Growth Hormone and the Human Hair Follicle

Abstract

Ever since the discoveries that human hair follicles (HFs) display the functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis, exhibit elements of the hypothalamic-pituitary-thyroid axis, and even generate melatonin and prolactin, human hair research has proven to be a treasure chest for the exploration of neurohormone functions. However, growth hormone (GH), one of the dominant neurohormones of human neuroendocrine physiology, remains to be fully explored in this context. This is interesting since it has long been appreciated clinically that excessive GH serum levels induce distinct human skin pathology. Acromegaly, or GH excess, is associated with hypertrichosis, excessive androgen-independent growth of body hair, and hirsutism in females, while dysfunctional GH receptor-mediated signaling (Laron syndrome) is associated with alopecia and prominent HF defects. The outer root sheath keratinocytes have recently been shown to express functional GH receptors. Furthermore, and contrary to its name, recombinant human GH is known to inhibit female human scalp HFs’ growth ex vivo, likely via stimulating the expression of the catagen-inducing growth factor, TGF-β2. These limited available data encourage one to systematically explore the largely uncharted role of GH in human HF biology to uncover nonclassical functions of this core neurohormone in human skin physiology.

Full text

International Journal of
Molecular Sciences
Review
Growth Hormone and the Human Hair Follicle
Elijah J. Horesh 1, Jérémy Chéret 1and Ralf Paus 1,2,3,*


Citation: Horesh, E.J.; Chéret, J.;
Paus, R. Growth Hormone and the
Human Hair Follicle. Int. J. Mol. Sci.
2021,22, 13205. https://doi.org/
10.3390/ijms222413205
Academic Editor: James M. Harper
Received: 9 November 2021
Accepted: 6 December 2021
Published: 8 December 2021
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Copyright: © 2021 by the authors.
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This article is an open access article
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Attribution (CC BY) license (https://
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4.0/).
1Dr. Philip Frost Department for Dermatology and Cutaneous Surgery, University of Miami,
Miami, FL 33136, USA; elijjonathan@med.miami.edu (E.J.H.); jpc219@med.miami.edu (J.C.)
2Monasterium Laboratory, D-48149 Münster, Germany
3
Centre for Dermatology Research, NIHR Manchester Biomedical Research Centre, University of Manchester,
Manchester M13 9PT, UK
*Correspondence: rxp803@med.miami.edu; Tel.: +1-305-243-7870
Abstract:
Ever since the discoveries that human hair follicles (HFs) display the functional peripheral
equivalent of the hypothalamic-pituitary-adrenal axis, exhibit elements of the hypothalamic-pituitary-
thyroid axis, and even generate melatonin and prolactin, human hair research has proven to be a
treasure chest for the exploration of neurohormone functions. However, growth hormone (GH), one
of the dominant neurohormones of human neuroendocrine physiology, remains to be fully explored
in this context. This is interesting since it has long been appreciated clinically that excessive GH
serum levels induce distinct human skin pathology. Acromegaly, or GH excess, is associated with
hypertrichosis, excessive androgen-independent growth of body hair, and hirsutism in females, while
dysfunctional GH receptor-mediated signaling (Laron syndrome) is associated with alopecia and
prominent HF defects. The outer root sheath keratinocytes have recently been shown to express
functional GH receptors. Furthermore, and contrary to its name, recombinant human GH is known to
inhibit female human scalp HFs’ growth ex vivo, likely via stimulating the expression of the catagen-
inducing growth factor, TGF-
β
2. These limited available data encourage one to systematically explore
the largely uncharted role of GH in human HF biology to uncover nonclassical functions of this core
neurohormone in human skin physiology.
Keywords: growth hormone; insulin-like growth factor-1; somatotropic axis; hair follicle
1. Introduction
The human hair follicle (HF) behaves as a neuroendocrine organ, even when isolated
from systemic (blood flow, peripheral nervous system) stimuli, and shows hormone and re-
ceptor expression analogous to several central pituitary neuroendocrine axes [
1
,
2
]. Namely,
the synthesis, secretion, and regulation of hormones of the hypothalamus-pituitary-adrenal
(HPA) axis have been documented in human scalp HFs ex vivo. In the absence of systemic
connections, cultured human scalp HFs express and respond to corticotropin-releasing
hormone (CRH) and adrenocorticotropic hormone (ACTH), resulting in the HF synthesis of
cortisol and activation of classical neuroendocrine feedback loops. Just as in the central HPA
axis, the expression of pro-opiomelanocortin (POMC), the precursor for ACTH,
α
-MSH,
and
β
-endorphin, is upregulated by CRH, while cortisol downregulates intrafollicular
CRH protein synthesis [
3
]. All three POMC-derived peptides listed above regulate HF
melanogenesis [
4
], while insufficient HF synthesis of melanotropic HPA axis hormones
may contribute to HF greying [5].
