Does D matter? The role of vitamin D in hair disorders and hair follicle cycling1. Department of Dermatology, University of Texas and MD Anderson Cancer Center, Houston, Texas. firstname.lastname@example.org
Karrie T Amor MD1, Rashid M Rashid MD PhD1, Paradi Mirmirani MD2,3,4
Dermatology Online Journal 16 (2): 3
2. Department of Dermatology, The Permanente Medical Group, Vallejo, California
3. Department of Dermatology, Case Western Reserve University, Cleveland, Ohio 4. University of California, San Francisco, California
Background: The role of vitamin D in the proliferation and differentiation of keratinocytes is well known within the field of dermatology. Objective: We sought to evaluate the role that vitamin D and the vitamin D receptor play in the hair cycle and assess how this can be clinically applied to the treatment of hair disorders. Methods: A MEDLINE search (1955-July 2009) was preformed to find relevant articles pertaining to vitamin D, the vitamin D receptor, and hair loss. Results: The vitamin D receptor, independent of vitamin D, plays an important role in hair cycling, specifically anagen initiation. The role of vitamin D in hair follicle cycling is not as well understood. Limitations: The review is broad and there are limited human studies available to date. Conclusion: Additional studies to evaluate the role of vitamin D in the hair cycle should be done. Treatments that up regulate the vitamin D receptor may be successful in treating hair disorders and are a potential area of further study.
Vitamin D is a steroid hormone that is synthesized in the epidermal keratinocytes under influence of UV-B light (290-315 nm) or acquired in the diet and dietary supplements. Vitamin D needs both 25- and 1-alpha-hydroxylation to become the active hormone 1,25-dihydroxyvitamin D . It is estimated that approximately 3 percent of the human genome is regulated directly or indirectly by the vitamin D endocrine system . The vitamin D receptor (VDR), a nuclear hormone receptor, can up regulate or down regulate gene transcription in both a 1,25-dihydroxyvitamin D dependent and a 1,25-dihydroxyvitamin D independent fashion . As such, the impact of vitamin D on human physiology and disease is broad and there is wide interest in the role of this hormone in many areas of medicine. New research demonstrating a high percentage of vitamin D deficiency or insufficiency in the population has sparked debate and controversy as to whether various disorders such as melanoma, premature aging, and cardiac disease among others can be correlated with inadequate vitamin D [3, 4, 5].
Within the field of dermatology, the role of vitamin D in the proliferation and differentiation of keratinocytes has been extensively studied and well reviewed in the literature . In addition, vitamin D analogs, such as calcitriol (a vitamin D3 analog), have been used clinically to treat psoriasis for almost a decade and there is extensive literature on their use and mechanism of action [7, 8].
The purpose of this review is to examine the role of vitamin D in hair growth and the hair cycle; we discuss the possible implications of vitamin D in the clinical care of patients with hair disorders.
Hair growth and hair cycle
The formation of the hair follicle during embryogenesis requires reciprocal signaling between the epithelium and mesenchymal cells. The major epithelial-derived signaling molecules involved in the early stages of hair follicle morphogenesis include fibroblast growth factors (FGF), bone morphogenic proteins (BMP), and sonic hedgehog (SHH) [9, 10].These signals result in elongation of the hair follicle in embryogenesis. The first hair cycle after birth is unique because it represents the completion of the embryological development of the hair follicle and it is not dependent on the factors required for the maintenance of the hair follicle postnatally . Therefore, deficiencies in factors required for maintenance of the hair cycle are not evident until the first hair is shed.
The maintenance of the hair follicle postnatally is dependent on the integrity of the dermis, epidermis, and the normal hair cycle. The hair cycle consists of three phases: anagen, catagen, and telogen. The anagen phase is the growth phase of the hair cycle. Anagen is initiated by signals from the mesodermal dermal papilla cells, which are at the base of the hair follicle, to the keratinocyte/hair follicle stem cells, which are located in the bulge of the hair follicle. These signals stimulate the follicular stem cell to proliferate and differentiate into a mature hair follicle, which consists of an outer root sheath, the inner root sheath, and the hair shaft. Approximately 85 percent of hairs are in anagen phase at one time, and this phase lasts two to six years. The catagen phase is the transition phase, which occurs when the anagen follicle receives a signal ends the growth phase. In catagen, apoptosis of the lower part of the hair follicle, located below the bulge, occurs. The dermal papilla cells also break away from the hair follicle and enter a rest stage. The catagen phase lasts one to two weeks. At the conclusion of the catagen phase, the hair follicle is one-sixth its original diameter. Telogen is the final phase of the hair cycle. It is also known as the resting phase. This phase lasts five to six weeks, until anagen is initiated again .
