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Melatonin in der topischen Behandlung der androgenetischen Alopezie
Abstract
Auf der Suche nach alternativen Substanzen zu Finasterid und Minoxidil für die Behandlung der androgenetischen Alopezie (AGA) wurde Melatonin, ein starkes Antioxidanz und Wachstumsmodulator, als Kandidat aus In-vitro- und In-vivo-Untersuchungen identifiziert. Insgesamt fünf klinische Studien zeigten bei guter Verträglichkeit positive Effekte einer topischen Melatonin-Behandlung auf die AGA bei Männern und Frauen: (1) Pharmakodynamisch zeigte sich unter einmal abendlicher topischer Anwendung kein signifikanter Einfluss auf die endogenen Melatonin-Plasmaspiegel. (2) In einer Anwendungsbeobachtung mit 30 Männern und Frauen mit Prüfarzt- und Probandenfragebögen zeigte sich nach 30 und 90 Tagen ein signifikanter Rückgang des Schweregrades der Alopezie (p < 0,001). (3) Mittels digitaler, Software-gestützter Auflichtmikroskopie (TrichoScan) wurde bei 35 Männern mit AGA bei 54,8 bzw. 58,1 % der Patienten nach 3 und 6 Monaten eine signifikante Zunahme der Haardichte um 29 % bzw. 41 % gemessen (M0: 123/cm²; M3: 159/cm²; M6: 173/cm²) (p < 0,001). (4) Bei 60 Männern und Frauen mit Haarausfall wurde eine signifikante Reduktion des Haarverlustes bei den Frauen festgestellt, während bei den Männern der Haarausfall konstant blieb (p < 0,001). (5) In einer Multizenterstudie mit über 1800 Probanden in 200 Zentren über 3 Monate nahm der Anteil der Patienten mit 2- bis 3-fach positivem Pull-Test von 61,6 % auf 7,8 % ab und der Anteil der Patienten mit negativem Pull-Test von 12,2 % auf 61,5 % zu (p < 0,001). Zusätzlich wurde ein Rückgang der Seborrhö und der seborrhoischen Dermatitis der Kopfhaut beobachtet. Da die Sicherheit und Verträglichkeit in allen Studien gut war, kann die topische Anwendung einer kosmetischen Melatonin-Lösung eine sinnvolle Behandlungsoption bzw. Ergänzung bei androgenetischer Alopezie darstellen.
Because of a strong reduction of life quality in patients with hair loss, a special questionnaire was developed following the general Skindex questionnaire for dermatoses.
The Hairdex was evaluated in 75 female hair patients. The aim of the study was to prove the questionnaire's statistical values, reliability, validity, general acceptance and accuracy. The clinical manifestation of hair loss was categorized as “not visible”, slightly visible” and “obviously visible”.
The hair loss lead to great differences in the life quality of both the patients with obvious hair loss and in patients with non-visible hair loss, especially in the categories “emotions”, “self-confidence” and “stigmatization”. The convergent and discriminant validity of the questionnaire was satisfactory. The acceptance of the questionnaire was very good with 90%.
The hairdex-questionnaire represents a reliable and patient-oriented instrument for evaluation of life quality in hair diseases. The reliability of the questionnaire concerning longitudinal therapeutic effects will need to be investigated in further studies.
Experimental evidence supports the hypothesis that oxidative stress plays a major role in the ageing process. Reactive oxygen species are generated by a multitude of endogenous and environmental challenges. Reactive oxygen species or free radicals are highly reactive molecules that can directly damage cellular structural membranes, lipids, proteins, and DNA. The body possesses endogenous defence mechanisms, such as antioxidative enzymes and non-enzymatic antioxidative molecules, protecting it from free radicals by reducing and neutralizing them. With age, the production of free radicals increases, while the endogenous defence mechanisms decrease. This imbalance leads to the progressive damage of cellular structures, presumably resulting in the ageing phenotype. Ageing of hair manifests as decrease of melanocyte function or graying, and decrease in hair production or alopecia. There is circumstantial evidence that oxidative stress may be a pivotal mechanism contributing to hair graying and hair loss. New insights into the role and prevention of oxidative stress could open new strategies for intervention and reversal of the hair graying process and age-dependent alopecia.