HFs are also extra-pituitary sources of prolactin [
6
] and thyrotropin-releasing hormone
(TRH) [
7
]. TRH and estradiol both regulate prolactin and prolactin receptor expression
in human HFs in a similar manner as they do in the pituitary gland [
8
]. However, the
HF expression of prolactin also underlies distinct controls, namely, it is not regulated by
dopamine (as in the pituitary gland) but by substance P and the proinflammatory cytokine
interferon-gamma [
9
]. Human HFs also express functional thyrotropin receptors [
10
],
whose stimulation promotes intrafollicular mitochondrial activity and biogenesis [11].
Int. J. Mol. Sci. 2021,22, 13205. https://doi.org/10.3390/ijms222413205 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2021,22, 13205 2 of 12
Yet, the role of another key neurohormone, growth hormone (GH, somatotropin), in
human HF biology remains insufficiently explored. After providing basic background on
general GH biology, we delineate in the current review clinical and experimental evidence
in support of GH as a potentially important regulator of human HF physiology. We argue
that the limited available data encourages one to systematically dissect the role of GH in
human HF biology in order to uncover nonclassical functions of this core neurohormone in
human skin physiology and to develop novel GH or GH receptor-targeting neuroendocrine
strategies for the therapeutic manipulation of hair loss (effluvium, alopecia) and unwanted
hair growth (hirsutism, hypertrichosis).
2. The Hypothalamus-Pituitary-Somatotropic Axis
The hypothalamus-pituitary-somatotropic (HPS) axis refers to the neuroendocrine
control of GH secretion and its downstream signaling. Growth hormone-releasing hormone
(GHRH) produced in the hypothalamus upregulates GH gene expression and stimulates
the release of GH from pituitary somatotrophs. Somatostatin (SST), also produced in
the hypothalamus, inhibits GH release (but not GH synthesis) in pituitary somatotrophs.
Both hormones act on the pituitary via the adenohypophyseal portal venous system. The
orexigenic gastric peptide ghrelin stimulates hypothalamic GHRH secretion and pituitary
GH release [
12
]. GH acts on peripheral cells in virtually every human tissue directly
through the growth hormone receptor (GHR) (Figure S1) and indirectly through the insulin-
like growth factor 1 (IGF-1). The downstream signaling from activating the GHR varies by
cell population but commonly involves the JAK2-STAT1/3/5 and/or MAPK pathways.
Downstream, suppressors of cytokine signaling (SOCS) are known to inhibit GHR signaling
effects. Interestingly, SOCS are upregulated by estrogen, which may cause sex-dependent
differences when studying the HPS [
13
]. IGF-1, usually upregulated by peripheral GH
signaling, inhibits GH secretion via negative feedback at the pituitary and hypothalamic
levels [12] (Figure 1).
The somatotrophic axis is closely linked to sleep and the circadian rhythm. GHRH
has sleep-promoting effects, and GH secretion occurs in a pulsatile fashion, with maximal
levels occurring after the onset of slow-wave sleep. Abnormal circadian rhythm disorders
like narcolepsy are associated with abnormalities in the HPS axis [
14
]. Interestingly, the
HF demonstrates circadian-dependent clock gene activity in the absence of central clock
influences ex vivo [
15
]. PER-1 and BMAL-1 were both shown to regulate human HF cycling,
as well as melanogenesis [
16
]. The peripheral clock activity has also been shown to be
modulated by neurohormones like thyroxine [
17
], suggesting that other neurohormones
like GH may also modulate HF biology directly or indirectly via modulation of clock genes.
GH serum levels correlate with serum estradiol levels, with higher concentrations found in
young people when compared with older people, as well as in females when compared
to males. The bulk of GH secretion in males occurs during the night, whereas in females,
nighttime secretion of GH corresponds to a smaller fraction of total daily GH secretion [
18
],
which confirms that GH and clock genes are in direct connection.