The role of the vitamin D receptor (VDR) in the hair cycle was first suggested by the observation of alopecia in patients with type IIA vitamin D dependent rickets (VDDR IIA) . VDDR IIA is an autosomal recessive disorder due to a defect in the VDR and is characterized by hypocalcemia, hypophosphatemia, hyperparathyroidism, rickets, osteomalacia, dental caries, and alopecia universalis . Patients with VDDR IIA have normal hair at birth, possibly because they have normal hair follicle morphogenesis, but they lose their hair between 1 to 3 months of age [1, 5]. The histological results of VDDR IIA alopecia include a normal infundibular portion of the hair follicle but the lower two-thirds of the hair follicle, below the level of the sebaceous glands is replaced by irregular epithelial structures and dermal cysts . Thus, it has been proposed that normal function of VDR is essential for initiation of the first postnatal hair cycle.
Like VDDR IIA, generalized atrichia, a rare hereditary condition caused by mutations in the Hairless gene, is associated with alopecia universalis that develops shortly after birth. The histological and phenotypic patterns in generalized atrichia are remarkably similar to those seen in VDDR IIA. This similarity suggests that the VDR gene and the Hairless gene are both involved in the same genetic pathway that regulates the postnatal cycle of the hair follicle [15, 16, 17].
In vitro studies
In vitro studies have supported the concept that VDR may play a vital role in the postnatal maintenance of the hair follicle. Mesodermal papilla cells and the outer root sheath of epidermal keratinocytes express VDR in varied degrees in correlation with the stages of the hair cycle . In late anagen and catagen there is an increase in VDR, which is associated with decreased proliferation and increased differentiation of the keratinocytes. These changes are thought to promote the progression of the hair cycle .
Animal models: VDR knockout mice
The role of the VDR in the hair cycle has been studied with a VDR knockout mouse model. The VDR homozygous knockout mouse model is phenotypically similar to humans with VDDR IIA. These mice are born with hair, possibly because they have normal follicular morphogenesis, but develop hair loss by 3 months of age and total hair loss by 8 months of age. The histopathology is similar, with dilation of the hair follicles and formation of dermal cysts that form at three weeks of age . Normalization of mineral ion homeostasis by a diet high in calcium, phosphorous, and lactose prevents hyperparathyroidism, rickets, and osteomalacia. However, like humans, the mice continue to develop alopecia regardless of their mineral homeostasis, suggesting that the mechanism for alopecia is unrelated to mineral levels .
This mouse model has been studied by multiple investigators. Sakai et al. showed that the alopecia in VDR knockout mice was due to a defect in the postnatal initiation of the hair cycle . When anagen was induced by depilation at 18 days of age, VDR knockout mice failed to initiate anagen and remained alopecic, unlike the wild type controls. Because 1,25-dihydroxyvitamin D levels are high in VDR knockout mice and 1,25-dihydroxyvitmain D has been shown to inhibit keratinocyte proliferation and promote differentiation, it was hypothesized that the inability to initiate anagen was secondary to toxic levels of 1,25-hydroxyvitamin D. This hypothesis was later disproven when it was shown that VDR knockout mice raised in an ultraviolet light free environment and fed a diet lacking in vitamin D metabolites still developed alopecia despite undetectable levels of circulating 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D . Panda et al. showed that mice with an alpha 1-hydroxylase deficiency, and therefore an inability to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, did not develop alopecia . This study further supported that toxic levels of vitamin D metabolites do not cause alopecia. Therefore, the alopecia seen in VDR knockout mice appears to be directly related to the lack of VDR.