Melatonin, the pineal gland hormone and a strong antioxidant, has long been known, particularly in animal-experiment based research and the wool-producing industry, to be a potent regulatory neuroendocrine substance in relation to hair growth, hair color and hair cycle, depending on light periods, seasonal rhythms, environmental factors and reproductive rhythms. Nevertheless, the biological mechanisms of this extremely versatile hormone, especially with regard to human hair follicles, are not fully understood. In recent years, however, essential knowledge has been gained on the melatoninergic system of the skin, melatonin levels in keratinocytes and hair follicles, extrapineal intrafollicular melatonin synthesis and noradrenalin-induced increase in synthesis, as well as hair cycle-dependent expression of the membrane-bound melatonin receptor MT2 and the nuclear receptor RORalpha. Functional data on the growth of human hair both in vitro and in vivo show that melatonin might play an essential role in hair physiology.
Melatonin has been experimentally implicated in skin functions such as hair growth cycling, fur pigmentation, and melanoma control, and melatonin receptors are expressed in several skin cells including normal and malignant keratinocytes, melanocytes, and fibroblasts. Melatonin is also able to suppress ultraviolet (UV)-induced damage to skin cells and shows strong antioxidant activity in UV exposed cells. Moreover, we recently uncovered expression in the skin of the biochemical machinery involved in the sequential transformation of l-tryptophan to serotonin and melatonin. Existence of the biosynthetic pathway was confirmed by detection of the corresponding genes and proteins with actual demonstration of enzymatic activities for tryptophan hydroxylase, serotonin N-acetyl-transferase, and hydroxyindole-O-methyltransferase in extracts from skin and skin cells. Initial evidence for in vivo synthesis of melatonin and its metabolism was obtained in hamster skin organ culture and in one melanoma line. Therefore, we propose that melatonin (synthesized locally or delivered topically) could counteract or buffer external (environmental) or internal stresses to preserve the biological integrity of the organ and to maintain its home-ostasis. Furthermore, melatonin could have a role in protection against solar radiation or even in the management of skin diseases.
Melatonin, which can be produced in the skin, exerts a protective effect against damage induced by UV radiation (UVR). We have investigated the effect of UVB, the most damaging component of UVR, on melatonin metabolism in HaCaT keratinocytes and in a cell-free system. Four metabolites were identified by HPLC and LC-MS: 6-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), 2-hydroxymelatonin (the main intermediate between melatonin and AFMK), and 4-hydroxymelatonin. Concentrations of these photoproducts were directly proportional to UVR-dose and to melatonin substrate content, and their accumulation was time-dependent. The UVR-dependent increase of AFMK and 2-hydroxymelatonin was also detected in keratinocytes, where it was accompanied by simultaneous consumption of intracellular melatonin. Of note, melatonin and its two major metabolites, 2-hydroxymelatonin and AFMK, were also detected in untreated keratinocytes, neither irradiated nor preincubated with melatonin. Thus, intracellular melatonin metabolism is enhanced under exposure to UVR. The additional biological activity of these individual melatonin metabolites increases the spectrum of potential actions of the recently identified cutaneous melatoninergic system.
Androgenetic alopecia (AGA), a hereditary disorder that involves the progressive thinning of hair in a defined pattern, is driven by androgens. The hair follicle dermal papilla (DP) expresses androgen receptors (AR) and plays an important role in the control of normal hair growth. In AGA, it has been proposed that the inhibitory actions of androgens are mediated via the DP although the molecular nature of these interactions is poorly understood. To investigate mechanisms of AGA, we cultured DP cells (DPC) from balding and non-balding scalp and confirmed previous reports that balding DPC grow slower in vitro than non-balding DPC. Loss of proliferative capacity of balding DPC was associated with changes in cell morphology, expression of senescence-associated beta-galactosidase, as well as decreased expression of proliferating cell nuclear antigen and Bmi-1; upregulation of p16(INK4a)/pRb and nuclear expression of markers of oxidative stress and DNA damage including heat shock protein-27, super oxide dismutase catalase, ataxia-telangiectasia-mutated kinase (ATM), and ATM- and Rad3-related protein. Premature senescence of balding DPC in vitro in association with expression of p16(INK4a)/pRB suggests that balding DPC are sensitive to environmental stress and identifies alternative pathways that could lead to novel therapeutic strategies for treatment of AGA.
