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Mind the (Gender) Gap: Does Prolactin Exert Gender and/or Site-Specific Effects on the Human Hair Follicle?

2009; Elsevier BV; Volume: 130; Issue: 3 Linguagem: Inglês

10.1038/jid.2009.340

ISSN

1523-1747

Autores

Ewan A. Langan, Yuval Ramot, Vincent Goffin, C.E.M. Griffiths, Kerstin Foitzik, Ralf Paus,

Tópico(s)

Hair Growth and Disorders

Resumo

hair follicle prolactin PRL receptor TO THE EDITOR The pleiotropic, cytokine-like polypeptide neurohormone prolactin (PRL), primarily produced by the pituitary gland, is most widely appreciated for its central role in the regulation of lactation and reproduction. However, PRL is important in a bewildering array of biological processes spanning growth and development, immunoregulation, osmoregulation, metabolism, and the stress response (Ben-Jonathan et al., 1996Ben-Jonathan N. Mershon J.L. Allen D.L. Steinmetz R.W. Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects.Endocr Rev. 1996; 17: 639-669PubMed Google Scholar, Ben-Jonathan et al., 2008Ben-Jonathan N. LaPensee C.R. LaPensee E.W. What can we learn from rodents about prolactin in humans?.Endocr Rev. 2008; 29: 1-41Crossref PubMed Scopus (415) Google Scholar; Bole-Feysot et al., 1998Bole-Feysot C. Goffin V. Edery M. Binart N. Kelly P.A. Prolactin (PRL) and its receptor: actions, signal transduction pathways, and phenotypes observed in PRL receptor knockout mice.Endocr Rev. 1998; 19: 225-268Crossref PubMed Google Scholar; Freeman et al., 2000Freeman M.E. Kanyicska B. Lerant A. Nagy G. Prolactin: structure, function and regulation of secretion.Physiol Rev. 2000; 80: 1523-1589Crossref PubMed Scopus (1848) Google Scholar; Grattan and Kokay, 2008Grattan D.R. Kokay I.C. Prolactin: a pleiotropic neuroendocrine hormone.J Neuroendocrinol. 2008; 20: 752-763Crossref PubMed Scopus (227) Google Scholar). The importance of PRL in cutaneous biology and pathology was first postulated almost two decades ago (Paus, 1991Paus R. Does prolactin play a role in skin biology and pathology?.Med Hypotheses. 1991; 36: 33-42Abstract Full Text PDF PubMed Scopus (39) Google Scholar), and interest in its role in skin biology has recently been revived (Foitzik et al., 2009Foitzik K. Langan E.A. Paus R. Prolactin and the skin: a dermatological perspective on an ancient pleiotropic peptide hormone.J Invest Dermatol. 2009; 129: 1071-1087Crossref PubMed Scopus (89) Google Scholar). Prolactin has been implicated in the pathogenesis of several inflammatory dermatoses, including psoriasis (Giasuddin et al., 1998Giasuddin A.S. El-Sherif A.I. El-Ojali S.I. Prolactin: does it have a role in the pathogenesis of psoriasis?.Dermatology. 1998; 197: 119-122Crossref PubMed Scopus (45) Google Scholar) and acne vulgaris (Davidovici et al., 2008Davidovici B.B. Orion E. Wolf R. Cutaneous manifestations of pituitary gland diseases.Clinics Dermatol. 2008; 26: 288-295Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar), and systemic diseases with cutaneous manifestations, including rheumatoid arthritis (Velkeniers et al., 1998Velkeniers B. Dogusan Z. Naessens F. Hooghe R. Hooghe-Peters E.L. Prolactin, growth hormone and the immune system in humans.Cell Mol Life Sci. 1998; 54: 1102-1108Crossref PubMed Scopus (47) Google Scholar), systemic lupus erythematosus (De Bellis et al., 2005De Bellis A. Bizzarro A. Pivonello R. Lombardi G. Bellastella A. Prolactin and autoimmunity.Pituitary. 2005; 8: 25-30Crossref PubMed Scopus (141) Google Scholar), systemic sclerosis (Shahin et al., 2002Shahin A.A. Abdoh S. Abdelrazik M. Prolactin and thyroid hormones in patients with systemic sclerosis: correlations with disease manifestations and activity.Z Rheumatol. 2002; 61: 703-709Crossref PubMed Scopus (30) Google Scholar), and Behcet's disease (Proença et al., 2007Proença H. Ferreira C. Miranda M. Castanheira-Dinis A. Monteiro-Grillo M. Serum prolactin levels and Behcet disease.Eur J Ophthalmol. 2007; 17: 404-407PubMed Google Scholar). Moreover, both mouse and human skin have been identified as nonclassical, extrapituitary sites of PRL expression, which also respond to PRL receptor (PRLR)-mediated signaling, for example, with changes in hair growth and hair keratinocyte proliferation in situ (Craven et al., 2001Craven A. Ormandy C. Robertson F. Kelly P. Nixon A. Pearson A. Prolactin signaling influences the timing mechanism of the hair follicle: analysis of hair growth cycles in prolactin receptor knockout mice.Endocrinology. 2001; 142: 2533-2539Crossref PubMed Scopus (62) Google Scholar; Foitzik et al., 2003Foitzik K. Krause K. Nixon A.J. et al.Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen.Am J Pathol. 2003; 162: 1611-1621Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, Foitzik et al., 2006Foitzik K. Krause K. Conrad F. Nakamura M. Funk W. Paus R. 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.Am J Pathol. 