2.1. Growth Hormone-Releasing Hormone
GHRH belongs to the secretin family of peptide hormones, which includes glucagon,
secretin, vasoactive intestinal polypeptide, and others [
19
]. GHRH undergoes rapid enzy-
matic degradation in the blood via dipeptidyl peptidase IV [
20
] and therefore has negligent
serum levels. While the primary function of GHRH is considered to be regulating pi-
tuitary GH synthesis and release, GHRH has been observed to be produced and have
autocrine/paracrine effects in extra-pituitary tissues (Table 1) that stimulate cell prolifer-
ation and inhibit apoptosis [
19
]. GHRH has been shown to promote wound healing by
stimulating proliferation and survival of human dermal fibroblasts via signaling of the
GHRH receptor [21].

Int. J. Mol. Sci. 2021,22, 13205 3 of 12
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 13
stimulating proliferation and survival of human dermal fibroblasts via signaling of the
GHRH receptor [21].
Figure 1. Schematic representation of the HPS axis interacting with the human hair follicle. In the
HPS axis, GHRH acts on the GHRHRs in somatotropic cells of the anterior pituitary to release GH
systemically, which interacts with GHRs systemically, including in the HF. GHR activation in-
creases IGF-1 transcription, which exhibits negative feedback on GH synthesis in the anterior pitu-
itary and GHRH synthesis in the hypothalamus. GHRs have been found in the human HF. Stimu-
lation of GHRs in HFs ex vivo has shown to inhibit hair growth in female human scalp HFs via
upregulation of TGF-β2 (Alam, et al. 2019). HPS = hypothalamic-pituitary-somatotropic, GH =
Growth Hormone, GHR = Growth Hormone Receptor, GHRH = Growth Hormone-Releasing Hor-
mone, GHRHR = Growth Hormone-Releasing Hormone Receptor, IGF-1 = Insulin-like Growth Fac-
tor-1, TGF-β = transforming growth factor β.
Table 1. Extrapituitary GH, GHR, GHRH, and GHRHR localization in humans. Extrapituitary findings of GH mRNA and
protein, GHR mRNA and protein, GHRH mRNA and protein, and GHRHR and its splice variant 1 (SV1) mRNA and pro-
tein.
Molecule Organs Cell Type, Condition Reference
GH mRNA
Skin Primary Human dermal fibroblasts, in vitro [22]
Immune system Human, in vivo [22]
Testis Human, in vivo [22]
Ovary Human, in vivo [22]
Uterus Human, in vivo [22]
Mammary gland Human, in vivo [22]
GH protein
Bone Human, in vivo [22]
Muscle Human, in vivo [22]
Lymphoid tissue Human, in vivo [22]
Brain Human, in vivo [22]
Eye Human, in vivo [22]
Testis Human, in vivo [22]
Figure 1.
Schematic representation of the HPS axis interacting with the human hair follicle. In
the HPS axis, GHRH acts on the GHRHRs in somatotropic cells of the anterior pituitary to release
GH systemically, which interacts with GHRs systemically, including in the HF. GHR activation
increases IGF-1 transcription, which exhibits negative feedback on GH synthesis in the anterior
pituitary and GHRH synthesis in the hypothalamus. GHRs have been found in the human HF.
Stimulation of GHRs in HFs ex vivo has shown to inhibit hair growth in female human scalp
HFs via upregulation of TGF-
β
2 (Alam, et al., 2019). HPS = hypothalamic-pituitary-somatotropic,
GH = Growth Hormone,
GHR = Growth Hormone Receptor, GHRH = Growth Hormone-Releasing
Hormone, GHRHR = Growth Hormone-Releasing Hormone Receptor, IGF-1 = Insulin-like Growth
Factor-1, TGF-β= transforming growth factor β.
Table 1.
Extrapituitary GH, GHR, GHRH, and GHRHR localization in humans. Extrapituitary findings of GH mRNA and
protein, GHR mRNA and protein, GHRH mRNA and protein, and GHRHR and its splice variant 1 (SV1) mRNA and protein.