In castrated prepubertal rats, pinealectomy enhanced the testosterone-induced growth response of the seminal vesicles and melatonin inhibited this effect in a dose-related manner. In entire animals, the serum concentration of LH was increased after pinealectomy with no significant changes in other parameters. Administration of melatonin to intact, pinealectomized rats did not affect the serum concentrations of LH or testosterone but caused a dose-related decrease in the weight of the seminal vesicles. The highest dose of melatonin tested reduced the weight of the ventral prostate gland and the uptake of radioactivity by both the ventral prostate gland and the testes after injection of [5-3H]uridine. It is suggested that the pineal gland and melatonin may exert an antagonistic effect on the biological activity of androgens administered to castrated rats and that melatonin can reduce the growth of the accessory sex organs of intact, pinealectomized rats, in spite of a high concentration of LH in the serum. The well-known inhibitory influence of systemically administered melatonin on the accessory sex organs in male rats may be due to its antagonistic effect at a peripheral level.
Finasteride (1 mg/day) is widely utilized by dermatologists for the treatment of androgenetic alopecia. Although enjoying a relatively good safety profile, several sex-related adverse effects have been reported with this drug. Here we report two cases of gynecomastia, one of them bilateral, caused by Propecia((R)) prescribed for the treatment of androgenetic alopecia. Although relatively rare, physicians should be aware of this side effect and inform their patients when prescribing this medication.
There is a need for a simple and reliable tool to evaluate hair loss and treatment effects in patients suffering from alopecia. In 2001 TrichoScan was introduced as a fully-automated method for the measurement of biological parameters of hair growth such as density, diameter and growth rate. However, the conventional phototrichogram method with manual marking of hairs on images is still performed and, although no real independent side-by-side comparison is available, the manual method is sometimes defined as the most precise method of measurement. The aim of this study was validation of the Trichoscan method by comparative assessment of TrichoScan analysis and manual marking of hairs. Digital images were taken from 10 patients with androgenetic alopecia (AGA) and validity and reliability of both methods were assessed. This study showed an excellent correlation of TrichoScan and manual marking of hairs. Considerable variability was noted in the results from manually evaluated images (range 2.71%-12.95%), compared to none in TrichoScan analyzed images. Results with TrichoScan were obtained more quickly and were more reproducible with a smaller margin of operator error. The consistency in the Trichoscan data allows statistically significant results to be obtained with a smaller sample size.
Androgenetic alopecia in the female occurs much more frequently than is generally believed. The condition is still considered infrequent, for it differs, in its clinical picture and in the sequence of events leading to it, from common baldness in men. To facilitate an early diagnosis (desirable in view of the therapeutic possibilities by means of antiandrogens) a classification of the stages of the common form (female type) of androgenetic alopecia in women is presented. The exceptionally observed male type of androgenetic alopecia can be classified according to Hamilton or to the modification of this classification proposed by Ebling & Rook.
The isolation and viability in vitro of anagen secondary hair follicles of the Cashmere goat were studied. Isolated hair follicles were used to determine the effects on hair shaft elongation, of prolactin and melatonin, hormones considered to influence hair follicle growth and activity in vivo. Intact hair follicles were isolated from the dermal layer of the skin singly or in groups using watchmakers' forceps under a dissecting microscope. The isolated follicles were maintained floating in Williams E medium. The medium was supplemented with 1 of 6 concentrations of ovine prolactin (0, 50, 200, 400, 800 and 4000 micrograms/l) for the culture of hair follicles isolated during July and August, and with 1 of 5 concentrations of melatonin (0, 50, 150, 300, 600 ng/l) for the culture of hair follicles isolated during September and October. There was clear evidence of DNA synthesis, observed by autoradiography, in matrix cells of freshly isolated follicles incubated for 6 h in the presence of [methyl-3H]-thymidine. Similar measurements after 96 h of maintenance indicated a marked reduction in the incorporation of [methyl-3H]-thymidine in matrix cells of the follicles studied. Prolactin and melatonin were shown to have a stimulating effect on hair shaft elongation of secondary follicles during 24 h periods of measurement and cumulatively over 120 h. Maximum hair follicle growth was observed in follicles exposed to 400 micrograms/l of prolactin and follicles exposed to 300 ng/l of melatonin. The number of follicles remaining viable during each 24 h measuring period was not affected by prolactin, but was significantly reduced by melatonin treatment after 96 h of maintenance.(ABSTRACT TRUNCATED AT 250 WORDS)
Pelage cycles of ferrets are poorly documented, although it is clear that their timing is sensitive to daylength, mediated by pineal melatonin. Hair follicles were monitored histologically in ferrets from 3 to 19 months of age in order to describe naturally occurring changes in follicle growth status and follicle number over three successive cycles of fur growth. Melatonin was administered to some of these animals in late summer to determine the long-term effects of perturbation of hormonal control. Circulating melatonin was elevated for approximately 50 days by 8-mg continuous release implants. Treated animals grew both their first winter coat, and subsequent summer coats 18 days in advance of untreated controls, but this effect did not extend to the second winter coat. Reimplantation the following year induced an advancement of the autumn follicle growth as in the 1st year. Autumn fiber growth occurred at similar times in untreated males and females, and response to melatonin did not differ between sexes. Hair follicle regression and shedding during the natural spring molt was also contemporaneous in males and females, but fiber regrowth occurred 4-6 weeks later in males as compared with females, suggesting that reproduction-related factors affect fiber growth initiation, and that fiber growth and shedding are physiologically distinct processes. Melatonin implants in autumn also affected reproduction in the spring, advancing oestrus by 3-4 weeks. These results show that interference with photoperiodic and hormonal control mechanisms in ferrets can affect pelage and reproductive cycles for up to 10 months.
