Lack of hair due to alopecia or skin grafting procedures causes significant distress due to hair's role in social and sexual communication. Only limited pharmacological agents are currently available to stimulate hair growth; their development is hampered by inappropriate model systems. Most research involves large terminal scalp follicles rather than the clinical targets of tiny vellus or intermediate follicles. The overall aim of this thesis was to develop a novel model system based on intermediate hair follicles. Initially, intermediate follicles from female pre-auricular skin were characterised and compared to matched terminal follicles. Intermediate follicles were smaller, less pigmented, shorter and possessed a more 'tubular' bulb morphology than their more 'bulbous' terminal counterparts. Significant correlations were demonstrated between various hair follicle measurements and corresponding dermal papilla diameters. Isolated terminal follicles grew significantly more than intermediate hair follicles in organ culture for 9 days. Testosterone (10nM), the major regulator of human hair growth, increased only intermediate follicle growth; the anti-androgen, cyproterone acetate (1μM), prevented this stimulation, unlike the 5α-reductase type 2 inhibitor finasteride (40ng/ml). Immunohistochemistry demonstrated androgen receptor and 5α-reductase type 2 proteins in both follicle types, while quantitative real-time PCR and gene microarray analysis detected their increased gene expression in intermediate follicles. Thus, smaller intermediate follicles showed major morphological and gene expression differences to terminal follicles in vivo and retained significant, biologically-relevant differences in vitro in organ culture including androgen-responsiveness. Therefore, intermediate hair follicles offer a novel, exciting, more clinically relevant, albeit technically difficult, model for future investigations into hair growth.

<p>Autoimmune polyendocrine syndrome type I (APS) is a monogenous, recessively inherited disease characterised by endocrine and non-endocrine autoimmune manifestations. One fifth of APS I patients suffer from periodic intestinal dysfunction with varying degrees of malabsorbtion, steatorrhea and constipation. Alopecia areata is found in one third of APS I patients. By immunoscreening human cDNA libraries derived from normal human duodenum and scalp with APS I sera, we identified tryptophan hydroxylase (TPH) as an intestinal autoantigen and tyrosine hydroxylase (TH) as a dermal autoantigen. Forty-eight percent (38/80) of the APS I patients had TPH antibodies (Ab) and 44% (41/94) showed TH immunoreactivity. No reactivity against TPH or TH was seen in healthy controls. TPH-Abs showed a statistically significant correlation with gastrointestinal dysfunction (p<0.0001) and TH-Abs were significantly correlated to alopecia (p=0.02). TPH-Ab positive APS I sera specifically immunostained TPH containing enterochromaffin cells in normal duodenal mucosa. In affected mucosa a depletion of the TPH containing EC cells was seen. In enzyme inhibition experiments TPH and TH activity <i>in vitro</i> was reduced by adding APS I sera. TPH and TH together with phenylalanine hydroxylase (PAH) constitute the group of pteridine dependent hydroxylases. These are highly homologous enzymes involved in the biosynthesis of neurotransmitters. Immunoprecipitation of PAH expressed <i>in vitro</i> showed that 27% (25/94) of APS I patients had antibodies reacting with PAH, but no associations with clinical manifestations was observed. An immunocompetition assay showed that the PAH reactivity reflects a cross-reactivity with TPH.</p><p>In conclusion, we have identified TPH and TH as intestinal and dermal autoantigens in APS I, coupled to gastrointestinal dysfunction and alopecia. We have also demonstrated immunoreactivity against PAH in APS I patient sera reflecting a cross-reactivity with TPH.</p>

Autoimmune polyendocrine syndrome type I (APS) is a monogenous, recessively inherited disease characterised by endocrine and non-endocrine autoimmune manifestations. One fifth of APS I patients suffer from periodic intestinal dysfunction with varying degrees of malabsorbtion, steatorrhea and constipation. Alopecia areata is found in one third of APS I patients. By immunoscreening human cDNA libraries derived from normal human duodenum and scalp with APS I sera, we identified tryptophan hydroxylase (TPH) as an intestinal autoantigen and tyrosine hydroxylase (TH) as a dermal autoantigen. Forty-eight percent (38/80) of the APS I patients had TPH antibodies (Ab) and 44% (41/94) showed TH immunoreactivity. No reactivity against TPH or TH was seen in healthy controls. TPH-Abs showed a statistically significant correlation with gastrointestinal dysfunction (p&lt;0.0001) and TH-Abs were significantly correlated to alopecia (p=0.02). TPH-Ab positive APS I sera specifically immunostained TPH containing enterochromaffin cells in normal duodenal mucosa. In affected mucosa a depletion of the TPH containing EC cells was seen. In enzyme inhibition experiments TPH and TH activity in vitro was reduced by adding APS I sera. TPH and TH together with phenylalanine hydroxylase (PAH) constitute the group of pteridine dependent hydroxylases. These are highly homologous enzymes involved in the biosynthesis of neurotransmitters. Immunoprecipitation of PAH expressed in vitro showed that 27% (25/94) of APS I patients had antibodies reacting with PAH, but no associations with clinical manifestations was observed. An immunocompetition assay showed that the PAH reactivity reflects a cross-reactivity with TPH. In conclusion, we have identified TPH and TH as intestinal and dermal autoantigens in APS I, coupled to gastrointestinal dysfunction and alopecia. We have also demonstrated immunoreactivity against PAH in APS I patient sera reflecting a cross-reactivity with TPH.