2006; 168: 748-756Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, Foitzik et al., 2009Foitzik K. Langan E.A. Paus R. Prolactin and the skin: a dermatological perspective on an ancient pleiotropic peptide hormone.J Invest Dermatol. 2009; 129: 1071-1087Crossref PubMed Scopus (89) Google Scholar). This is not surprising given that the regulatory effects of PRL on hair growth, in several species, have been documented for over 20 years (see Foitzik et al., 2009Foitzik K. Langan E.A. Paus R. Prolactin and the skin: a dermatological perspective on an ancient pleiotropic peptide hormone.J Invest Dermatol. 2009; 129: 1071-1087Crossref PubMed Scopus (89) Google Scholar for review). However, more detailed analysis of the regulatory effects of PRL on hair growth reveals surprising and at times seemingly contradictory, inter- and intraspecies variations in the hair follicle (HF) response to PRL (Table 1). Murine skin and human scalp HFs express both PRL and functional PRLR at the gene and protein levels, and PRL operates as a potent modulator of HF cycling (Craven et al., 2001Craven A. Ormandy C. Robertson F. Kelly P. Nixon A. Pearson A. Prolactin signaling influences the timing mechanism of the hair follicle: analysis of hair growth cycles in prolactin receptor knockout mice.Endocrinology. 2001; 142: 2533-2539Crossref PubMed Scopus (62) Google Scholar, Craven et al., 2006Craven A.J. Nixon A.J. Ashby M.G. et al.Prolactin delays hair regrowth in mice.J Endocrinol. 2006; 191: 415-425Crossref PubMed Scopus (43) Google Scholar; Foitzik et al., 2003Foitzik K. Krause K. Nixon A.J. et al.Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen.Am J Pathol. 2003; 162: 1611-1621Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, Foitzik et al., 2006Foitzik K. Krause K. Conrad F. Nakamura M. Funk W. Paus R. 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.Am J Pathol. 2006; 168: 748-756Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). In mice, PRL appears to operate primarily as a potent hair growth inhibitor; it induces premature catagen development and hair matrix keratinocyte apoptosis, and inhibits hair matrix keratinocyte proliferation in skin organ culture of back skin pelage follicles, whereas PRLR knockout mice have longer and coarser hair than wild-type controls (Craven et al., 2001Craven A. Ormandy C. Robertson F. Kelly P. Nixon A. Pearson A. Prolactin signaling influences the timing mechanism of the hair follicle: analysis of hair growth cycles in prolactin receptor knockout mice.Endocrinology. 2001; 142: 2533-2539Crossref PubMed Scopus (62) Google Scholar, Craven et al., 2006Craven A.J. Nixon A.J. Ashby M.G. et al.Prolactin delays hair regrowth in mice.J Endocrinol. 2006; 191: 415-425Crossref PubMed Scopus (43) Google Scholar; Foitzik et al., 2003Foitzik K. Krause K. Nixon A.J. et al.Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen.Am J Pathol. 2003; 162: 1611-1621Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar).Table 1Published contradictory effects of PRL on hair growth in various species, with specific reference to site and genderSpeciesGenderSiteEffects of PRLReferencesHumanMaleOccipital scalpCatagen-inducing effect, inhibition of hair growth in vitro Decreased proliferation and upregulated apoptosis of HF keratinocytes in vitroFoitzik et al., 2006Foitzik K. Krause K. Conrad F. Nakamura M. Funk W. Paus R. 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.Am J Pathol. 2006; 168: 748-756Abstract Full Text Full Text PDF PubMed Scopus (118) Google ScholarMiceFemale Balb/c and PRLR knockout mice, both gendersDorsal skinDelayed hair regrowth Differences in dorsoventral HF response to PRL corresponded to site difference in timing of hair growth wave in vivo. Sex differences observed in HF behavior in PRLR knockout miceCraven et al., 2006Craven A.J. Nixon A.J. Ashby M.G. et al.Prolactin delays hair regrowth in mice.J Endocrinol. 2006; 191: 415-425Crossref PubMed Scopus (43) Google ScholarMiceFemale (including pregnant females)Dorsal skinInduction of premature catagen in vitro Decreased proliferation of keratinocytes in vitroFoitzik et al., 2003Foitzik K. Krause K. Nixon A.J. et al.Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen.Am J Pathol. 2003; 162: 1611-1621Abstract Full Text Full Text PDF PubMed Scopus (85) Google ScholarMiceMale and femaleDorsal skinAdvancement in hair replacement in PRLR-deficient mice, more pronounced in female mice, in vivo. PRLR-deficient mice had longer and coarser hair with normal sexual dimorphism eliminatedCraven et al., 2001Craven A. Ormandy C. Robertson F. Kelly P. Nixon A. Pearson A. Prolactin signaling influences the timing mechanism of the hair follicle: analysis of hair growth cycles in prolactin receptor knockout mice.Endocrinology. 