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Thyroid Hormones Directly Alter Human Hair Follicle Functions: Anagen Prolongation and Stimulation of Both Hair Matrix Keratinocyte Proliferation and Hair Pigmentation
Abstract and Figures
Both insufficient and excess levels of thyroid hormones (T3 and T4) can result in altered hair/skin structure and function (e.g. effluvium). However, it is still unclear whether T3 and T4 exert any direct effects on human hair follicles (HFs), and if so, how exactly human HFs respond to T3/T4 stimulation.
Our objective was to asses the impact of T3/T4 on human HF in vitro.
Human anagen HFs were isolated from skin obtained from females undergoing facelift surgery. HFs from euthyroid females between 40 and 69 yr (average, 56 yr) were cultured and treated with T3/T4.
Studying microdissected, organ-cultured normal human scalp HFs, we show here that T4 up-regulates the proliferation of hair matrix keratinocytes, whereas their apoptosis is down-regulated by T3 and T4. T4 also prolongs the duration of the hair growth phase (anagen) in vitro, possibly due to the down-regulation of TGF-beta2, the key anagen-inhibitory growth factor. Because we show here that human HFs transcribe deiodinase genes (D2 and D3), they may be capable of converting T4 to T3. Intrafollicular immunoreactivity for the recognized thyroid hormone-responsive keratins cytokeratin (CK) 6 and CK14 is significantly modulated by T3 and T4 (CK6 is enhanced, CK14 down-regulated). Both T3 and T4 also significantly stimulate intrafollicular melanin synthesis.
Thus, we present the first evidence that human HFs are direct targets of thyroid hormones and demonstrate that T3 and/or T4 modulate multiple hair biology parameters, ranging from HF cycling to pigmentation.
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... Clinically, thyroid hormones (THs), namely triiodothyronine (T3) and L-thyroxine (T4), have long been appreciated as endocrine mediators whose serum levels potently affect human hair growth and hair shaft quality (van Beek et al. 2008;Gharaei Nejad et al. 2022;Hussein et al. 2023). Yet, THs remain to be systematically explored as a candidate for hair growth-modulatory therapeutics in dermatology (Hussein et al. 2023;Paus et al. 2020). ...
... THs alter hair growth in vivo in mice, rats, sheep, and humans (Hale and Ebling 1975;Hussein et al. 2023;Safer et al. 2001). Rapidly growing (anagen) human scalp HFs prominently express TRβ, can enzymatically deiodinate T4 into T3, and directly respond to TH stimulation ex vivo (van Beek et al. 2008;Kaplan et al. 1988;Safer et al. 2009). Human anagen scalp HFs are unusually sensitive to even minor variations in the serum level of the two main THs, T3, and T4 -independent of whether these are disease-related or caused by medication with T4, one of the most frequently prescribed drugs in clinical medicine (van Beek et al. 2008;Hussein et al. 2023). ...
... Rapidly growing (anagen) human scalp HFs prominently express TRβ, can enzymatically deiodinate T4 into T3, and directly respond to TH stimulation ex vivo (van Beek et al. 2008;Kaplan et al. 1988;Safer et al. 2009). Human anagen scalp HFs are unusually sensitive to even minor variations in the serum level of the two main THs, T3, and T4 -independent of whether these are disease-related or caused by medication with T4, one of the most frequently prescribed drugs in clinical medicine (van Beek et al. 2008;Hussein et al. 2023). In patients with hypothyroidism, this can result in substantially increased hair shaft shedding (telogen effluvium) and brittle, dull, and dry hair shafts (Freinkel and Freinkel 1972;Schell et al. 1991). ...
We have previously shown that the thyroid hormones triiodothyronine (T3) and thyroxine (T4) prolong anagen, mitigate stem cell apoptosis, and stimulate mitochondrial functions in microdissected human scalp HFs ex vivo. To circumvent the systemic adverse effects of T3/T4, we have asked in the current pilot study whether topically applied T3/T4 retains hair growth-promoting properties. To prove this, we have topically treated healthy full-thickness human scalp skin with T3 (1, 10nM) and T4 (1, 10μM) for six days in serum-free organ culture, using an HF-targeting vehicle that contains only FDA-approved ingredients. This showed that, at distinct doses, topical T3 and T4 significantly increased the percentage of HFs in anagen, decreased the percentage of proliferative (Ki-67+) cells in the hair matrix, did not promote melanogenesis (as measured by quantitative Warthin-Starry histochemistry), and significantly increased keratin 15 expression in the bulge. Finally, T3 and T4, at low concentrations, increase the expression of the hair growth promoters IGF-1 and FGF-7. The lower concentration of T3 and both of T4 also significantly increases the number of CD31+ endothelial cells, suggesting a pro-angiogenic effect, which is also important for hair growth promotion. These preliminary results strongly suggest that topically applied thyroid hormones promote hair growth in intact human scalp on multiple levels ex vivo. This invites the intermittent pulse application of topical T3 and T4 as a novel therapeutic intervention for managing hair loss disorders associated with telogen effluvium, such as androgenetic alopecia.