To further evaluate this hypothesis, hair reconstitution assays were performed in nude mice. These showed normal follicular morphogenesis regardless of the VDR genotype of the keratinocytes and dermal papilla cells used, confirming that VDR is not required for prenatal follicle development . However, the presence of VDR in the keratinocyte is essential for anagen initiation  and alopecia could be prevented in VDR knockout mice when wild-type VDR is targeted to VDR keratinocytes . Hence, the absence of VDR in the keratinocyte is responsible for the formation of alopecia in VDR knockout mice. In addition to its role in anagen initiation, studies suggest that the vitamin D receptor is required for normal differentiation of the interfollicular epidermis and the hair follicle .
The functional domains of the VDR are involved in anagen initiation to various degrees. When VDR-null keratinocytes express a VDR transgene with a mutation in the hormone binding domain, the normal hair cycle is restored . However, when VDR-null keratinocytes express a VDR transgene with a mutation in the activation function 2 domain, which impairs nuclear receptor coactivation, the traditional VDR knockout phenotype persists. These results imply that VDR is responsible for hair cycle independent of ligand binding.
Role of VDR and the hairless gene
It has been observed that Hairless knockout mice and VDR knockout mice have phenotypically and histologically similar alopecias. Therefore, it was hypothesized that an abnormal expression of Hairless (Hr), a nuclear receptor co-repressor that binds directly to VDR, independent of vitamin D, and represses transcription, may be the cause of the alopecia seen in VDR knockout mice [24, 25, 26]. Studies have shown Hr levels in the VDR knockout mice to be higher than controls, and these levels peak in catagen. These results also suggest that VDR plays a role in regulation of Hr .
VDR and the retinoid X receptor
The retinoid X receptor (RXR) is expressed in the skin and can homodimerize or heterodimerize with the VDR . Mice with targeted deletions of RXR also develop alopecia similar to VDR knockout mice, suggesting that VDR-RXR heterodimerization is needed for postnatal hair cycle. Interestingly, the occurrence of increased hair shed with treatment with oral retinoids has been widely reported, however the mechanism of this hair loss is not well understood .
VDR and the canoncial Wnt signaling pathway
The canonical Wnt signaling pathway has been found to play an important role in follicle development. VDR, Lef1, and beta-catenin form a complex that activates the canonical Wnt pathway . Similar to the VDR knockout mice and Hairless knockout mice, mice that express the keratinocyte-specific Lef1 transgene mutation that prevents Lef1 from interaction with beta-catenin develop alopecia associated with dermal cysts and increased sebaceous glands . When VDR is absent, the synergistic activation of a Wnt response element by beta-catenin and Lef1 is prevented . The Hairless gene also plays a role in promotion of the canonical Wnt signaling pathway . Therefore, impairment of canonical Wnt signaling may explain the total alopecia observed in both VDR knockout mice and Hairless knockout mice .
Animal studies on clinical application of vitamin D in the hair cycle
The effect of topical calcitriol on cyclophosphamide chemotherapy-induced alopecia has been studied in mouse models . Although pretreatment with 0.45 micrograms of topical calcitriol for five days prior to chemotherapy did not prevent chemotherapy-induced alopecia, it accelerated and enhanced hair shaft regrowth after chemotherapy-induced alopecia occurred . The accelerated hair regrowth occurred over the entire animal, not just the site of topical calcitriol application. It was suggested that the hair follicles pretreated with calcitriol favored the “dystrophic catagen pathway” of response to chemical injury, which allows for fast reconstruction of an undamaged anagen hair bulge [33, 34].
Subsequently, researchers used a rat model to study the protective effect of intramuscular vitamin D3 (calcitriol) from radiation-induced hair toxicity . In contrast to controls, the animals pretreated with intramuscular vitamin D had no significant difference between the number of hair follicles in the irradiated field and the outside fields  Also, immunohistochemical studies showed that the mice pretreated with vitamin D3 had a stronger immunoreactivity for VDR than controls . This study suggests that vitamin D3 may play a protective role in radiation-induced alopecia, possibly by upregulating VDR. Additional studies need to be done to further investigate this effect . Several vitamin D3 analogs have been developed that are more potent than physiologically active 1,25-dihydroxyvitamin D3 at inducing differentiation and inhibiting proliferation, and produce less hypercalcemia. Vegesna et al. studied the ability of vitamin D3 analogs to stimulate hair growth in nude mice, which are born with a congenital alopecia due to a defect in the Whn transcription factor . They found that the more potent vitamin D3 analogs stimulated hair growth but the parent compound did not. The formation of normal hair follicles caused by the vitamin D3 analogs occurred in a cyclical pattern and was associated with increased expression of keratins, which are the target genes of Whn. When these compounds were given to wild type mice after hair plucking to stimulate anagen, the rate of hair growth was not accelerated. These results suggest that vitamin D3 analogs act downstream of Whn, but do not play a role in the induction of anagen.