Molecule Organs Cell Type, Condition Reference
GH mRNA
Skin Primary Human dermal fibroblasts, in vitro [22]
Immune system Human, in vivo [22]
Testis Human, in vivo [22]
Ovary Human, in vivo [22]
Uterus Human, in vivo [22]
Mammary gland Human, in vivo [22]
GH protein
Bone Human, in vivo [22]
Muscle Human, in vivo [22]
Lymphoid tissue Human, in vivo [22]
Brain Human, in vivo [22]
Eye Human, in vivo [22]
Testis Human, in vivo [22]
Ovary Human, in vivo [22]
Salivary gland Human, in vivo [22]
Pancreas Human, in vivo [22]
Liver Human, in vivo [22]
Kidney Human, in vivo [22]
Colon Human, in vivo [22]
Stomach Human, in vivo [22]
Lung Human, in vivo [22]
Heart Human, in vivo [22]
GHR mRNA 1Human hair follicles Human, in vivo [23]

Int. J. Mol. Sci. 2021,22, 13205 4 of 12
Table 1. Cont.
Molecule Organs Cell Type, Condition Reference
GHR protein 1
Healthy female scalp skin Human, in vivo [23]
HF epithelium Human, in vivo [23,24]
ORS keratinocytes Human, in vivo [23,24]
Dermal fibroblasts Human, in vivo [23,24]
Sebocytes Human, in vivo [23,24]
Melanocytes Human, in vivo [23,24]
Matrix keratinocytes Human, in vivo [23,24]
GHRH mRNA
Placenta Human, in vivo [19]
Ovary Human, in vivo [19]
Testis Human, in vivo [19]
Malignant cells Human, in vivo [19]
GHRH protein
Myocardium Human, in vivo [19]
Lymphocytes Human, in vivo [19]
Testis Human, in vivo [19]
Ovary Human, in vivo [19]
Endometrium Human, in vivo [19]
GHRHR/SV1 mRNA
Non-Hodgkin’s lymphoma Human, in vivo [19,25]
Glioblastoma Human, in vivo [19,25]
Kidney Human, in vivo [19,25]
Liver Human, in vivo [19,25]
Lung Human, in vivo [19,25]
Prostate Human, in vivo [19,25]
GHRHR/SV1 protein
Prostate Human, in vivo [19,25]
Apocrine Glands Human, in vitro [26]
Dermal fibroblasts Human, in vitro [21]
1GHR mRNA and protein are found in almost every human tissue, so only relevant hair follicle and skin cell populations are listed.
The GHRH receptor (GHRHR) is a class II B GPCR found on the cell membrane of
the pituitary somatotroph. Activating this receptor stimulates the exocytosis of GH and
transcription of the GHRHR gene [
20
]. GHRHR activation is also vital to somatotroph cell
proliferation via
βγ
subunit-mediated activation of Ras-MAP kinase and ERK phosphory-
lation. Extrapituitary GHRH activity is mediated by GHRHR and its splice variant type 1
(SV1), found in several cancerous and noncancerous human tissues, including apocrine
glands and dermal fibroblasts (Table 1) [
21
,
25
,
26
]. GHRH signaling, via the GHRHR and
the SV1, has been implicated in the growth of human apocrine tumors and metastatic
melanoma [
21
,
27
]. GHRHR antagonists have been shown to inhibit cancer growth
in vitro
and in vivo and have anti-inflammatory and antioxidative effects [28,29].
2.2. Insulin-like Growth Factor-1
IGF-1, also called somatomedin-c, is a 70 amino acid protein with structural homology
to pro-insulin. Gene expression of IGF-1 has traditionally been thought to be regulated by GH
stimulation primarily in the liver. However, IGF-1 is expressed in most, if not all, tissues. GH
stimulation is known to regulate both IGF-1 and many IGF-binding proteins (IGFBPs) [30].
IGF-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor consisting of two
α
subunits and two
β
subunits synthesized from a single mRNA precursor. Activating
IGF1R leads to autophosphorylation of tyrosine kinases, leading to activation of several
downstream signaling pathways, all of which stimulate the growth and proliferation of
different cell populations [
30
]. For example, IGFs stimulate fibroblast proliferation, survival,
migration, and production of growth factors like platelet-derived growth factors A and
B [
31
]. IGF-1 is also known to be the most potent anagen prolonging growth factor in
HFs [
31
,
32
]. In addition, IGF1Rs were found to be expressed in the hair matrix and outer
root sheath keratinocytes of human scalp HF, where their signaling promotes proliferation
and maintains the anagen phase [23,24,32,33].
Human fibroblast culture
in vitro
and human skin ex vivo has been shown to increase
the expression of IGF-1/-2 and their receptors in response to GH and other factors [
23
,
24
].
IGF-1 plays a critical role in both skin and hair physiology, so it is not surprising to observe
GH influencing hair growth.