... The DEL is located in the intron 16 of TPO, overlapping an enhancer (GH02J001509) annotated by GeneHancer database that potentially regulates TPO and PXDN expression according to the Genehancer database [40]. Previous studies suggest that TPO is involved in thyroid hormone production, which in uences hair follicle pigmentation [44,45], and PXDN mutations can result in the white spot at the belly in mice [46]. ...
Background Structural variations (SVs) are important genomic elements in evolution and disease, yet they remain underutilized in genome-wide association studies (GWAS) due to technical challenges and high cost in their detection and genotyping. Results We developed a comprehensive haplotype reference panel incorporating over 35 million variants, including 172,569 SVs, from 943 Han Chinese individuals. Our novel hybrid phasing approach, combining long-read-based and statistical methods, achieved phasing accuracy in unrelated individuals comparable to trio-based phasing, and significantly reduced error rates for both small variants and SVs compared to conventional statistical phasing. The panel enabled a four-fold improvement in high-quality SV imputation and 31% higher SV imputation sensitivity compared to the expanded 1000 Genomes Project panel. GWAS analysis incorporating SVs identified 37 independent SV signals and 99 previously unreported regions across 62 skin-related phenotypes, demonstrating superior performance over GWAS using only short-read sequencing variants. Further analysis using our panel-imputed variants revealed two significantly associated SVs and two novel regions for fingerprint phenotypes, expanding upon findings from the original study that used the 1000 Genomes Project reference panel. Conclusions This study presents a comprehensive SV-enriched haplotype reference panel and demonstrates the value of including SVs in GWAS for understanding the genetic architecture of complex traits and diseases.
... Evidence provided by studies suggest the role of iron in the modulation of the enzyme tyrosinase, an essential enzyme in melanogenesis. In their study, van Beek et al. 2 showed that triiodothyronine (T3) and tetraiodothyronine (T4) can significantly stimulate melanin synthesis in the hair follicle. Many researchers believe that premature greying might be a predictor of an underlying systemic disease, particularly cardiovascular disease. ...
Context
Serum thyrotropin and thyroid hormone (TH) levels are routine markers of thyroid function. However, their diagnostic performance is limited under special conditions, such as in amiodarone-induced hyperthyroidism (AIH). Such cases would require the assessment of tissue TH action, which is currently unfeasible.
Objective
Development of an approach that determines how well serum parameters are reflected in tissue TH action of patients.
Methods
TH-responsive marker genes were identified from human hair follicles (HFs) with next-generation sequencing, validated by quantitative polymerase chain reaction. A classification model was built with these markers to assess tissue TH action and was deployed on amiodarone-treated patients. The impact of amiodarone on tissue TH action was also studied in thyroid hormone action indicator (THAI) mice.
Results
The classification model was validated and shown to predict tissue TH status of subjects with good performance. Serum- and HF-based TH statuses were concordant in hypothyroid and euthyroid amiodarone-treated patients. In contrast, amiodarone decreased the coincidence of serum-based and HF-based TH statuses in patients with hyperthyroidism, indicating that AIH is not unequivocally associated with tissue hyperthyroidism. This was confirmed in the THAI model, where amiodarone prevented tissue hyperthyroidism in THAI mice despite high serum free thyroxine.
Conclusion
We developed a minimally invasive approach using HF markers to assess tissue TH economy that could complement routine diagnostics in controversial cases. We observed that a substantial proportion of patients with AIH do not develop tissue hyperthyroidism, indicating that amiodarone protects tissues from thyrotoxicosis. Assessing tissue TH action in patients with AIH may be warranted for treatment decisions.
The review highlights the available published data on the etiopathogenesis of early graying, hair involution and restoration methods. Early graying of hair is defined as settlement before the age of 20 in Caucasians, before the age of 25 in Asians and before the age of 30 in Africans. In etiopathogenesis, an imbalance between oxidative stress and the antioxidant system is considered as the leading mechanism, a significant role is played by genetic predisposition, hormonal disorders of the thyroid gland, acute stress; the causes may also be deficiency of vitamin B12, copper, iron. Currently, the active molecule palmitoyl tetrapeptide-20 is used to prevent pigment loss and restore it. The endocannabinoid system in the hair follicle is also considered as a target for stimulation during the restoration of hair growth.