In order to investigate female Djungarian hamsters' reactions to changes of the photoperiod, the following two experiments were performed. Experiment I: Age-matched female hamsters were exposed to either short (8L:16D) or long days (16L:8D) for 38 weeks. Initially, the short-day group showed a decline in body weight, associated with changes in gonadal function and fur color. This was not maintained by the short-day group which returned, on the most part, to long-day levels, thus becoming insensitive to this regressive lighting regimen. The time courses of these events compare well with those observed in males, which suggests a common mechanism. Experiment II: Two groups of female hamsters were exposed for 8 weeks to either long days or short days. At the end of the test period, the diurnal variations in pineal content of melatonin, serotonin, hydroxyindole acetic acid, and serum melatonin were estimated, revealing marked differences between the two groups. Not only was there a prolongation of melatonin synthesis observed in the short-day animals, but there was also a significant elevation of the melatonin levels when compared to the long-day animals. Together with recent findings in males, these findings lend support to the hypothesis that, in the Djungarian hamster, the elevation of nocturnal melatonin levels may be of additional significance, with respect to the physiological changes induced by short-day photoperiods.
Human benign prostatic epithelial cells contain functional melatonin receptors that can suppress cell growth and viability. The development of benign prostatic hyperplasia in men is assumed to result from androgen-estrogen imbalance. The impact of sex steroids on melatonin receptors in human benign prostate epithelial cells was investigated. The suppression by melatonin of [³H]thymidine incorporation and cGMP, and the enhancement of cAMP levels in the cells were used as markers of melatonin responses.
Dihydrotestosterone (DHT) and 17β-estradiol (E2) separately increased[ ³H]thymidine incorporation into the cells, but suppressed it when combined. In cells grown with DHT, melatonin responses were extenuated. E2 greatly reduced the apparent affinity of [¹²⁵I]melatonin binding in these cells without affecting binding site density. In parallel, the ability of melatonin to suppress [³H]thymidine incorporation into the cells was ablated within 1 h after the addition of E2. The melatonin-mediated increase in cAMP and decrease in cGMP concentrations were also ablated by E2.
Preincubation of the cells with bis-indolylmaleimide (GF 102903X), a specific inhibitor of protein kinase C, prevented the E2-mediated inactivation of melatonin binding and the inhibitory action on [³H]thymidine incorporation. Prolonged (18-h) incubation of the cells with phorbol 12-myristate 13-acetate to down regulate protein kinase activity, partially restored[ ¹²⁵I]melatonin binding and responsiveness in the E2-treated cells.
These data indicate that 1) DHT and E2 enhance prostate epithelial cells growth, but reduce cell growth when combined; 2) DHT extenuates the inhibitory effects of melatonin on epithelial cell growth; and 3) E2 acts to inactivate melatonin receptors and consequently responses in human epithelial benign prostatic hyperplasia cells. This process is probably mediated by protein kinase C.
Together, these results show an interplay between melatonin and sex steroids in the regulation of benign prostatic epithelial cell growth.