Abstract A hypothesis is created that an association between androgenetic alopecia (AGA) and serious cardiovascular events, such as myocardial infarction and fatal ischaemic heart disease has been reported, but the mechanism explaining this association has remained unclear. The aim of this study was to analyze the relationship between insulin resistance, (coronary) artery disease and AGA. Moreover, a hypothesis on the role of electromagnetic cell adhesion in the development of AGA is presented. In the present series of men aged 19–50 years (n = 154) with early (&lt;  35 years of age), significant AGA of at least grade 3 (vertex) in the Hamilton classification modified by Norwood (Norwood 1975) was hyperinsulinaemia encountered twice as often as on age-matched controls. Other signs of the insulin resistance syndrome, such as obesity, lipid lowering and antihypertensive drugs were also found to correlate with early AGA. In a population-based case-control study, male patients living a small rural town who had undergone an urgent or elective coronary revascularization procedure (n =  85) and their age-matched controls were analysed after stratification by age at operation and hair status. The findings showed AGA to be more common coronary artery disease and early AGA as those with early coronary artery disease. In a population aged 63 years (n = 541, 217 men), neck circumference was found to correlate with the conventional anthropometric indicators of insulin resistance and with elevated serum insulin in both genders, which means that neck circumference is a simple anthropometric indicator of android type obesity and insulin resistance. In the same female population other factors of insulin resistance (whr, waist circumference, serum insulin level and microalbuminuria) were associated with marked (grade 2 or 3 on a modified Ludwig scale) hair loss. Paternal heredity was clearly characteristic of AGA in both genders, particularly of early AGA in men. We present a hypothesis that the overactive androgen state inhibits cell mitosis in the dermal papilla of the hair follicle and contributes to a weaker electromagnetic attraction between the undifferentiated germ cells and the dermal papilla and also to a shortened anagen phase of the hair growth cycle. Insulin resistance has an additional pathogenic role in the excessive miniaturization of the hair follicle. As a conclusion, along with android obesity, early alopecia can be considered a sign of insulin resistance and a possible risk factor for an early onset of coronary artery disease. Timely intervention in the risk factors may help to slow down or prevent the development of arterial disease and possibly also to alleviate the cosmetic and psychosocial consequences of hair loss. / Tiivistelmä Insuliiniresistenssin, (sepel)valtimotaudin ja AGA:n välillä on yhteyksiä. Taustalla olevat patomekanismit ovat kuitenkin epäselviä. Tässä väitöskirjatyössä tutkittiin insuliiniresistenssin ja (sepel)valtimotaudin suhdetta AGA:an. Lisäksi luotiin hypoteesi sähkömagneettisen soluadheesion roolista AGA:n kehittymisessä. Aineiston 19–50-vuotiailla miehillä (n = 154), joilla oli varhainen (&lt; 35 v), merkittävä, vähintään kolmannen (vertex) asteen AGA Norwoodin modifioiman Hamiltonin luokituksen mukaan (Norwood 1975) seerumin insuliinipitoisuus oli suurentunut liki kaksi kertaa useammin kuin samanikäisillä verrokeilla. Myös muiden insuliiniresistenssioireyhtymään liitettyjen vaaratekijöiden, kuten ylipainon, havaittiin liittyvän varhaiseen AGA:an. Pienen maaseutukaupungin kaikki sepelvaltimoiden revaskularisaatioon joutuneet miehet (n = 85) analysoitiin toimenpiteeseen joutumisiän ja hiusstatuksen mukaan. Tulokset osoittavat AGA:n olevan yhteydessä sepelvaltimotautiin ja varhaisen AGA:n varhaiseen sepelvaltimotautiin. Aineiston 63-vuotiailla (n = 541, miehiä 217) kaulan ympärysmitan todettiin korreloivan selvästi antropometrisiin, insuliiniresistenssiä kuvaaviin mittoihin ja seerumin insuliinipitoisuuden kasvuun sekä miehillä että naisilla. Kaulan ympärysmitta soveltuu siten käytettäväksi antropometrisena mittana androidityyppisen ylipainon ja insuliiniresistenssin selvittämisessä. Saman väestöotoksen naisilla tehdyssä tutkimuksessa havaittiin muiden insuliiniresistenssin osatekijöiden (vyötärö-lantiosuhteen, vyötärön ympärysmitan, seerumin insuliinipitoisuuden ja mikroalbuminurian) liittyvän huomattavaan hiustenlähtöön (asteet II ja III modifioidulla Ludwigin skaalalla). AGA:ssa isän suvun perimän vaikutus oli selvä molemmilla sukupuolilla. Se oli voimakas erityisesti miesten varhaisessa AGA:ssa. Laatimamme hypoteesin mukaan suuri androgeenipitoisuus estää dermaalipapillan solujen mitoosia ja heikentää sähkömagneettista vetovoimaa. Tällöin hiusfollikkelin solujen määrää vähenee ja hiuksen kasvuvaihe lyhenee haittaavasti. Insuliiniresistenssillä on hypoteesin mukaan toissijainen rooli hiusfollikkelin pienenemisprosessissa. Aikaista hiustenlähtöä androidin ylipainon ohella voidaan pitää insuliiniresistenssin merkkinä ja riskinä sepelvaltimotaudin tavanomaista aiempaan ilmaantumiseen. Puuttumalla ajoissa vaaratekijöihin valtimotaudin kehittymistä voidaan hidastaa tai estää ja ehkä myös vähentää kosmeettisesti ja psykososiaalisesti haittaavaa hiusten menetystä.

