Context: Both insufficient and excess levels of thyroid hormones (T 3 and T 4 ) can result in altered hair/skin structure and function (e.g. effluvium). However, it is still unclear whether T 3 and T 4 exert any direct effects on human hair follicles (HFs), and if so, how exactly human HFs respond to T 3 /T 4 stimulation.Objective: Our objective was to asses the impact of T 3 /T 4 on human HF in vitro. Methods: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 T 3 /T 4 . Results:Studying microdissected, organ-cultured normal human scalp HFs, we show here that T 4 up-regulates the proliferation of hair matrix keratinocytes, whereas their apoptosis is down-regulated by T 3 and T 4 . T 4 also prolongs the duration of the hair growth phase (anagen) in vitro, possibly due to the down-regulation of TGF-␤2, 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 T 4 to T 3 . Intrafollicular immunoreactivity for the recognized thyroid hormone-responsive keratins cytokeratin (CK) 6 and CK14 is significantly modulated by T 3 and T 4 (CK6 is enhanced, CK14 down-regulated). Both T 3 and T 4 also significantly stimulate intrafollicular melanin synthesis. Conclusions:Thus, we present the first evidence that human HFs are direct targets of thyroid hormones and demonstrate that T 3 and/or T 4 modulate multiple hair biology parameters, ranging from HF cycling to pigmentation. (J Clin Endocrinol Metab 93: 4381-4388, 2008) C linically, it has long been observed that patients with thyroid dysfunction may show prominent hair abnormalities (1-4) and several in vivo studies have demonstrated (partially conflicting) hair growth-modulatory effects of thyroid hormone (TH) in sheep, rats, and mice (5-8). In humans, hypothyroidism can be associated with telogen effluvium, along with the presentation of dry, brittle, and dull hair shafts (2-4). Confusingly, hyperthyroid states can also lead to effluvium, together with thinned hair shaft diameter and brittle, greasy hair (1, 9 -11), despite an apparently increased hair matrix proliferation (3). Hair shafts of patients with hyperthyroidism also show substantially reduced tensile strength (10). Early graying has been claimed to be related to autoimmune thyroid disease, hypothyroidism, and hyperthyroidism (11, 12), whereas darkening of

Background: Genetic and environmental factors are involved in the pathogenesis of autoimmune thyroid disease (AITD). Family members of patients with AITD are at increased risk for AITD, but not all will develop overt hypothyroidism or hyperthyroidism. Our goal was to develop a simple predictive score that has broad applicability and is easily calculated at presentation for progression to overt hypothyroidism or hyperthyroidism within 5 years in female relatives of patients with AITD. Methods: We conducted a prospective observational cohort study of 790 healthy first-or second-degree female relatives of patients with documented Graves or Hashimoto disease in the Netherlands. Baseline assessment included measurement of serum thyrotropin (TSH), free thyroxine (FT 4), and thyroid peroxidase (TPO) antibody levels as well as evaluation for the presence and levels of Yersinia enterocolitica antibodies. We also gathered data on family background, smoking habits, use of estrogen medication, pregnancy, and exposure to high levels of iodine. In follow-up, thyroid function was investigated annually for 5 years. As main outcome measures, termed events, we looked for overt hypothyroidism (TSH levels Ͼ5.7 mIU/L and FT 4 levels Ͻ0.72 ng/dL) or overt hyperthyroidism (TSH levels Ͻ0.4 mIU/L and FT 4 levels Ͼ1.56 ng/dL). Results: The cumulative event rate was 7.5% over 5 years. The mean annual event rate was 1.5%. There were 38 hypothyroid and 13 hyperthyroid events. Independent risk factors for events were baseline findings for TSH and TPO antibodies in a level-dependent relationship (for TSH the risk already starts to increase at values Ͼ2.0 mIU/L) and family background (with the greatest risk attached to subjects having 2 relatives with Hashimoto disease). A numerical score, the Thyroid Events Amsterdam (THEA) score, was designed to predict events by weighting these 3 risk factors proportionately to their relative risks (maximum score, 21): low (0-7), medium (8-10), high (11-15), and very high (16-21). These THEA scores were associated with observed event rates of 2.7%, 14.6%, 27.1%, and 76.9%, respectively. Conclusions: An accurate simple predictive score was developed to estimate the 5-year risk of overt hypothyroidism or hyperthyroidism in female relatives of patients with AITD. However, in view of the small number of observed events, independent validation of the THEA score is called for.

Several elements of the hypothalamic-pituitary-thyroid axis (HPT) reportedly are transcribed by human skin cell populations, and human hair follicles express functional receptors for TSH. Therefore, we asked whether the epidermis of normal human skin is yet another extrathyroidal target of TSH and whether epidermis even produces TSH. If so, we wanted to clarify whether intraepidermal TSH expression is regulated by TRH and/or thyroid hormones and whether TSH alters selected functions of normal human epidermis in situ. TSH and TSH receptor (TSH-R) expression were analyzed in the epidermis of normal human scalp skin by immunohistochemistry and PCR. In addition, full-thickness scalp skin was organ cultured and treated with TSH, TRH, or thyroid hormones, and the effect of TSH treatment on the expression of selected genes was measured by quantitative PCR and/or quantitative immunohistochemistry. Here we show that normal human epidermis expresses TSH at the mRNA and protein levels in situ and transcribes TSH-R. It also contains thyrostimulin transcripts. Intraepidermal TSH immunoreactivity is up-regulated by TRH and down-regulated by thyroid hormones. Although TSH-R immunoreactivity in situ could not be documented within the epidermis, but in the immediately adjacent dermis, TSH treatment of organ-cultured human skin strongly up-regulated epidermal expression of involucrin, loricrin, and keratins 5 and 14. Thus, normal human epidermis in situ is both an extrapituitary source and (possibly an indirect) target of TSH signaling, which regulates defined epidermal parameters. Intraepidermal TSH expression appears to be regulated by the classical endocrine controls that determine the systemic HPT axis.

Thyrotropin-releasing hormone (TRH) is the most proximal component of the hypothalamic-pituitary-thyroid axis that regulates thyroid hormone synthesis. Since transcripts for members of this axis were detected in cultured normal human skin cells and since human hair follicles (HFs) respond to stimulation with thyrotropin, we now have studied whether human HF functions are also modulated by TRH. Here we report that the epithelium of normal human scalp HFs expresses not only TRH receptors (TRH-R) but also TRH itself at the gene and protein level. Stimulation of microdissected, organ-cultured HFs with TRH promotes hair-shaft elongation, prolongs the hair cycle growth phase (anagen), and antagonizes its termination by TGF-beta2. It also increases proliferation and inhibits apoptosis of hair matrix keratinocytes. These TRH effects may be mediated in part by reducing the ATM/Atr-dependent phosphorylation of p53. By microarray analysis, several differentially up- or down-regulated TRH-target genes were detected (e.g., selected keratins). Thus, human scalp HFs are both a source and a target of TRH, which operates as a potent hair-growth stimulator. Human HFs provide an excellent discovery tool for identifying and dissecting nonclassical functions of TRH and TRH-mediated signaling in situ, which emerge as novel players in human epithelial biology.

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