Int. J. Mol. Sci. 2021,22, 13205 5 of 12
3. Ex Vivo, rGH Induces Premature Catagen Entry in Female Hair Follicles
The known clinical hair phenotype associated with Laron syndrome or reduced GH
serum levels (Table 2), which is also associated with decreased expression of IGF-1, would
have led one to expect that the growth of organ-cultured human scalp HFs would be
promoted by GH treatment. Unexpectedly, GH-treated microdissected human female scalp
HFs showed premature catagen induction, most probably mediated via the upregulation of
the potent catagen-inducting growth factor, TGF-
β
2 [
23
]. Even though IGF-1 expression in
the outer root sheath keratinocyte was also upregulated, as expected, the overall increase
of TGF-
β
2 expression in response to GH treatment may have been dominant over IGF-1,
resulting in the observed growth inhibition in female HFs.
However, these phenomena may not necessarily reflect only the direct effects of
GHR stimulation within the HF itself. They might represent the overall HF response
to complex neuroendocrine changes associated with excessive or insufficient GH/GHR-
mediated signaling. For example, chronic excessive GH signaling interferes with insulin
and creates GH-induced insulin resistance [
34
]. Accordingly, many cutaneous findings
(listed in Table 2) are found both in settings of insulin resistance and GH excess.
Table 2.
Well-documented cutaneous manifestations of GH excess and deficiency in human skin.
First listed is growth hormone (GH) excess, leading to acromegaly or gigantism, as seen in soma-
totroph adenoma of the anterior pituitary, neurofibromatosis-1, McCune Albright syndrome, multiple
endocrine neoplasia type 1, Carney complex, and others. Then listed is growth hormone deficiency,
as seen in Noonan syndrome, Turner syndrome, Prader–Willi Syndrome, and Laron syndrome,
referenced from Kanaka-Gantenbein et al., 2016.
Condition Cutaneous Manifestation Reference
GH excess
Hypertrichosis
[35]
Hirsutism
Cutis verticis gyrata
Acrochordons
Lentiginous spots
Melanocytic nevi
Acanthosis nigricans
Acne
Seborrhea
Hyperidrosis
GH deficiency
Alopecia
[35,36]
Frontal hairline recession
Telogen effluvium
Dryness
Thinner dermis
Hypopigmentation
Hypohidrosis
SST Therapy Reversible scalp hair loss [37–40]
Low IGF-1 levels Hair loss [41]
GHRH deficiency No hair loss; delayed pigmentation [42]
4. Cutaneous Effects of Excessive or Reduced GH Receptor-Mediated Signaling Levels
Numerous extrapituitary tissues and cells express mRNA and protein for GH, GHRH,
along with their receptors, including the skin [
22
,
43
] and HF [
23
], but it remains unknown
whether human skin and its appendages transcribe and translate the GH and GHRH genes
in vivo
(Table 1). Most of what we currently know about the effects of GHR-mediated
signaling arises from clinical observations in patients with excessive or insufficient serum
levels of GH or defective GHR-mediated signaling.
Pathologies leading to GH deficiency, like Noonan Syndrome, Turner Syndrome,
and Prader–Willi syndrome, are associated with alopecia, telogen effluvium, and frontal
hairline recession [
35
]. These syndromes are also associated with hypogonadism, which is

Int. J. Mol. Sci. 2021,22, 13205 6 of 12
also known to be associated with alopecia [
44
]. However, the interplay of androgens and
GH on hair pathology is unknown and needs to be kept in mind. Male patients with GH
deficiency of any cause were found to have reduced sweating [
35
]. These clinical findings
clearly suggest that the HF and pilosebaceous unit [
45
,
46
] is a target for GH and can serve
as a model system for studying how GH impacts a human mini-organ model as previously
shown for other hormones (i.e., TRH, TSH, prolactin, CRH, ACTH). In this context, Laron
syndrome, characterized by a loss of function mutation in the growth hormone receptor
gene, leading to high levels of GH combined with low levels of IGF-1 [
47
], is particularly
instructive. Laron syndrome is associated with sparse hair growth, various degrees of
alopecia, and frontal hairline recession (Figure 2A). Structural defects are found under
microscopy such as grooving, tapered hair, pili torti and canaliculi, and trichorrhexis
nodosa [
48
] as well as hypotrichosis [
49
] (Table 2). Recently, Laron syndrome has been
mimicked in porcine models with GHR knockout mutations [
50
]. Both humans and the
porcine model develop juvenile hypoglycemia with preservation of glucose tolerance
and the development of normoglycemia with the onset of puberty [
51
]. Simulating GHR
deficiency in organ-cultured human HFs by knocking down GHR using our established
gene silencing methodology by transient siRNA transfection ex vivo [
32
,
52
,
53
] should
instructively complement the use of this porcine model.