Alopecia areata (AA) is a putative autoimmune hair loss disorder. It mainly affects the scalp hair but can also involve body hair, and can also affect the nail and the eye. While there are may be several lines of evidence to support the autoimmune basis of AA, there is still very little information on the hair follicle autoantigen(s) involved in its pathogenesis. In this project, serum antibodies (AA=10, control=10) were used to immunoprecipitate AA-relevant target antigens from normal human scalp hair follicle extracts. These immunoprecipitates were analysed by LC-MALDI-TOF/TOF mass spectrometry for target protein identification. This part of the project involved substantial methods development. Trichohyalin was immunoprecipitated by all AA sera, but by only 5 normal sera. Importantly, the mean Mascot scores of the AA group was significantly higher than the normal group (p=0.005). Keratin 16 was also identified from immunoprecipitates as another potential AA-relevant target antigen. Functional studies by ex vivo whole hair follicle organ culture using commercial antibodies to trichohyalin and keratin 16 significantly inhibited hair fibre elongation compared to controls. Indirect immunofluorescence studies revealed that AA sera contained higher immunoreactivity against normal human scalp anagen hair follicles compared to normal sera. Immunoreactivities were mainly in the outer root sheath and inner root sheath, and less so to the medulla and hair bulb matrix. Double immunofluorescence studies of AA and normal serum with anti-trichohyalin antibody (AE15) revealed co-localisation of 9 of the AA sera antibodies with trichohyalin in the inner root sheath (mostly in Henle¿s, less in Huxley¿s/inner root sheath cuticle), but only weakly in 3 normal sera. This study supports the involvement of an antibody response to anagen-specific hair follicles antigens in AA. Moreover, there may be some evidence that these antibodies may have a pathogenic role.

Hair plays an important role in human social and sexual communication. The androgen-stimulated, patterned loss of hair in cases of androgenetic alopecia (or common baldness) in genetically pre-disposed individuals, is associated with ageing and can cause marked phychological distress. However, it is poorly controlled. To investigate the effectiveness of daily topical application of a Chinese medicine-derived herbal mixture, Xiantene, on balding progression, two double-blind, placebo-controlled studies (3 and 12 months) were carried out on balding men using the trichogram approach. Xiantene significantly increased both the total number of hairs and those in anagen, improving the ratio of anagen:telogen hairs. This suggests that topical Xiantene increased the length of the anagen phase and may promote a cessation, or partial reversal, of the progression of androgenetic alopecia in men. Canities, loss of scalp hair colour, is another mark of ageing. To investigate whether early greying may protect follicles from androgenetic alopecia, the extent of alopecia, assessed using the Hamilton scale, was compared between men who first became grey before, or after, 30. Both alopecia and greying increased with age in 843 men (217 European, 626 Thai) whenever they first started greying. However, men who showed greying before 30 were significantly less bald, though more grey, in both groups. Hair follicle melanocytes synthesise the pigment melanin, producing reactive oxygen species (ROS) and oxidative stress; losing melanocyte pigmentary activity, and therefore these toxic factors, appears to enable hair follicles to maintain their full size for longer, despite the androgen drive to miniaturisation. / Tri-Mill Charitable Trust, Global Beauty International Management Ltd.