2001; 142: 2533-2539Crossref PubMed Scopus (62) Google ScholarSheepRams and ewesMid-side skinHigh circulating PRL and peak PRLR expression correlated with the initiation of HF growth. PRL mRNA downregulation preceded catagen in vivo. Specific gender differences not examinedNixon et al., 2002Nixon A.J. Ford C.A. Wildermoth J.E. Craven A.J. Pearson A.J. Regulation of prolactin receptor expression in ovine skin in relation to circulating prolactin and wool follicle growth status.J Endocrinol. 2002; 172: 605-614Crossref PubMed Scopus (56) Google ScholarSheepEwesLeft mid-side skinEntry of anagen wool follicles into catagen in vivoPearson et al., 1996Pearson A.J. Parry A.L. Ashby M.G. Choy V.J. Wildermoth J.E. Craven A.J. Inhibitory effect of increased photoperiod on wool follicle growth.J Endocrinol. 1996; 148: 157-166Crossref PubMed Scopus (40) Google ScholarCashmere goatMale and female goatsPRL shown to have a stimulating effect on hair shaft elongation of secondary HFs in vitro. In addition, increasing PRL levels reactivate telogen HFs and induce anagen. Keeping Cashmere goats in continuous light (elevating concentrations of blood PRL) increased mean fiber lengthRyder and Stephenson, 1968Ryder M. Stephenson S. Wool Growth. Academic Press, London1968Google Scholar; Dicks et al., 1994Dicks P. Russel A.J. Lincoln G.A. The role of prolactin in the reactivation of hair follicles in relation to moulting in Cashmere goats.J Endocrinol. 1994; 143: 441-448Crossref PubMed Scopus (66) Google Scholar; Ibraheem et al., 1994Ibraheem M. Galbraith H. Scaife J. Ewen S. Growth of secondary hair follicles of the Cashmere goat in vitro and their response to prolactin and melatonin.J Anat. 1994; 185: 135-142PubMed Google ScholarDjungarian hamsterEndogenous PRL found to be necessary for the development and maintenance of summer pelage in vivoDuncan and Goldman, 1984Duncan M.J. Goldman B.D. Hormonal regulation of the annual pelage color cycle in the Djungarian hamster, Phodopus sungorus. II. Role of prolactin.J Exp Zool. 1984; 230: 97-103Crossref PubMed Scopus (116) Google ScholarRed deerProlactin stimulated hair growth in cultured follicles of red deer summer coat in vivo.Thomas et al., 1993Thomas D. Brinkow B. Randall V. Prolactin and triiodothyronine (T3) stimulate hair growth in cultured follicles of red deer summer coat.J Endocrinol. 1993; 130: 50Google ScholarAbbreviations: HF, hair follicle; PRL, prolactin; PRLR, prolactin receptor. Open table in a new tab Abbreviations: HF, hair follicle; PRL, prolactin; PRLR, prolactin receptor. Interestingly, administration of bromocriptine, a dopaminergic inhibitor of pituitary PRL secretion, induces telogen effluvium in women (Fabre et al., 1993Fabre N. Montastruc J.L. Rascol O. Alopecia: an adverse effect of bromocriptine.Clin Neuropharmacol. 1993; 16: 266-268Crossref PubMed Scopus (17) Google Scholar), but not in men. This is likely to be due to premature catagen induction. This raises the possibility that, in women, PRL may actually be a hair-growth-promoting/anagen-maintaining factor. The predominantly hair-growth-inhibitory effect seen in (female) mice is recapitulated in the serum-free organ culture of human HFs (Lu et al., 2007Lu Z. Hasse S. Bodo E. Rose C. Funk W. Paus R. Towards the development of a simplified long-term organ culture method for human scalp skin and its appendages under serum-free conditions.Exp Dermatol. 2007; 16: 37-44Crossref PubMed Scopus (107) Google Scholar; Philpott et al., 1990Philpott M.P. Green M.R. Kealey T. Human hair growth in vitro.J Cell Sci. 1990; 97: 463-471PubMed Google Scholar): high-dose PRL (400ngml−1, a level that can be found in patients with macroprolactinoma) stimulated premature catagen development and inhibited hair shaft production and hair matrix keratinocyte proliferation in microdissected HFs from male occipital scalp skin (Foitzik et al., 2006Foitzik K. Krause K. Conrad F. Nakamura M. Funk W. Paus R. 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.Am J Pathol. 2006; 168: 748-756Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Thus, we were surprised to find that, in a repeat HF organ culture experiment, using a small number of HFs derived from female frontotemporal scalp skin, the same dose of PRL (400ngml−1) resulted in significant HF shaft elongation. Therefore, we repeated these experiments with a larger number of female HFs, derived from frontotemporal scalp skin specimens from additional donors, used a well-characterized specific PRLR antagonist (Goffin et al., 2005Goffin V. Bernichtein S. Touraine P. Kelly P.A. Development of potential clinical uses of human prolactin receptor antagonists.Endocr Rev. 2005; 26: 400-422Crossref PubMed Scopus (159) Google Scholar), assessed PRLR expression immunohistologically, and used microarray technology to examine the modulation of intrafollicularly expressed genes. In these repeat analyses, PRL treatment (400ngml−1) of female frontotemporal scalp HFs again significantly promoted hair shaft elongation in serum-free HF organ culture. This effect was reduced in the presence of a pure PRLR antagonist (del1-9-G129R-hPRL, 4μgml−1) (Bernichtein et al., 2003Bernichtein S. Kayser C. Dillner K. et al.Development of pure prolactin receptor antagonists.J Biol Chem. 2003; 278: 35988-35989Crossref PubMed Scopus (101) Google Scholar; Figure 1a). In contrast to the prominent catagen-inducing effects seen in male occipital scalp HFs (Foitzik et al., 2006Foitzik K. Krause K. Conrad F. Nakamura M. Funk W. Paus R. 