Human studies done to investigate the clinical applications of the role of the vitamin D and the hair cycle
Limited studies have been done in humans to elaborate the role of vitamin D in the hair cycle. A potential application for vitamin D is in chemotherapy-induced alopecia. Topical calcitriol has been shown to protect against chemotherapy-induced alopecia caused by paclitaxel and cyclophosphamide [33, 38, 39]. However, topical calcitriol failed to protect against chemotherapy-induced alopecia caused by a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide and a combination of cyclophosphamide, methotrexate, and 5-fluorouracil [36, 37]. The ability of topical calcitriol to prevent chemotherapy-induced alopecia may therefore depend on the chemotherapy agents used. Of note, the studies in which no effects were observed, were small and may have used doses of vitamin D that were inadequate to protect against chemotherapy-induced alopecia. The more potent vitamin D3 analogs used on mice by Vegesna et al. have yet to be evaluated in humans.
Another potential application for vitamin D is in hair loss due to scalp psoriasis, which is associated with an increased telogen to anagen ratio. Although vitamin D3 analogs have been used in combination or as an alternative to topical steroids to treat scalp psoriasis for many years, their ability to combat the associated alopecia has not been thoroughly evaluated. A placebo-controlled trial with 26 patients showed that calcipotriol did not affect the telogen to anagen ratio after 6 weeks of treatment , but the optimal effect of calcipotriol on scalp psoriasis is not seen until 8 weeks . Thus, the follow up may have been too brief to detect an effect of calcipotriol on hair loss.
It has been suggested that an optimal concentration of vitamin D is necessary to delay the aging phenomena, including hair loss. A cross sectional study of 296 healthy men was done to determine the association, if any, between male pattern baldness and serum 25-hydroxyvitamin D levels . Based on this study, the extent and severity of male pattern baldness does not appear to be associated with serum 25-hydroxyvitamin D levels (p=0.60) . Additional studies in subjects with age-related or senescent thinning as well as in women with female pattern hair loss could be considered to see if there is an association of hair loss with serum 25-hydroxyvitamin D levels.
Because it is known that the absence of VDR leads to alopecia, it was hypothesized that there may be VDR gene polymorphisms (Bsml, Apal, and Taql) in patients with alopecia areata. A study of VDR genotypes in 32 patients with alopecia areata and 27 controls showed no association between these VDR gene polymorphisms and alopecia areata . A separate study also showed that there was no relationship between the VDR gene FokI polymorphism and alopecia areata . These studies were small and limited to only one ethnic group, Caucasians in Turkey.
Extensive data from animal models clearly show that the VDR, independent of vitamin D3 hormone, plays an important role in the hair follicle cycle, specifically anagen initiation. Studies have demonstrated the ability of vitamin D3 analogs to stimulate hair regrowth, but clinical trials of calcitriol in humans have been unable to replicate these results. Reasons for this may be that more potent analogs of vitamin D3 were used in the animal studies than the human trials. Also, the mechanism of hair recovery in nude mice may not be applicable to humans with alopecia. The latter is reflected in one study that used nude mice with congenital alopecia, which does not have an equivalent in humans. This review shows the need for further exploration of the role of vitamin D and the VDR in the hair cycle. For clinical hair disorders in which there is an abnormal hair cycle, such as chemotherapy-induced alopecia, treatments that up regulate the expression of the vitamin D receptor may be successful. Developments of such treatments are a future area of study. Furthermore, studies on the optimal levels of local and systemic vitamin D levels are still limited and there is currently no evidence-based data to recommend vitamin D supplementation for various types of alopecia. In order to fully understand the effects of vitamin D supplementation in alopecia, future studies should compare results in vitamin D deficient patients to those in vitamin D sufficient patients.
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