(1)-methylspermidine (N(1)-MeSpd). N(1)-MeSpd was confirmed to be a metabolically stable compound, with a half life of 90 h. 0.5 µM N(1)-MeSpd strongly prolonged anagen and decreased cell apoptosis in HFs in culture after 6 days, accompanied by specific stimulation of the expression of the epithelial stem cell-associated keratin, K15. N(1)-MeSpd also reduced lactate dehydrogenase activity in the culture supernatant, a parameter of cell death and cell lysis. N(1)-MeSpd diminished intracellular reactive oxygen species production in cultured keratinocytes, and reduced tumor necrosis factor-α, interleukin (IL)-1β and IL-6 gene and protein expression after lipopolysaccharide stimulation. This suggests that some effects of N(1)-MeSpd may be mediated by anti-oxidative and anti-inflammatory effects. These additional properties of N(1)-MeSpd could be clinically important for the treatment of inflammatory alopecias and inflammatory scalp diseases.
Article
Polyamines are cationic amines essential for cellular proliferation. Recently, their role in hair follicle (HF) growth has started to be explored, but their exact function is still obscure. In the October issue of Experimental Dermatology, Luke et al. follow the observation that putrescine overproducing mice and hairless (HR) mutant mice show a similar clinical phenotype of hair loss and dermal cyst formation. They show that HR and putrescine form a negative regulatory feedback mechanism, which might regulate hair cycling and therefore control hair growth. This study clearly demonstrates that a strong connection exists between HR and polyamines although there are probably additional molecular pathways involved in the polyamine regulation of hair growth which remain to be discovered.
Article
Hairless (HR) is a nuclear protein with corepressor activity that is highly expressed in the skin and hair follicle. Mutations in Hairless lead to hair loss accompanied by the appearance of papules (atrichia with papular lesions), and similar phenotypes appear when the key polyamine enzymes ornithine decarboxylase (ODC) and spermidine/spermine N(1) -acetyltransferase (SSAT) are overexpressed. Both ODC and SSAT transgenic mice have elevated epidermal levels of putrescine, leading us to investigate the mechanistic link between putrescine and HR. We show here that HR and putrescine form a negative regulatory network, as epidermal ODC expression is elevated when HR is decreased and vice versa. We also show that the regulation of ODC by HR is dependent on the MYC superfamily of proteins, in particular MYC, MXI1 and MXD3. Furthermore, we found that elevated levels of putrescine lead to decreased HR expression, but that the SSAT-TG phenotype is distinct from that found when HR is mutated. Transcriptional microarray analysis of putrescine-treated primary human keratinocytes demonstrated differential regulation of genes involved in protein-protein interactions, nucleotide binding and transcription factor activity, suggesting that the putrescine-HR negative regulatory loop may have a large impact on epidermal homeostasis and hair follicle cycling.
Article
Recent studies using transgenic animals have revealed a crucial role for polyamines in the development and the growth of skin and hair follicles. In mammals, the growth of hair is characterized by three main cyclic phases of transformation, including a rapid growth phase (anagen), an apoptosis-driven regression phase (catagen) and a relatively quiescent resting phase (telogen). The polyamine pool during the anagen phase is higher than in telogen and catagen phases. In this study, we used α-methylspermidine, a metabolically stable polyamine analog, to artificially elevate the polyamine pool during telogen. This manipulation was sufficient to induce hair growth in telogen phase mice after 2 weeks of daily topical application. The application site was characterized by typical features of anagen, such as pigmentation, growing hair follicles, proliferation of follicular keratinocytes and upregulation of β-catenin. The analog penetrated the protective epidermal layer of the skin and could be detected in dermis. The natural polyamines were partially replaced by the analog in the application site. However, the combined pool of natural spermidine and α-methylspermidine exceeded the physiological spermidine pool in telogen phase skin. These results highlight the role of polyamines in hair cycle regulation and show that it is possible to control the process of hair growth using physiologically stable polyamine analogs.
Article
We recently generated a transgenic mouse line with activated polyamine catabolism due to overexpression of spermidine/spermine N1-acetyltransferase. Phenotypic changes in these animals included permanent loss of hair at the age of 3 wk. We have now further explored development of hair loss during early postnatal life. The first hair cycle appeared to be completed normally in the transgenic animals. At postnatal day 15, although macroscopically indistinguishable from their syngenic littermates, the transgenic animals already showed microscopically signs of hair follicle degeneration. Wild-type mice started their second anagen phase at day 27, whereas the transgenic animals did not display functional hair follicles at that time. Hair follicles were replaced by dermal cysts and epidermal utriculi. Analysis of skin polyamines revealed that the transgenic animals continuously overaccumulated putrescine. The view that an overaccumulation of putrescine was related to the disturbed hair follicle development was strengthened by the finding that doubly transgenic mice overexpressing, both spermidine/spermine N1-acetyltransferase and ornithine decarboxylase and with extremely high levels of putrescine in the skin, showed distinctly more severe skin changes compared with the singly transgenic animals. Interest ingly, in spite of their hairless phenotype, the spermidine/spermine N1-acetyltransferase transgenic mice, were significantly more resistant to the development of papillomas in response to the two-stage skin carcinogenesis. Analysis of skin polyamines indicated that the syngenic mice tripled their spermidine content when exposed to promotion, whereas the transgenic animals showed only modest changes. These results suggest that putrescine plays a pivotal part in normal hair follicle development.
Article
Alopecia areata (AA) is a common autoimmune condition, causing inflammation-induced hair loss. This disease has very limited treatment possibilities, and no treatment is either curative or preventive. Platelet-rich plasma (PRP) has emerged as a new treatment modality in dermatology, and preliminary evidence has suggested that it might have a beneficial role in hair growth. To evaluate the efficacy and safety of PRP for the treatment of AA in a randomized, double-blind, placebo- and active-controlled, half-head, parallel-group study. Forty-five patients with AA were randomized to receive intralesional injections of PRP, triamcinolone acetonide (TrA) or placebo on one half of their scalp. The other half was not treated. Three treatments were given for each patient, with intervals of 1 month. The endpoints were hair regrowth, hair dystrophy as measured by dermoscopy, burning or itching sensation, and cell proliferation as measured by Ki-67 evaluation. Patients were followed for 1 year. PRP was found to increase hair regrowth significantly and to decrease hair dystrophy and burning or itching sensation compared with TrA or placebo. Ki-67 levels, which served as markers for cell proliferation, were significantly higher with PRP. No side-effects were noted during treatment. This pilot study, which is the first to investigate the effects of PRP on AA, suggests that PRP may serve as a safe and effective treatment option in AA, and calls for more extensive controlled studies with this method.