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.Am J Pathol. 2006; 168: 748-756Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar), PRL did not have such an effect in female frontotemporal HFs. Moreover, treatment with PRLR antagonist alone significantly inhibited both HF hair shaft production (Figure 1b) and spontaneous catagen development (Figure 1c). This catagen-promoting effect of the used PRLR antagonist suggests that endogenous, intrafollicular PRL production actually maintains human female frontotemporal scalp HFs in anagen VI. These data were independently confirmed by calculation of the hair cycle score (Figure 1d), and by the microarray-based demonstration that PRL downregulated the steady-state transcript levels for a number of catagen-associated genes (Table 2).Table 2Genes related to catagen induction that appear to be downregulated by PRL treatment of female scalp HFsGeneFold changeP-valueReferencesTGFBR1-1.550.017Foitzik et al., 2000Foitzik K. Lindner G. Mueller-Roever S. et al.Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo.FASEB J. 2000; 14: 752-760Crossref PubMed Scopus (271) Google Scholar; Sowden et al., 2007Sowden H.M. Karoo R.O. Tobin D.J. Transforming growth factor-beta receptor II is preferentially expressed in the companion layer of the human anagen hair follicle.Br J Dermatol. 2007; 157: 161-164Crossref PubMed Scopus (5) Google ScholarTGFBR2-1.810.0005Foitzik et al., 2000Foitzik K. Lindner G. Mueller-Roever S. et al.Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo.FASEB J. 2000; 14: 752-760Crossref PubMed Scopus (271) Google Scholar; Sowden et al., 2007Sowden H.M. Karoo R.O. Tobin D.J. Transforming growth factor-beta receptor II is preferentially expressed in the companion layer of the human anagen hair follicle.Br J Dermatol. 2007; 157: 161-164Crossref PubMed Scopus (5) Google ScholarTGFBR3-2.370.001Foitzik et al., 2000Foitzik K. Lindner G. Mueller-Roever S. et al.Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo.FASEB J. 2000; 14: 752-760Crossref PubMed Scopus (271) Google Scholar; Sowden et al., 2007Sowden H.M. Karoo R.O. Tobin D.J. Transforming growth factor-beta receptor II is preferentially expressed in the companion layer of the human anagen hair follicle.Br J Dermatol. 2007; 157: 161-164Crossref PubMed Scopus (5) Google ScholarTAIP-2-6.061,75E-11Foitzik et al., 2000Foitzik K. Lindner G. Mueller-Roever S. et al.Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo.FASEB J. 2000; 14: 752-760Crossref PubMed Scopus (271) Google Scholar; Sowden et al., 2007Sowden H.M. Karoo R.O. Tobin D.J. Transforming growth factor-beta receptor II is preferentially expressed in the companion layer of the human anagen hair follicle.Br J Dermatol. 2007; 157: 161-164Crossref PubMed Scopus (5) Google ScholarBMP2-1.830.00007Blessing et al., 1993Blessing M. Nanney L.B. King L.E. Jones C.M. Hogan B.L. Transgenic mice as a model to study the role of TGF-beta related molecules in hair follicles.Genes Dev. 1993; 7: 204-215Crossref PubMed Scopus (158) Google Scholar; Paus and Foitzik, 2004Paus R. Foitzik K. In search of the "hair cycle clock": a guided tour.Differentiation. 2004; 72: 489-511Crossref PubMed Scopus (232) Google ScholarBMP4-1.440.01Blessing et al., 1993Blessing M. Nanney L.B. King L.E. Jones C.M. Hogan B.L. Transgenic mice as a model to study the role of TGF-beta related molecules in hair follicles.Genes Dev. 1993; 7: 204-215Crossref PubMed Scopus (158) Google Scholar; Paus and Foitzik, 2004Paus R. Foitzik K. In search of the "hair cycle clock": a guided tour.Differentiation. 2004; 72: 489-511Crossref PubMed Scopus (232) Google ScholarIGFBP3-1.50.006Schlake et al., 2004Schlake T. Beibel M. Weger N. Boehms T. Major shifts in genomic activity accompany progression through different stages of the hair cycle.Gene Expr Patterns. 2004; 4: 141-152Crossref PubMed Scopus (25) Google Scholar; Buckbinder et al., 1995Buckbinder L. Talbott R. Velasco-Miguel S. et al.Induction of the growth inhibitor IGF-binding protein 3 by p53.Nature. 