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 7 of 13
and the development of normoglycemia with the onset of puberty [51]. Simulating GHR
deficiency in organ-cultured human HFs by knocking down GHR using our established
gene silencing methodology by transient siRNA transfection ex vivo [32,52,53] should in-
structively complement the use of this porcine model.
On the contrary, conditions of GH excess or deficiency have well-documented cuta-
neous manifestations (Table 2). Increased plasma GH level in burn patients leads to im-
proved re-epithelialization, increased granulation tissue, and reduced healing time [54].
Conditions with excess GH result in acromegaly in adulthood, and gigantism in child-
hood (before the epiphyseal growth plates fuse). Clinically, the leading cause of GH excess
is a GH-producing pituitary adenoma (incidence/prevalence: 0.4–1.1 cases per 100,000/4–
13 cases per 100,000 [55]), which occurs much more rarely than prolactin-secreting pitui-
tary adenomas. McCune Albright syndrome, neurorofibromatosis-1, multiple endocrine
neoplasia type 1, and Carney complex, which can also be associated with excessive GH
serum levels, are even more rarely encountered orphan diseases [35]. Despite their rarity,
the skin abnormalities seen in these diseases (Table 2) provide important clinical pointers
to the overall net impact of excessive GH serum levels on human skin and skin append-
ages in vivo. Excess GH is associated with hypertrichosis and hirsutism (Figure 2B), as well
as hyperhidrosis and increased sebum production [35].
Supplementing recombinant human growth hormone (rGH) may be key to therapies
for encouraging wound healing and preventing or reversing aging-related damage. Treat-
ing elderly men with rGH has led to an increase in skin thickness [56]. Increased plasma
GH in burn patients leads to improved epithelialization, increased granulation tissue, and
reduced healing time [54]. Recombinant GH in human skin mice models has been shown
to accelerate healing in pressure ulcer wounds [57]. Moreover, a large meta-analysis study
suggested that rGH treatment may be used in the treatment of diabetic foot ulcers in hu-
mans [58]. Indeed, GH is known to promote cell proliferation, stimulate immune cells,
and promote angiogenesis [57,59], all of which are known to be deficient in DFU patients.
Figure 2.
Impact of excessive and insufficient GHR stimulation on human scalp HFs: (
A
) HPS axis in the case of absent GH
signaling, like Laron’s syndrome, leading to almost absent levels of IGF-1 due to absent GHR stimulation. Clinical findings
include alopecia, frontal hairline recession, and structural defects. (
B
) HPS axis in the case of GH excess, like acromegaly,
which upregulates both IGF-1, an anagen promoter, and TGF-
β
, a catagen promoter. Clinically, acromegaly patients show
increased hair growth and hirsutism.
On the contrary, conditions of GH excess or deficiency have well-documented cu-
taneous manifestations (Table 2). Increased plasma GH level in burn patients leads to
improved re-epithelialization, increased granulation tissue, and reduced healing time [
54
].
Conditions with excess GH result in acromegaly in adulthood, and gigantism in childhood
(before the epiphyseal growth plates fuse). Clinically, the leading cause of GH excess is

Int. J. Mol. Sci. 2021,22, 13205 7 of 12
a GH-producing pituitary adenoma (incidence/prevalence: 0.4–1.1 cases per 100,000/4–
13 cases per 100,000 [
55
]), which occurs much more rarely than prolactin-secreting pituitary
adenomas. McCune Albright syndrome, neurorofibromatosis-1, multiple endocrine neo-
plasia type 1, and Carney complex, which can also be associated with excessive GH serum
levels, are even more rarely encountered orphan diseases [
35
]. Despite their rarity, the
skin abnormalities seen in these diseases (Table 2) provide important clinical pointers to
the overall net impact of excessive GH serum levels on human skin and skin appendages
in vivo
. Excess GH is associated with hypertrichosis and hirsutism (Figure 2B), as well as
hyperhidrosis and increased sebum production [35].