Alopecia areata (AA) is a putative autoimmune hair loss disorder. It mainly affects the scalp hair but can also involve body hair, and can also affect the nail and the eye. While there are may be several lines of evidence to support the autoimmune basis of AA, there is still very little information on the hair follicle autoantigen(s) involved in its pathogenesis. In this project, serum antibodies (AA=10, control=10) were used to immunoprecipitate AA-relevant target antigens from normal human scalp hair follicle extracts. These immunoprecipitates were analysed by LC-MALDI-TOF/TOF mass spectrometry for target protein identification. This part of the project involved substantial methods development. Trichohyalin was immunoprecipitated by all AA sera, but by only 5 normal sera. Importantly, the mean Mascot scores of the AA group was significantly higher than the normal group (p=0.005). Keratin 16 was also identified from immunoprecipitates as another potential AA-relevant target antigen. Functional studies by ex vivo whole hair follicle organ culture using commercial antibodies to trichohyalin and keratin 16 significantly inhibited hair fibre elongation compared to controls. Indirect immunofluorescence studies revealed that AA sera contained higher immunoreactivity against normal human scalp anagen hair follicles compared to normal sera. Immunoreactivities were mainly in the outer root sheath and inner root sheath, and less so to the medulla and hair bulb matrix. Double immunofluorescence studies of AA and normal serum with anti-trichohyalin antibody (AE15) revealed co-localisation of 9 of the AA sera antibodies with trichohyalin in the inner root sheath (mostly in Henle's, less in Huxley's/inner root sheath cuticle), but only weakly in 3 normal sera. This study supports the involvement of an antibody response to anagen-specific hair follicles antigens in AA. Moreover, there may be some evidence that these antibodies may have a pathogenic role.