1995; 377: 646-649Crossref PubMed Scopus (806) Google ScholarAbbreviations: BMP, bone morphogenetic protein; IGFBP, insulin-like growth factor binding protein; TAIP, TGF-β-induced apoptosis protein; TGFBR, transforming growth factor-β receptor.Gene expression analysis of freshly isolated human scalp HFs (25 per group) treated with vehicle/PRL (400ngml−1) for 48h. The analysis was performed using Human Whole Genome Oligo Microarray (44K) by Miltenyi Biotech GmbH (Bergisch-Gladbach, Germany). Open table in a new tab Abbreviations: BMP, bone morphogenetic protein; IGFBP, insulin-like growth factor binding protein; TAIP, TGF-β-induced apoptosis protein; TGFBR, transforming growth factor-β receptor. Gene expression analysis of freshly isolated human scalp HFs (25 per group) treated with vehicle/PRL (400ngml−1) for 48h. The analysis was performed using Human Whole Genome Oligo Microarray (44K) by Miltenyi Biotech GmbH (Bergisch-Gladbach, Germany). In line with a hair-growth-promoting effect of PRL in female frontotemporal scalp HFs, quantitative immunohistomorphometry revealed increased hair matrix keratinocyte proliferation in situ. This was reversed by treatment with a PRLR antagonist (Figure 1e). In fact, a stimulatory effect of PRL on the proliferation of human (epidermal) keratinocytes in vitro had been previously published in this journal (Girolomoni et al., 1993Girolomoni G. Phillips J.T. Bergstresser P.R. Prolactin stimulates proliferation of cultured human keratinocytes.J Invest Dermatol. 1993; 101: 275-279Abstract Full Text PDF PubMed Google Scholar). These unexpected findings run contrary to the well-documented hair-growth-inhibitory effects of PRL in mice and humans (Craven et al., 2001Craven A. Ormandy C. Robertson F. Kelly P. Nixon A. Pearson A. Prolactin signaling influences the timing mechanism of the hair follicle: analysis of hair growth cycles in prolactin receptor knockout mice.Endocrinology. 2001; 142: 2533-2539Crossref PubMed Scopus (62) Google Scholar, Craven et al., 2006Craven A.J. Nixon A.J. Ashby M.G. et al.Prolactin delays hair regrowth in mice.J Endocrinol. 2006; 191: 415-425Crossref PubMed Scopus (43) Google Scholar; Foitzik et al., 2003Foitzik K. Krause K. Nixon A.J. et al.Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen.Am J Pathol. 2003; 162: 1611-1621Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, Foitzik et al., 2006Foitzik K. Krause K. Conrad F. Nakamura M. Funk W. Paus R. 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.Am J Pathol. 2006; 168: 748-756Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). They re-focus our attention on hair-growth-modulatory effects of PRL that had been reported in the older literature and that cannot be easily reconciled with the notion that PRL is an across-the-board hair-growth inhibitor (see Table 1). Taken together with the increasing awareness of sexual dimorphism in the mammalian response to defined neuroendocrine stimuli (e.g., Aoki et al., 2001Aoki M.P. Aoki A. Maldonado C.A. Sexual dimorphism of apoptosis in lactotrophs induced by bromocryptine.Histochem Cell Biol. 2001; 116: 215-222Crossref PubMed Scopus (22) Google Scholar; Pi and Voogt, 2002Pi X. Voogt J.L. Sex difference and estrous cycle: expression of prolactin receptor mRNA in rat brain.Brain Res Mol Brain Res. 2002; 103: 130-139Crossref PubMed Scopus (19) Google Scholar; Rocha et al., 2002Rocha E.M. Hirata A.E. Carneiro E.M. et al.Impact of gender on insulin signaling pathway in lacrimal and salivary glands of rats.Endocrine. 2002; 18: 191-199Crossref PubMed Scopus (16) Google Scholar; Amador-Noguez et al., 2005Amador-Noguez D. Zimmerman J. Venable S. Darlington G. Gender-specific alterations in gene expression and loss of liver sexual dimorphism in the long-lived Ames dwarf mice.Biochem Biophys Res Commun. 2005; 332: 1086-1100Crossref PubMed Scopus (39) Google Scholar; Senovilla et al., 2008Senovilla L. Núñez L. Villalobos C. García-Sancho J. Rapid changes in anterior pituitary cell phenotypes in male and female mice after acute cold stress.Endocrinology. 2008; 149: 2159-2167Crossref PubMed Scopus (12) Google Scholar), the gender-dependent differences in the response of human scalp HFs to estrogens (Conrad et al., 2005Conrad F. Ohnemus U. Bodo E. et al.Substantial sex-dependent differences in the response of human scalp hair follicles to estrogen stimulation in vitro advocate gender-tailored management of female versus male pattern balding.J Investig Dermatol Symp Proc. 2005; 10: 243-246Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar; Ohnemus et al., 2006Ohnemus U. Uenalan M. Inzunza J. Gustafsson J.A. Paus R. The hair follicle as an estrogen target and source.Endocr Rev. 2006; 27: 677-706Crossref PubMed Scopus (141) Google Scholar), and the well-known paradoxical, strictly site-dependent effects of androgens (Randall, 2008Randall V.A. Androgens and hair growth.Dermatol Ther. 2008; 21: 314-328Crossref PubMed Scopus (187) Google Scholar), our new findings (Figure 1) beg the question of whether the response of human HFs to PRL stimulation may actually be highly gender and/or location dependent. Re-analysis of the older literature reveals an awareness of the