Supplementing recombinant human growth hormone (rGH) may be key to therapies
for encouraging wound healing and preventing or reversing aging-related damage. Treat-
ing elderly men with rGH has led to an increase in skin thickness [
56
]. Increased plasma
GH in burn patients leads to improved epithelialization, increased granulation tissue,
and reduced healing time [
54
]. Recombinant GH in human skin mice models has been
shown to accelerate healing in pressure ulcer wounds [
57
]. Moreover, a large meta-analysis
study suggested that rGH treatment may be used in the treatment of diabetic foot ulcers in
humans [
58
]. Indeed, GH is known to promote cell proliferation, stimulate immune cells,
and promote angiogenesis [57,59], all of which are known to be deficient in DFU patients.
5. Other Skin Phenotype Changes Associated with Signaling Abnormalities in the
Hypothalamic-Pituitary Somatotropic (HPS) Axis
SST analogues are used in therapies for several pathologies, including Merkel cell
carcinoma, pancreatic endocrine neoplasms, and pituitary adenomas [
60
,
61
]. The use of
SST analogues in therapies has been associated with scalp hair loss that resolves with
discontinuation of treatment [37–40].
Classically, SST downregulates GHRH and GH signaling, which decreases IGF-1
signaling downstream. Decreased IGF-1 levels in dermal papillary fibroblasts of the hair
follicle are found in balding scalp follicles when compared to nonbalding scalp HFs [
62
].
Furthermore, low circulating IGF-1 levels were associated with hair loss in middle-aged
women [
41
]. In one study observing patients post transsphenoidal adenomectomy, 54%
of patients who had acromegaly experienced hair loss 3 to 6 months postoperatively,
compared to 6% of patients who had nonfunctional adenomas [
36
]. This study also showed
hair loss was more common in patients cured by surgery than in non-cured patients, i.e.,
hair loss was more common in patients that experienced acute decreases in GH and/or
IGF-1, behaving as a relative insufficiency [
36
]. More interestingly, topical liposomal IGF-1
was associated with more rapid hair growth and thicker hair in a hamster model [63].
In mice, GHRH treatment was found to reverse age-related changes, increasing the
thickness of the epidermis and dermis, increasing moisture content, and improving the
morphology of the skin tissue and collagen fibers [
64
]. GHRH deficiency in a Brazilian
cohort showed delayed pigmentation, and reported to have youthful hair and no alopecia,
even with profoundly decreased serum GH and IGF-1 levels [
42
]. This cohort aligns with
GH acting as an inhibitor of hair growth previously seen ex vivo in female donors [
23
].
This population did show wrinkly skin, which implicates the HPS axis’ role in age-related
damaging of human skin even more.
6. Major Open Questions
The surprising hair growth-inhibitory results reported above ex vivo, including the
upregulation of TGF-
β
2, question conventional concepts that the direct stimulation of
GHR in human peripheral tissues always has a growth-stimulatory effect. It also raises
the question to which extent GH/GHR-mediated signaling has tissue- and context (sex)-
dependent outcomes in human skin and its appendages. We know that a strong positive
correlation exists between excess GH levels and insulin resistance and that both higher
GH serum levels and insulin resistance are found in females. This may, at least partially,
explain why the upregulation of IGF-1 after GH treatment in female scalp HFs ex vivo
did not prolong hair growth. One possibility to answer this question might be to inves-

Int. J. Mol. Sci. 2021,22, 13205 8 of 12
tigate if the same GH concentration tested in female HFs prolongs the anagen phase in
male scalp HFs via prominently increasing IGF-1 over any potential increase of TGF-
β
2
expression. Clinically, primary decreases in GH and IGF-1 have been associated with hair
loss and alopecia [
36
], while decreases in GH and IGF-1 due to GHRH deficiency have
not [
42
]. Furthermore, hair growth stimulation has been seen in acromegaly patients [
35
].
Understanding how hair and skin respond to GH and GHRH stimulation separately may
be key in understanding these discrepancies. Dissecting the effects of GH stimulation
in human HF and skin organ culture [
65
–
68
] in the presence/absence of GHR siRNA,
followed by laser capture microdissection-based RNAseq analysis of defined HF and skin
compartments or single-cell RNAseq, should help to clarify which cell population(s) in
human skin are most receptive to GHR stimulation. These studies can also shed light on
how they differ in their target genes and signaling pathways. Furthermore, GH signaling
in the skin and HF still needs to be further characterized in the context of GHRH, SST, and
IGF-1 expression, with any of their potential negative feedback mechanisms. Clinically,
GH excess and deficiencies are often accompanied by other hormonal abnormalities, such
as hypothyroidism and hyperprolactinemia, both of which are also known to affect hair
growth [
6
–
8
,
10
,
69
–
71
]. It will then be important to understand how these GH effects are
amplified or hampered by other hormone profiles (e.g., prolactin, TRH, TSH).
