Hair Loss

Am J Pathol. 2006 March; 168(3): 748–756.
doi: 10.2353/ajpath.2006.050468. PMCID: PMC1606541

Copyright © American Society for Investigative Pathology

Title: Human Scalp Hair Follicles Are Both a Target and a Source of Prolactin, which Serves as an Autocrine and/or Paracrine Promoter of Apoptosis-Driven Hair Follicle Regression

Kerstin Foitzik et al

From "discussion" section

" Here, we provide the first evidence that human scalp HFs not only express functional PRL-R but also serve as an important extrapituitary site of PRL expression on the gene and protein level (Figure 1, A–D, and Figure 4). Given that human skin has been calculated to display ~5 million HFs, this calls attention to a very substantial, newly identified source of potential PRL synthesis in humans. This deserves further scrutiny and characterization, eg, in healthy versus inflamed human skin, and definition of the quantity of HF-derived PRL that is actually secreted systemically and thus exerts genuine endocrine, rather than autocrine or paracrine activities.Although our finding of intracutaneous transcription of the PRL gene in human skin in situ is well in line with the previous finding of PRL transcription in murine skin in vivo and in human cultured dermal fibroblasts, keratinocytes, and sweat glands in vitro,36,39 it conflicts with the report of Slominski and colleagues40 who could not detect PRL mRNA in human skin by RT-PCR. In our experiments, we detected PRL transcripts of the expected length both in human full-thickness skin and in isolated human HFs, using pituitary gland as positive control, and confirmed our data by sequencing the PRL RT-PCR product. The negative PRL expression data of Slominski and colleagues40 may be related to the fact that these investigators studied sun-exposed truncal skin (containing primarily vellus HFs, approximately half of which are in the telogen stage of the hair cycle), whereas we analyzed scalp skin, which is unusually rich in very large terminal HFs, 80 to 90% of which are in anagen VI HF. In addition, we used different primer sequences and PCR conditions than these investigators, who may well have identified an alternatively spliced PRL mRNA variant that could not be detected because of the exonal location of their primers. The sense primer used by Slominski and colleagues40 was located in exon 3, and the anti-sense primer contained both the end of exon 4 sequences and the initial part of exon 5 sequences. In contrast, our sense primer is in exon 2 and anti-sense primer is in exon 4.PRL mRNA as well as PRL and PRL-R immunoreactivity can be detected within the same epithelial human HF compartments (Figure 1, A–D, and Figure 4), and culture of microdissected, denervated, and avascular HFs in the presence of exogenous PRL exerts significant growth-modulatory effects (Figure 1, E–H, and Figure 2, a and b). This supports the hypothesis that PRL acts in an autocrine and/or paracrine manner on locally expressed high-affinity receptors and functions as a catagen-promoting signal in human HFs just as it does in mouse HFs. The strictly epithelial immunoreactivity pattern of PRL and PRL-R identified here for human scalp HFs corresponds well to the one previously described in mice. However, in ovine HFs, PRL-R expression has also been detected in the dermal papilla. Thus, expression of PRL-R seems to be differentially regulated in seasonally dependent HFs (ovine) compared to seasonally independent HFs (mouse, human).Steroid hormones stimulate cognate receptors in the HF epithelium and mesenchyme and change the secretion of potent hair growth modulators such as TGF-â, which then act back on the epithelium. In contrast, the polypeptide hormone PRL seems capable of signaling more directly within the HF epithelium as an autocrine and/or paracrine promoter of apoptosis-driven HF regression. However, our currently available data do not allow us to exclude that the observed HF effects of PRL were mediated at least in part also indirectly. This could happen via the recognized effects of PRL on peripheral androgen27 and estrogen metabolism, and/or via induction of changes in the intrafollicular expression of PRL-sensitive growth factors, cytokines, and enzymes with recognized hair growth-modulatory functions,21 such as TGF-â1,55 vascular endothelial growth factor,2 IGF-2, interferon-ã, and ornithine decarboxylase.58Treatment of isolated human HFs in culture with PRL results in apoptosis-driven HF regression (catagen), decreased proliferation, and increased apoptosis of follicular keratinocytes (Figure 3). These data correspond well to the rapid, premature induction of apoptosis-driven catagen development in murine anagen skin organ culture22 and to the reported catagen induction by PRL in sheep in vivo. However, PRL has also been shown to exert anti-apoptotic functions, eg, in cultured human breast cancer cell lines in vitro, to act as a larval growth hormone and to be required for limb regeneration in amphibians.61 Therefore, the anti-proliferative and proapoptotic properties of PRL in HF epithelium may not extend to all epithelial-mesenchymal interaction systems and may be developmentally controlled.Although it remains to be clarified how PRL exerts its activities on human HFs, we show that PRL is a potent catagen-promoter of human HFs in vitro, with efficacy comparable to that of TGF-â2, yet is lower than that of interferon-ã. We also show that the catagen-promoting activity of PRL is independent of the hypothalamus-pituitary-adrenal axis and systemic hormone levels. It applies to HFs of a mammalian species with mosaic and seasonally independent HF cycling (=human scalp HF). PRL has long been recognized to play a role in hair growth control in seasonally dependent coat changes, because both rising and falling daily plasma PRL levels can induce moulting. The current human data fit well with the previous reports that PRL induces premature catagen in the, also seasonally independent, murine hair cycle22 and that murine PRL-R-null mutants show longer and coarser hair as well as hair cycle perturbations.23 The present data, therefore, underscore the importance of PRL as a hair growth modulator for both seasonally dependent and independent HF cycling across different mammalian species.PRL has also been implicated in the pathogenesis of androgenetic alopecia25 by modulation of androgens, and hyperprolactemia is associated with an androgenetic alopecia-type hair loss pattern, along with hirsutism (in females). Usually, occipital scalp HFs are insensitive to hormones such as androgens. In our experiments we used mostly occipital scalp HFs and additionally frontal HFs. It is therefore particularly interesting that PRL was able to induce catagen in these hormone-insensitive HFs. It is important to mention that PRL may have distinct functions on distinct areas of scalp and body HFs and that this will be an interesting issue to investigate in the future. Recently, it has been shown that neuroendocrine factors mediate stress-induced acne. HFs and the sebaceous glands express functional receptors for stress-related hormones, which are able to modulate androgen metabolism in the sebaceous gland. These up-regulated androgens in the sebaceous gland could also be involved in stress-induced hair loss. Therefore, it will be interesting to investigate whether PRL is able to modulate androgen receptor expression and/or androgen metabolism in the human pilosebaceous unit. In summary, our study shows that human anagen scalp HFs are very sensitive for inhibitory PRL-R-mediated signals. This is clinically relevant, because it provides a reasonable mechanism to explain the, as yet ill-understood, telogen effluvium associated with hyperprolactinemia.25 It also points to novel therapeutic strategies for the management of stress-related and hormonal hair loss in men and women, by use of recently developed PRL-R antagonists...."

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