existence of gender differences in the response of the HF to PRL and hyperprolactinemia. For example, although hirsutism can be a feature of hyperprolactinemia in females (Tekin et al., 2004Tekin O. Avci Z. Isik B. et al.Hirsutism: common clinical problem or index of serious disease?.Med Gen Med. 2004; 6: 56Google Scholar), males with hyperprolactinemia usually suffer from reduced growth of facial and/or body hair (Buvat et al., 1985Buvat J. Lemaire A. Buvat-Herbaut M. Fourlinnie J.C. Racadot A. Fossati P. Hyperprolactinemia and sexual function in men.Horm Res. 1985; 22: 196-203Crossref PubMed Scopus (75) Google Scholar; Walsh et al., 1994Walsh J.P. Bhagat C.I. Pullan P.T. Rampono J.G. Drug-induced hyperprolactinaemia.Med J Aust. 1994; 161: 443-444Google Scholar). In addition, dopaminergic agonists, which inhibit pituitary PRL secretion and are used to treat PRL-secreting prolactinoma, reportedly cause hair loss. Strikingly, out of the 14 dopamine agonist-induced hair loss cases reported in the literature, only 1 patient was man (Grauer and Sieb, 2002Grauer M.T. Sieb J.P. Alopecia induced by dopamine agonists.Neurology. 2002; 59: 2012Crossref PubMed Scopus (9) Google Scholar; Miwa and Kondo, 2003Miwa H. Kondo T. Hair loss induced by dopamine agonist: case report and review of the literature.Parkinsonism Relat Disord. 2003; 10: 51-52Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar; Katz et al., 2006Katz K.A. Cotsarelis G. Gupta R. Seykora J.T. Telogen effluvium associated with the dopamine agonist pramipexole in a 55-year-old woman with Parkinson's disease.J Am Acad Dermatol. 2006; 55: S103-S104Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar). Even in that patient, alopecia was reported in the beard area, and not in the scalp (Grauer and Sieb, 2002Grauer M.T. Sieb J.P. Alopecia induced by dopamine agonists.Neurology. 2002; 59: 2012Crossref PubMed Scopus (9) Google Scholar). Gender differences in the hair response to PRL have also been reported earlier in mice (Craven et al., 2001Craven A. Ormandy C. Robertson F. Kelly P. Nixon A. Pearson A. Prolactin signaling influences the timing mechanism of the hair follicle: analysis of hair growth cycles in prolactin receptor knockout mice.Endocrinology. 2001; 142: 2533-2539Crossref PubMed Scopus (62) Google Scholar). In PRLR knockout mice, female pelage replacement was advanced by 4 weeks, compared to an advancement of only 4 days in males. This led to the elimination of the normal sexual dimorphism in murine pelage replacement (Craven et al., 2001Craven A. Ormandy C. Robertson F. Kelly P. Nixon A. Pearson A. Prolactin signaling influences the timing mechanism of the hair follicle: analysis of hair growth cycles in prolactin receptor knockout mice.Endocrinology. 2001; 142: 2533-2539Crossref PubMed Scopus (62) Google Scholar). In addition, site-dependent differences in HF sensitivity to PRL, as well as to bromocriptine treatment, were also observed when dorsal was compared with axillary mouse skin. For example, bromocriptine treatment resulted in new hair growth, in both axillae and dorsal skin, at a younger age than in control mice. PRL treatment abrogated this premature hair growth (Craven et al., 2006Craven A.J. Nixon A.J. Ashby M.G. et al.Prolactin delays hair regrowth in mice.J Endocrinol. 2006; 191: 415-425Crossref PubMed Scopus (43) Google Scholar). Although these differential effects were attributed to distinct hair cycle stages, they may well have also represented site-specific differences in the HF response. Interestingly, human skin appears to show related site-specific differences; such as, PRL and PRLR are expressed at the gene and protein levels in human scalp skin (Foitzik et al., 2006Foitzik K. Krause K. Conrad F. Nakamura M. Funk W. Paus R. 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.Am J Pathol. 2006; 168: 748-756Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar), whereas no evidence for PRL gene transcription was found in corporal skin (Slominski et al., 2001Slominski A. Malarkey W.B. Wortsman J. Asa S.L. Carlson A. Human skin expresses growth hormone but not the prolactin gene.J Lab Clin Med. 2001; 136: 476-481Abstract Full Text Full Text PDF Scopus (38) Google Scholar). On this basis, we propose the unreported hypothesis that intracutaneous PRL effects are highly gender and/or site dependent. Conversely, this may be related to gender- and/or location-dependent differences in the distribution of PRLR. This differential response may depend on the post-receptor signal transduction pathways that are predominantly used by the same cell populations in different genders/skin locations, and/or on gender- and/or site-specific differences in the key target genes, whose expression is up- or downregulated after PRLR stimulation (Figure 2). We speculate that this can account for diametrically opposed functional effects of PRL and PRLR antagonists on identical peripheral target organs, such as the skin and its appendages. Thus, we propose that the distinct hair-growth-modulatory effects of PRL in female frontotemporal (Figure 1) versus male occipital scalp HFs (Foitzik et al., 2006Foitzik K. Krause K. Conrad F. Nakamura M. Funk W. Paus R. 