Androgenetic alopecia (male pattern hair loss) is caused by androgen-dependent miniaturization of scalp hair follicles, with scalp dihydrotestosterone (DHT) implicated as a contributing cause. Finasteride, an inhibitor of type II 5alpha-reductase, decreases serum and scalp DHT by inhibiting conversion of testosterone to DHT.
Our purpose was to determine whether finasteride treatment leads to clinical improvement in men with male pattern hair loss.
In two 1-year trials, 1553 men (18 to 41 years of age) with male pattern hair loss received oral finasteride 1 mg/d or placebo, and 1215 men continued in blinded extension studies for a second year. Efficacy was evaluated by scalp hair counts, patient and investigator assessments, and review of photographs by an expert panel.
Finasteride treatment improved scalp hair by all evaluation techniques at 1 and 2 years (P < .001 vs placebo, all comparisons). Clinically significant increases in hair count (baseline = 876 hairs), measured in a 1-inch diameter circular area (5.1 cm2) of balding vertex scalp, were observed with finasteride treatment (107 and 138 hairs vs placebo at 1 and 2 years, respectively; P < .001). Treatment with placebo resulted in progressive hair loss. Patients' self-assessment demonstrated that finasteride treatment slowed hair loss, increased hair growth, and improved appearance of hair. These improvements were corroborated by investigator assessments and assessments of photographs. Adverse effects were minimal.
In men with male pattern hair loss, finasteride 1 mg/d slowed the progression of hair loss and increased hair growth in clinical trials over 2 years.
Androgenetic alopecia (AGA) is the most common type of hair loss in men and women. This continuous process results in a type of alopecia that follows a definite pattern in those individuals who are genetically predisposed. At present the predisposing genes are unknown but the relatively strong concordance of the degree of baldness in fathers and sons is not consistent with a simple Mendelian trait and a polygenic basis is therefore most likely. AGA can be defined as a DHT-dependent process with continuous miniaturization of sensitive HF. Today we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss in AGA. However, recent experimental and clinical advances enable us to explain some pathogenetic steps leading to androgenetic hair loss. Among other steroidogenic isoenzymes such as 17b- and 3b- hydroxysteroid dehydrogenases, the type 2 5a-reductase within the dermal papilla plays a central role by the intrafollicular conversion of T to DHT.
Hair loss or hair thinning is a common complaint in clinical dermatology, and patients seeking advice for hair loss are not necessarily bald. Also the effects of treatment attempts are hard to measure. Consequently, there is a need for a sensitive tool to monitor hair loss and treatment response. Such a method must be able to analyze the biological parameters of hair growth, which are: 1: hair density (n/cm2), 2: hair diameter (mm), 3: hair growth rate (mm/day) and 4: anagen/telogen ratio. Here we present the TrichoScan as a method which combines epiluminescence microscopy (ELM) with automatic digital image analysis for the measurement of human, and potentially animal hair, in situ. The TrichoScan is able to analyze all biological parameters of hair growth with a so-called intraclass correlation of approx. ninety-one percent with the same TrichoScan operator and an intraclass correlation of approx. ninety-seven percent for different TrichoScan operators. The application of the technique is demonstrated by comparison of the hair parameters in individuals without apparent hair loss with men with untreated AGA and men after treatment with finasteride (1 mg/day), where we were able to detect a significant increase in hair counts and cumulative hair thickness 3 and 6 months after treatment. The advantage of the TrichoScan is that it can be used for clinical studies to compare placebo versus treatment or to compare different capacities of different hair growth promoting substances, it can be used for studying AGA or other forms of diffuse hair loss, and it can be adopted to study the effect of drugs or laser treatment on hypertrichosis or hirsutism.
Reactive oxygen species (ROS) are presumed to be involved in inflammatory UV reactions of the skin. This in vitro study was performed to investigate the suppressive effect of melatonin in interleukin-3 (IL-3) stimulated leukocytes. Neutrophilic granulocytes were isolated from EDTA-treated whole blood and placed in a phosphate-buffered saline (PBS) containing IL-3. Cell suspensions were either treated with PBS (control) or with increasing doses of melatonin (0.1, 0.5, 1, 2, 3, 5, 7.5, 10 mmol). One PBS solution was left unirradiated and the other nine solutions (PBS and melatonin) were irradiated with 750 mJ/cm2 UVB light (280-360 nm, max: 310 nm). Radical formation was measured by the chemiluminescence technique. UV-irradiated leukocytes showed a 5-fold higher radical formation than unirradiated leukocytes. Melatonin, in increasing doses in powers of ten, led to a maximum suppression of free radicals at 10 nmol (P= 0.01) and 1 mmol melatonin (P= 0.001), showing a biphasic, non-linear, dose response relationship. Melatonin, given in amounts of 0.1-10 mmol, led to a direct dose-dependent suppression of ROS. Radical formation was suppressed significantly in a range from 0.5 to 10 mmol (P= 0.001). Melatonin is known to function as a radical scavenger and antioxidant; some of these melatonin effects may be receptor independent, while others may be receptor dependent.