Background and aim
This case–control study was conducted to evaluate serum ferritin, vitamin D, and thyroid functions in patients with telogen effluvium (TE) in comparison with controls and to find if they can be used as diagnostic biomarkers of TE.
Patients and methods
A retrospective matched case–control study was performed using data from Hera Hospital database, Makkah, Saudi Arabia. The case records of 100 women diagnosed with TE and treated in the dermatology outpatient clinic were analyzed retrospectively. To obtain appropriate controls, records were searched for age-matched and sex-matched women who came to the hospital for a condition other than TE during the same period.
Results
The mean levels of patients’ serum ferritin and vitamin D were significantly lower than those of the controls. With respect to thyroid function tests, the mean levels of thyroid-stimulating hormone, thyroxine, and triiodothyronine showed no statistically significant differences between patients and controls. Although nonsignificant, 7% of patients with TE had laboratory evidence of hypothyroidism compared with 2% of controls, and 16% had subclinical hypothyroidism compared with 10% of controls, suggesting a role of thyroid dysfunction in TE.
Conclusions
Low serum ferritin, vitamin D deficiency, and thyroid dysfunction could be the risk factors for TE and can be used as diagnostic biomarkers of TE; hence, treating such patients with iron, vitamin D, and correction of thyroid dysfunction would be valuable. Prospective clinical studies with a larger number of participants are required to further address the risk factors for TE.
In wound healing and many pathologic conditions, keratinocytes become activated: they turn into migratory, hyperproliferative cells that produce and secrete extracellular matrix components and signaling polypeptides. At the same time, their cytoskeleton is also altered by the production of specific keratin proteins. These changes are orchestrated by growth factors, chemokines, and cytokines produced by keratinocytes and other cutaneous cell types. The responding intracellular signaling pathways activate transcription factors that regulate expression of keratin genes. Analysis of these processes led us to propose the existence of a keratinocyte activation cycle, in which the cells first become activated by the release of IL-1. Subsequently, they maintain the activated state by autocrine production of proinflammatory and proliferative signals. Keratins K6 and K16 are markers of the active state. Signals from the lymphocytes, in the form of Interferon-, induce the expression of K17 and make keratinocytes contractile. This enables the keratinocytes to shrink the provisional fibronectin-rich basement membrane. Signals from the fibroblasts, in the form of TGF-, induce the expression of K5 and K14, revert the keratinocytes to the healthy basal phenotype, and thus complete the activation cycle.Abbreviations: ERK, extracellularly regulated kinase; IKK, IkB kinase; IRAK, IL-1 receptor associated kinase; JAK, Janus activated kinase; MAPK, mitogen activated protein kinase; MEK, MAPK/ERK kinase; NIK, NFkB inducing kinase; PKC, protein kinase-C; TAK, TRAF associated kinase; TRADD, TNF receptor associated death domain; TRAF, TNF receptor associated factor
We have investigated expression of molecular elements of the hypothalamic-pituitary-adrenal (HPA) axis in the human retinal pigment epithelium (RPE) cells. The presence of corticotropin-releasing factor (CRF); urocortins I, II and III; CRF receptor type 1 (CRFR1); POMC and prohormone convertases 1 and 2 (PC1 and PC2) mRNAs were shown by RT-PCR; the protein products were detected by ELISA, western blot or immunocytochemical methods in an ARPE-19 cell line derived from an adult human donor. CRFR2 was below the level of detectability. The CRFR1 was functional as evidenced by CRF stimulation of cAMP and inositol triphosphate production as well as by ligand induction of transcriptional activity of inducible cis-elements cAMP responsive element (CRE), activator protein 1 responsive element (AP-1) and POMC promoter) in ARPE-19 using luciferase reporter assay. Immunoreactivities representative of CRF, pre-urocortin, CRFR1 receptor and ACTH were also detected in mouse retina by in situ immunocytochemistry. Finally, using RT-PCR, we detected expression of genes encoding four key enzymes participating in steroids synthesis (CYP11A1, CYP11B1, CYP17 and CYP21A2) and showed transformation of progesterone into cortisol-immunoreactivity in cultured ARPE-19 cells. Therefore, we suggest that ocular tissue expresses CRF-driven signalling system that follows organisational structure of the HPA axis.