Understanding the growth hormone’s effect on the HF and skin and its related signal-
ing pathways is key to understanding future clinical therapies for dermatopathology. It
might be interesting to investigate the expression levels of the different members of the
HPS axis, keeping in mind potential sex differences in healthy skin and HFs as well as in
some hair growth disorders (telogen effluvium, female/male pattern hair loss, alopecia
areata). Moreover, since GH influences the expression level of IGF-1 and TGF-
β
2, it would
be interesting to evaluate the impact of GH/GHR signaling on the hair follicle immune
privilege (and consequently in alopecia areata) as both growth factors are well-known
immune privilege guardians. This raises the question regarding the potential insensibility
of the hair matrix and outer root sheath keratinocytes to some immune privilege guardians
under excessive GH stimulation, and if that contributes to a patient’s susceptibility to hair
disorders, such as alopecia areata, with excessive GH stimulation.
The effect of GHRH and GH on hair physiology and wound healing should be
further explored as well. GH and GHRH have both shown wound healing properties
ex vivo and shown to have a strong effect on human dermal fibroblast proliferation and
differentiation [
21
]. Robust clinical trials with rGH or rGHRH have yet to be done regarding
wound healing in humans.
This physiological loss of the HPS axis hormones with age may be a key player in
the aging process. Restoring GHRH and GH signaling could very well be a key player in
anti-aging therapies to inhibit or reverse age-related damage of the skin. The hormones
of the HPS axis are known to decrease with age, and mouse models have found anti-
aging properties with treatment of GHRH via reduction of malondialdehyde and matrix
metalloproteinases [64].
Recombinant growth hormone is very well-established and is safely used therapeu-
tically [
72
]. GH and GHRH have already been shown to have physiological effects on
catagen promotion, carcinogenesis, and wound healing. Understanding the potential
effects of the somatotrophic hormones in the HF can further help regulate hair cycling
and hair pathologies and guide novel therapies in wound healing and cancer. Indeed,
as suggested by our study [
23
], a slight change in GH levels may have a dramatic effect
on hair growth, suggesting GH levels and GHR stimulation needs to be fine-tuned and
tightly regulated. It might then be essential to measure with precision GH levels (not
only serum levels) to avoid unwanted effects, suggesting that GH disorders might require
personalized treatment.

Int. J. Mol. Sci. 2021,22, 13205 9 of 12
7. Conclusions
The human HF has been shown to express a wide array of neurohormones and even
display negative feedback mechanisms that mirror central neurohormone axes.
Both GH release and the HF exhibit circadian-dependent regulation that may be
interdependent.
Pathological GH serum levels produce profound clinical effects on hair. Excess GH
levels, and therefore excess GHR stimulation and excess IGF-1 levels are associated with
hypertrichosis and hirsutism. Absent GHR stimulation, and thus severely decreased IGF-1
levels, is associated with alopecia, telogen effluvium, frontal hairline recession, as well as
severe HF structural changes like pili torti et canaliculi and trichorrhexis nodosa.
GHRs are found in virtually every human tissue and prominently in the HF. Stimula-
tion of the GHR may have a profound effect on hair growth. Ex vivo, female human scalp
HFs were inhibited by GH stimulation, suggesting a complex sex-dependent interaction
between hair growth and GH stimulation.
Further investigation of how GH and GHR stimulation affect hair follicle biology can
guide feasible treatment options for different hair disorders.
Supplementary Materials:
The following are available online at https://www.mdpi.com/article/10
.3390/ijms222413205/s1.
Author Contributions:
Writing—original draft preparation, E.J.H.; figures and tables, E.J.H.; writing—
review and editing, J.C. and R.P. All authors have read and agreed to the published version of
the manuscript.
Funding:
This research was funded by a Frost Endowed Scholarship and start-up funds from the
Department of Dermatology, University of Miami, to R.P. Funding was also provided to E.J.H. by
the University of Miami Miller School of Medicine’s Dean’s Research Excellence Award in Medicine
(DREAM) Scholarship Program.
Conflicts of Interest: The authors declare no conflict of interest.
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