Although many theories relating the pineal secretory product melatonin to aging have been put forward, the role of this agent in the aging process is not clear. However, there are several reasons to postulate a role for melatonin in this process. Melatonin levels fall gradually over the life-span. Melatonin is a potent free radical scavenger. Melatonin deficiency is related to suppressed immunocompetence. In at least one animal model melatonin supplementation increased life-span although several other studies have failed. The aging process is multifactorial, and no single element seems to be of basic importance. It seems, however, that although melatonin can not be univocally recognized as a substance delaying aging, some of its actions may be beneficial for the process of aging. However, the precise role of melatonin in the aging process remains to be determined.
We investigated the cutaneous expression of genes and enzymes responsible for the multistep conversion of tryptophan to serotonin and further to melatonin. Samples tested were human skin, normal and pathologic (basal cell carcinoma and melanoma), cultured normal epidermal and follicular melanocytes, melanoma cell lines, normal neonatal and adult epidermal and follicular keratinocytes, squamous cell carcinoma cells, and fibroblasts from dermis and follicular papilla. The majority of the samples showed simultaneous expression of the genes for tryptophan hydroxylase, arylalkylamine N-acetyltransferase (AANAT), and hydroxyindole-O-methyltransferase (HIOMT). The products of AANAT activity were identified by RP-HPLC with fluorimetric detection in human skin and in cultured normal and malignant melanocytes and immortalized keratinocytes; HIOMT activity was detected in human skin, keratinocytes, and melanoma cells. N-acetylserotonin (NAS) was detected by RP-HPLC in human skin extracts. NAS identity was confirmed further by LC/MS in keratinocytes. In conclusion, we provide evidence that the human skin expresses intrinsic serotonin and melatonin biosynthetic pathways.
Besides being the single most preventable cause of significant morbidity and an important cause of death in the general population, tobacco smoking has been associated with adverse effects on the skin. Smoke-induced premature skin ageing has attracted the attention of the medical community, while only recently an observational study has indicated a significant relationship between smoking and baldness. The mechanisms by which smoking causes hair loss are multifactorial and are probably related to effects of cigarette smoke on the microvasculature of the dermal hair papilla, smoke genotoxicants causing damage to DNA of the hair follicle, smoke-induced imbalance in the follicular protease/antiprotease systems controlling tissue remodeling during the hair growth cycle, pro-oxidant effects of smoking leading to the release of pro-inflammatory cytokines resulting in follicular micro-inflammation and fibrosis and finally increased hydroxylation of oestradiol as well as inhibition of the enzyme aromatase creating a relative hypo-oestrogenic state. In view of the psychological impact of androgenetic alopecia on affected men and women, increasing public awareness of the association between smoking and hair loss offers an opportunity for health education against smoking that may be more effective than the link between smoking and facial wrinkles or grey hair, since the latter can be effectively counteracted by current aesthetic dermatologic procedures, while treatment options for androgenetic alopecia are limited.
Hypertrichosis has been reported more frequently in females than in males who use minoxidil topical solution (MTS) for the treatment of androgenetic alopecia (AGA). This article examines the occurrence of MTS-induced hypertrichosis in females.
Data from placebo-controlled clinical trials in females (up to 5% MTS) were analysed based on spontaneous reports of hypertrichosis/facial hair and investigators' inquiries (solicited) about the presence of any new hair growth on body parts other than the scalp. A postmarketing drug surveillance database for MTS was also examined for reports of hypertrichosis/facial hair.