Most pro-neuropeptides are processed by the prohormone convertases, PC1 and PC2. We previously reported that changes in thyroid status altered anterior pituitary PC1 mRNA and this regulation was due to triiodothyronine (T 3 )-dependent interaction of thyroid hormone receptor (TR) with negative thyroid hormone response elements (nTREs) contained in a large region of the human PC1 promoter. In this study, we demonstrated that hypothyroidism stimulated, while hyperthyroidism suppressed, PC1 mRNA levels in rat hypothalamus and cerebral cortex, but not in hippocampus. In situ hybridization was used to confirm real-time PCR changes and localize the regulation within the hypothalamus and cortex. Using a human PC1 (hPC1) promoter construct (with and without deletions in two regions that each contain a negative TRE) transiently transfected into GH3 cells, we found that T 3 negatively regulated hPC1 promoter activity, and this regulation required both of these two regions. Electrophoretic mobility shift assays (EMSAs) using purified thyroid hormone receptor α1 (TRα1) and retinoid X receptor β (RXRβ) proteins demonstrated that RXR and TRa both bound the PC1 promoter. Addition of TRα1/RXRβ to the wild-type PC1 probe demonstrated binding as both homodimers and a heterodimer. EMSAs with oligonucleotides containing deletion mutations of the putative nTREs demonstrated that the proximal nTRE binds more strongly to TR and RXR than the distal nTRE, but that both regions exhibit specific binding. We conclude that there are multiple novel TRE-like sequences in the hPC1 promoter and that these regions act in a unique manner to facilitate the negative effect of thyroid hormone on PC1.
The relative proportions of telogen (club) to anagen (growing) hairs in the scalp were examined in hypothyroid subjects with hair loss to asses the basis for the alopecia which occurs when thyroid hormone is lacking. Patients with spontaneous as well as iatrogenic myxedema were examined and serial measurements were secured during restoration of eumetabolism. In all instances, deficiency of thyroid hormone was associated with an increase in the percentage of telogen hairs. Normal telogen-anagen hair relationships were restored during replacement therapy with thyroid hormone; this response was elicited even during the concurrent administration of antithyroid drugs (ie, thiourylenes). The response to treatment with thyroid hormone and the temporal correlations indicate that the alopecia is mediated via effects of the hormone on the initiation as well as the duration of hair growth.
Numerous systemic disorders can lead to ocular involvement. Corneal findings in systemic diseases sometimes help to find the diagnosis or monitor the treatment. Some corneal changes are without consequences; some are disastrous, threatening vision and the eye itself. Keratoconjunctivitis and sclerokeratitis are manifestations of collagen vascular diseases. Crystalline deposits of the cornea can be found in multiple myeloma and gammopathies. Keratoconjunctivitis in ocular rosacea can be effectively treated with systemic doxycycline and tetracycline hydrochloride. Several dermatologic disorders can lead to chronic keratoconjunctivitis in which long-term sequelae can lead to corneal perforation. Various corneal infectious diseases can be observed in patients with AIDS. Graft-versus-host disease can lead to severe ocular complications resulting in corneal perforation.
Background and objectivesDarkening of gray and white hairs occurred in 2 patients with increased exogenous triiodothyronine (T3) due to treatment of myxedema coma in one case and iatrogenic hyperthyroidism in the other. We hypothesized that thyroid hormone may affect the homeostasis of hair follicles. To test our hypothesis and investigate the influence of thyroid hormone on the hair cycle, we used an in vivo murine model and an in vitro model based on culture of follicular units.
The human keratin family comprises 54 members, 28 type I and 26 type II. Out of the 28 type I keratins, 17 are epithelial and 11 are hair keratins. Similarly, the 26 type II members comprise 20 epithelial and 6 hair keratins. As, however, 9 out of the 37 epithelial keratins are specifically expressed in the hair follicle, the total number of hair follicle-specific keratins (26) almost equals that of those expressed in the various forms of epithelia (28). Up to now, more than half of the latter have been found to be involved in inherited diseases, with mutated type I and type II members being roughly equally causal. In contrast, out of the 26 hair follicle-specific keratins only 5 have, at present, been associated with inherited hair disorders, while one keratin merely acts as a risk factor. In addition, all hair follicle-specific keratins involved in pathologies are type II keratins. Here we provide a detailed description of the respective hair diseases which are either due to mutations in hair keratins (monilethrix, ectodermal dysplasia of hair and nail type) or hair follicle-specific epithelial keratins (two mouse models, RCO3 and Ca(Rin) as well as pseudofolliculitis barbae).
A literature review tries to diminish the ambiguity between hormones and hairs. Therefore the hormonal action in general (regulation of the protein synthesis indirectly by enzymatical regulation of the AMP-system or directly by hormones as active metabolites) and the methods to explore hormones-hair-interaction are discussed. Hormones pertaining to the pituitary-adrenal-gonadal axis are regarded as the paramount hormones; therefore the results of research in testosterone, 5-alpha-dihydrotestosterone, estrogens, progesterone, glucocorticoids, the hypophysis and its tropins are recapitulated. The main disorders of hair-growth, pattern baldness and "idiopathic" hirsutism, which would be dependent on a similar disturbance of androgen metabolism, are discussed. Pathology in hair-growth may arise in any point of the cascade of hormone action.