Background Hair and epithelial keratins constitute the major structural components of the skin and its appendages, including the hair fibre. While it is appreciated that selected steroid hormones regulate specific keratins, little is known about the neuroendocrine control of human hair keratin expression. Preliminary evidence had suggested that thyrotropin-releasing hormone (TRH) may regulate keratin gene transcription. Objectives To clarify whether TRH operates as a novel neuroendocrine regulator of human hair and epithelial keratin expression under physiologically relevant conditions in situ. Methods Microdissected human female scalp hair follicles (HFs) and female scalp skin were treated in serum-free organ culture for 12 h to 6 days with 100 ng mL -1 TRH or vehicle. Both quantitative immunohistomorphometry and quantitative real-time polymerase chain reaction were utilized to assess expression of selected keratins. Results TRH significantly increased expression of the hair keratins K31 and K32, while that of K85 and K86, and of the epithelial keratins K14 and K17, was reduced. In the interfollicular epidermis, TRH stimulated expression of K6, K14 and K17, both at the mRNA and protein levels. Stimulation of the same keratins was also evident in the eccrine sweat and sebaceous glands. Conclusions Selected human hair and epithelial keratins are modulated in situ. This may be relevant to explain hair shaft growth-promoting effects of TRH. Our pilot study suggests that the neuroendocrine controls that regulate the expression of human keratins deserve more systematic exploration and that these may be harnessed therapeutically. What's already known about this topic? Although keratins are one of the major structural components of the hair fibre and skin epithelium, their hormonal regulation is still relatively ill understood. Because the role of neuropeptide hormones in the control of keratin expression remains largely obscure, we have followed up preliminary microarray-based evidence which had suggested that thyrotropin-releasing hormone (TRH) may modulate keratin expression in human hair follicles. What does this study add? The current study provides evidence that the neuropeptide hormone TRH can act as a novel neuroendocrine modulator of the expression of human hair and epithelial keratins in situ; this identifies the neuroendocrine regulation of keratin expression as an exciting new research frontier in skin biology and dermatology. Together with the recently identified stimulatory activity of TRH on mitochondrial activity, hair pigmentation and hair growth in human skin, the potent keratin expression-modulating effects of TRH revealed here may serve as a basis for novel therapeutic strategies that recruit neurohormones to modulate keratin expression in human skin and its appendages.