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.Am J Pathol. 2006; 168: 748-756Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar) are the manifestation of gender- and/or location-dependent differential responses to PRL. To identify, characterize, and mechanistically dissect gender- and/or site-specific differences in the response of peripheral tissues to PRLR ligands is of evident biological and clinical importance. Not only is this needed to adequately and more efficiently tailor PRL-related therapeutic strategies to each gender and/or to PRL target organs in defined anatomical locations, but also because the increasingly appreciated adverse effects of PRL and its antagonists in rodents and humans (Buvat et al., 1985Buvat J. Lemaire A. Buvat-Herbaut M. Fourlinnie J.C. Racadot A. Fossati P. Hyperprolactinemia and sexual function in men.Horm Res. 1985; 22: 196-203Crossref PubMed Scopus (75) Google Scholar; Katz et al., 2006Katz K.A. Cotsarelis G. Gupta R. Seykora J.T. Telogen effluvium associated with the dopamine agonist pramipexole in a 55-year-old woman with Parkinson's disease.J Am Acad Dermatol. 2006; 55: S103-S104Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar; Harvey et al., 2008Harvey P.W. Everett D.J. Springall C.J. Adverse effects of prolactin in rodents and humans: breast and prostate cancer.J Psychopharmacol. 2008; 22: 20-27Crossref PubMed Scopus (56) Google Scholar) may differ between the genders and/or distinct tissue locations. Furthermore, we propose that the serum-free organ culture of human HFs from female versus male scalp skin, and from defined scalp skin locations (frontotemporal vs occipital), offers a very sensitive and instructive, physiologically and clinically highly relevant research tool to further dissect the proposed gender and/or location dependence of PRL effects on nonclassical, peripheral PRL target tissues in the human system. Drawing from the example of sexual dimorphism in the human HF response to estrogens (Conrad et al., 2005Conrad F. Ohnemus U. Bodo E. et al.Substantial sex-dependent differences in the response of human scalp hair follicles to estrogen stimulation in vitro advocate gender-tailored management of female versus male pattern balding.J Investig Dermatol Symp Proc. 2005; 10: 243-246Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar; Ohnemus et al., 2006Ohnemus U. Uenalan M. Inzunza J. Gustafsson J.A. Paus R. The hair follicle as an estrogen target and source.Endocr Rev. 2006; 27: 677-706Crossref PubMed Scopus (141) Google Scholar), and the recognized gender differences in PRLR expression, for example, in rat brains (Pi and Voogt, 2002Pi X. Voogt J.L. Sex difference and estrous cycle: expression of prolactin receptor mRNA in rat brain.Brain Res Mol Brain Res. 2002; 103: 130-139Crossref PubMed Scopus (19) Google Scholar), one reasonable explanation for gender- and/or location-dependent differences in the response to PRL and PRL antagonists could arise from differences in PRLR distribution and expression level. In fact, we had previously observed striking differences in estrogen receptor expression between male and female scalp skin HFs (Conrad et al., 2005Conrad F. Ohnemus U. Bodo E. et al.Substantial sex-dependent differences in the response of human scalp hair follicles to estrogen stimulation in vitro advocate gender-tailored management of female versus male pattern balding.J Investig Dermatol Symp Proc. 2005; 10: 243-246Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). In addition, various isoforms of the PRLR exist, whose stimulation exerts different biological effects (Gadd and Clevenger, 2006Gadd S.L. Clevenger C.V. Ligand-independent dimerization of the human prolactin receptor isoforms: functional implications.Mol Endocrinol. 2006; 20: 2734-2746Crossref PubMed Scopus (99) Google Scholar). Thus, gender- and/or location-dependent differences in the predominant PRLR isoform need to be considered (Figure 2). The constitutive gender difference in human daytime serum PRL levels may "prime" gender-dependent differences in PRLR expression and/or sensitivity to PRL stimulation. Furthermore, gender- and/or location-dependent differences in post-receptor signaling and PRL target genes need to be considered (Figure 2). The previously noted major differences in the gene expression profile induced by 17-β-estradiol in male versus female organ-cultured human HFs (Conrad et al., 2005Conrad F. Ohnemus U. Bodo E. et al.Substantial sex-dependent differences in the response of human scalp hair follicles to estrogen stimulation in