Abstract Alopecia has been suggested to be associated with coronary artery diseases (CAD). However, the mechanism underlying this association has remained unclear. The purpose of the present study was to examine the relationships between metabolic syndrome-related risk factors, cardiovascular diseases (CVD) and alopecia among Finnish population. In addition, health-related quality of life (HRQOL) was studied in respect of alopecia among both genders. The data come from the national Finrisk survey alopecia sub-study (4 066 men aged 25–74 years old) and two community samples of men and women (aged 55 and 63 years) living in the city of Oulu in 2001 and 1998, respectively. The degree of alopecia was assessed using the Norwood-Hamilton classification scale for men and the Ludwig scale for women. This study showed a high prevalence of alopecia in the general male Finnish population varying from 17% to 73% among men aged 25–74 years, and its association with CVD particularly in age-groups older than 55 years. In addition, insulin resistance, as a metabolic syndrome-related risk factor, was associated with alopecia in middle-aged men. Among men younger than 35 years, low-grade inflammation was associated with alopecia, especially combined with central obesity. Further, in middle-aged general Finnish population, obesity associated most closely with low-grade inflammation, which is in line with the findings among young men with alopecia. Compared to subjects with no alopecia, HRQOL dimension scores (RAND-36) were significantly lower in physical functioning, role limitations due to physical health and general health among women with alopecia, and in physical functioning and social functioning among men with alopecia. Regression analyses of HRQOL-related factors revealed that alopecia was associated with role limitations due to physical health in women but not in men. An association between alopecia and CVD was strengthened in this study. In addition, low-grade inflammation and insulin resistance were associated with alopecia, especially with early onset alopecia. In elderly women, alopecia seemed to be associated with morbidity in vascular diseases. In the future, recognition of the risk factors for cardiovascular disease among subjects with alopecia is a challenge for primary health care that may prevent the development of arterial diseases. / Tiivistelmä Hiustenlähdön yhteys sydän- ja verisuonisairauksiin on ollut tiedossa jo pitkään, mutta yhteyden taustalla olevat patofysiologiset mekanismit ovat edelleenkin epäselviä. Tässä väitöskirjatyössä tutkittiin hiustenlähdön yhteyksiä metaboliseen oireyhtymään ja siihen liittyviin riskitekijöihin suomalaisessa väestössä yleisesti. Lisäksi tutkittiin elämänlaadun yhteyttä hiustenlähtöön 63-vuotiailla miehillä ja naisilla. Tutkimukseen käytettiin kolmea aineistoa; kansallisen Finrisk 2002 tutkimuksen alopecia (hiustenlähtö) alaotos (4066 iältään 25–74-vuotiasta miestä) ja kaksi aineistoa Oulun kaupungista (Oulussa asuneet 55- ja 63-vuotiaat miehet ja naiset vuonna 2001 ja 1998). Hiustenlähdön laajuus määriteltiin miehillä Norwood-Hamiltonin ja naisilla Ludwigin luokitteluasteikon mukaan. Hiustenlähdön esiintyvyys suomalaisessa miesväestössä vaihteli 17 %:sta (25–34-vuotiaat) 73 %:iin (65–74-vuotiaat) ja se näytti liittyvän sydän- ja verisuonisairauksiin 55-vuotiailla ja sitä vanhemmilla miehillä. Lisäksi alentunut insuliiniherkkyys metabolisen oireyhtymän merkkinä oli yhteydessä hiustenlähtöön keski-ikäisillä miehillä. Varhain alkanut hiustenlähtö (alle 35-vuotiaat) liittyi matala-asteiseen tulehdukseen erityisesti keskivartalolihavilla kaljuuntuvilla nuorilla miehillä. Samansuuntainen tulos tuli esille myös väestötutkimuksessa 55-vuotiailla oululaisilla miehillä ja naisilla, jonka mukaan matala-asteinen tulehdus oli yhteydessä erityisesti yleiseen lihavuuteen eikä pelkästään vyötärölihavuuteen. Terveyteen liittyvän elämänlaadun osa-alueiden pisteet (RAND-36) 63-vuotialla hiustenlähdöstä kärsivillä naisilla olivat merkittävästi matalampia kolmella osa-alueella; fyysiset toiminnot, fyysisen terveydentilan aiheuttamat muutokset roolitoiminnoissa ja yleinen terveys. Samanikäisillä kaljuuntuvilla miehillä merkittävästi matalammat terveyteen liittyvät elämänlaadun osakomponentit olivat fyysisten ja sosiaalisten toimintojen alueella. Tilastollisessa regressioanalyysissä ilmeni, että hiustenlähtö selitti fyysisen terveydentilan aiheuttamia rajoituksia roolitoimintoihin erityisesti kaljuuntuvilla naisilla, mutta ei miehillä. Hiustenlähdön yhteys eri sydän- ja verisuonisairauksiin vahvistui tässä tutkimuksessa. Varhainen hiustenlähtö on ilmeisesti merkki sekä matala-asteisesta tulehduksesta että alentuneesta insuliiniherkkyydestä. Myös naisilla hiustenlähtö näyttäisi liittyvän suurempaan sairastavuuteen. Terveydenhuollon tulisi jatkossa tarkemmin paneutua sydän- ja verisuonisairauksien riskin kartoittamiseen hiustenlähdöstä kärsivien potilaiden kohdalla.

This study is an examination of ovarian and uterine cancer patients’ perceptions of chemotherapy-induced alopecia and how it impacts quality-of-life over the course of chemotherapy. The chapters in this dissertation address the following research questions: How do ovarian and uterine cancer patients communicate about their experiences of alopecia over the course of chemotherapy? How does chemotherapy-induced alopecia influence patients’ understandings of quality-of-life? Longitudinal interviews were conducted with a patient population of twenty-three, and each patient was interviewed at least twice over the course of chemotherapy. The data set was composed of fifty-five interviews, and a thematic analysis was performed across interview transcripts. Analysis of the data revealed four themes: 1) chemotherapy-induced alopecia and quality-of-life; 2) the “mirror moment”; 3) performance of social roles; and 4) gendered visibility. Data indicate ovarian and uterine cancer patients experienced substantial daily distress related to chemotherapy-induced alopecia. The ability to perform social roles deemed important to patients’ quality-of-life such as the familial roles of partner and mother/grandmother were negatively impacted by hair loss. Patients’ distress concerning alopecia was strongly connected to the ability to function in the public sphere without feeling approachable or being approached by “strangers” because of their alopecia. Clinicians might consider repeatedly asking about chemotherapy-induced alopecia over the course of chemotherapy, both because it could help patients cope with the side effect and because it may generate dialogue related to other important concerns late-stage cancer patients may feel are too trivial to mention in clinical discussions. Women’s social and familial roles may be impacted by alopecia and chemotherapy in unique ways that deserve additional study.

No description available.