vitro advocate gender-tailored management of female versus male pattern balding.J Investig Dermatol Symp Proc. 2005; 10: 243-246Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar) further suggests that male and female HFs can show distinct gene regulation in response to the same hormonal stimulus. Using microarray technology, we carried out a tentative attempt to explore gender- and/or location-dependent differences in the response of HFs to PRL. The limited available results suggest that these do indeed exist (Table 3). This underscores that human scalp HFs are indeed well suited as a biologically and clinically highly relevant, PRL-sensitive test system for picking up differentially expressed genes, whose transcription appears to differ between the genders and skin locations tested, and supports our hypothesis of gender- and/or site-dependent differences in the HF response to PRL stimulation (Table 3). Although these data evidently require quantitative confirmation on the mRNA and protein levels, and reproduction in additional human donors, they lend further support to our hypothesis of gender- and/or site-specific differences in the effect of PRL on an exemplary, nonclassical peripheral human target tissue: the scalp HF.Table 3PRL-mediated site and gender-specific gene regulation in human scalp HFsMale occipital1Microarray 1.Gene namePatient 1Patient 2Female temporal2Microarray 2.Female occipital2Microarray 2.Genes downregulated in male occipital scalp HFs (>2.1-fold change in at least 1 patient) RBP4-1.54-2.86-1.651.07Ubiquitin2.251.52-1.28-1.14 CYP1B12.121.53-1-1.15 SERPINA12.042.231.641.08 LCN21.812.411.21.3Genes regulated in female frontotemporal scalp HFs (>2.1-fold change) GJA11.251.28-2.441.44 Cornifin B1.31.69-2.421.05 BAX1.071.05-2.39-1.33 COL3A1-1.12-1.2-2.271.12 ABME1.071.122.26-1.1 HMOX1-1.32-1.08-2.161.08 COL6A11.08-1.1-2.131.27Genes regulated in female occipital scalp HFs (>2.1-fold change) CDC2L1-1.231.02-2.05-2.19 NKTR1.10.961.06-2.18Abbreviations: ABME, apolipoprotein B mRNA-editing enzyme; BAX, BCL2-associated X protein; CDC2L1, PITSLRE protein kinase; COL3AI, collagen type III, α1; COL6A1, collagen type VI, α1; CYP1B1, cytochrome P450 1B1; GJA1, gap junction α1 protein (connexin 43); HMOX1, heme oxygenase 1; LCN2, lipocalin 2; NKTR, NK-tumor recognition protein; RBP4, retinal-binding protein 4.Gene expression analysis of HFs from male occipital and female temporal and occipital scalp HFs treated with 400ngml−1 PRL. Several genes are differentially regulated in a site, and gender-specific manner. For example, ubiquitin is significantly upregulated in male occipital skin HF, but downregulated in female temporal and occipital HFs treated with prolactin. ABME is only upregulated in PRL-treated female temporal HFs, and NKTR only downregulated in PRL-treated female occipital scalp HFs. The analysis was performed using Human Whole Genome Oligo Microarray (44K) by Miltenyi Biotech GmbH.1 Microarray 1.2 Microarray 2. Open table in a new tab Abbreviations: ABME, apolipoprotein B mRNA-editing enzyme; BAX, BCL2-associated X protein; CDC2L1, PITSLRE protein kinase; COL3AI, collagen type III, α1; COL6A1, collagen type VI, α1; CYP1B1, cytochrome P450 1B1; GJA1, gap junction α1 protein (connexin 43); HMOX1, heme oxygenase 1; LCN2, lipocalin 2; NKTR, NK-tumor recognition protein; RBP4, retinal-binding protein 4. Gene expression analysis of HFs from male occipital and female temporal and occipital scalp HFs treated with 400ngml−1 PRL. Several genes are differentially regulated in a site, and gender-specific manner. For example, ubiquitin is significantly upregulated in male occipital skin HF, but downregulated in female temporal and occipital HFs treated with prolactin. ABME is only upregulated in PRL-treated female temporal HFs, and NKTR only downregulated in PRL-treated female occipital scalp HFs. The analysis was performed using Human Whole Genome Oligo Microarray (44K) by Miltenyi Biotech GmbH. The effects of PRL on hair growth have been studied in many species, including mammals with both seasonally dependent and independent hair pelage replacement cycles. The seemingly conflicting effects reported in the literature (Table 1) may well be reconciled if one interprets them as representations of site- and/or gender-dependent HF responses to PRL. If confirmed, these differences will add a fascinating new dimension to our understanding of sexual dimorphism in HF responses to hormonal stimulation, and highlight the need for a systematic exploration of gender- and/or location-specific PRL-mediated signaling in the physiology and pathology of peripheral PRL target tissues in the human system. The authors state no conflict of interest. CEMG and RP received funding from the Manchester Biomedical Research Centre, National Institute for Health Research.

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