In the clinical trials involving a total of 1333 females, spontaneous reports of hypertrichosis/facial hair were noted for 50 (4%) females in a dose-related pattern of response (5% MTS > 2% MTS > placebo). Nine females (seven and two in the 5% MTS and 2% MTS groups, respectively) discontinued treatment because of hypertrichosis/facial hair. Solicited reports of excessive hair growth (primarily facial) also showed a dose-related pattern of response. Post-marketing data showed a lower occurrence (0.5%) of hypertrichosis/facial hair than in the clinical trials. Of interest, in one clinical trial, 27% of the females enrolled (MTS and placebo treated) had facial hair growth reported at baseline.
Females with some hirsutism are particularly prone to seek treatment for AGA, and this may explain the high occurrence of hypertrichosis/facial hair found in the MTS clinical trials. Furthermore, some demographic groups of females are prone to develop facial hair and the problem of unwanted facial hair growth seems to be underestimated. Some females may have hair follicles that are very sensitive to MTS and should use the lowest strength of MTS (2%) to help avoid unwanted hair growth. The hypertrichotic effect of MTS on other sites than the scalp, including the face, is reversible and does not always require discontinuation of therapy.
We tested the expression of genes coding receptors of a cutaneous serotoninergic/melatoninergic system in whole human skin and in normal and pathologic cultured skin cells. Evaluation of serotonin (5HT), melatonin (MT), and melatonin-related receptors (MRR) showed expression of the isoforms 5HT2B, 5HT7, and MT1 genes in almost all the tested samples. Expression of other isoforms was less prevalent; 5HT2C, MRR, and MT2 were rarely detected. We also found novel isoforms for MT2, MRR, and 5HT2B and documented the process of RNA editing for 5HT2C. Testing for functional activity of these receptors with serotonin and melatonin (10(-14) to 10(-10) M) showed variable effects depending on cell type and culture conditions. Thus, serotonin stimulated proliferation of melanocytes in medium deprived of growth factors, while inhibiting cell growth in the presence of growth factors. Melatonin inhibited both apoptosis of HaCaT keratinocytes incubated in serum-free media, and proliferation of cells cultured in medium supplemented with serum. Melatonin also increased the numbers of viable fibroblasts incubated in serum free medium. N-acetylserotonin (NAS) and 5 methoxytryptamine (5MTT) were generally without effect on cell proliferation, with the exception of an inhibition of melanocyte proliferation at the higher 5MTT concentration of 10(-10) M. Thus, skin cells represent a true target for the products of the serotoninergic/melatoninergic cutaneous pathway with their actions modulating cell proliferation or viability.
It was recently discovered that mammalian skin can produce serotonin and transform it into melatonin. Pathways for the biosynthesis and biodegradation of serotonin and melatonin have been characterized in human and rodent skin and in their major cellular populations. Moreover, receptors for serotonin and melatonin receptors are expressed in keratinocytes, melanocytes, and fibroblasts and these mediate phenotypic actions on cellular proliferation and differentiation. Melatonin exerts receptor-independent effects, including activation of pathways protective of oxidative stress and the modification of cellular metabolism. While serotonin is known to have several roles in skin-e.g., pro-edema, vasodilatory, proinflammatory, and pruritogenic-melatonin has been experimentally implicated in hair growth cycling, pigmentation physiology, and melanoma control. Thus, the widespread expression of a cutaneous seorotoninergic/melatoninergic syste,m(s) indicates considerable selectivity of action to facilitate intra-, auto-, or paracrine mechanisms that define and influence skin function in a highly compartmentalized manner. Notably, the cutaneous melatoninergic system is organized to respond to continuous stimulation in contrast to the pineal gland, which (being insulated from the external environment) responds to discontinuous activation by the circadian clock. Overall, the cutaneous serotoninergic/melatoninergic system could counteract or buffer external (environmental) or internal stresses to preserve the biological integrity of the organ and to maintain its homeostasis.-Slominski, A. J., Wortsman, J., Tobin, D. J. The cutaneous serotoninergic/melatoninergic system: securing a place under the sun.
The treatment of androgenetic alopecia (AGA) is usually long lasting, and the effects of treatment attempts are difficult to measure. Consequently, there was a need for a sensitive tool to monitor hair loss and treatment response. Therefore, we developed the Trichoscan as a method which combines epiluminescence microscopy with automatic digital image analysis for the measurement of human hair. The Trichoscan is able to analyze all important parameters of hair growth (density, diameter, growth rate, vellus and terminal hair density) with an intraclass correlation of approximately 91% within the same Trichoscan operator and an intraclass correlation of approximately 97% for different Trichoscan operators. The application of the technique was demonstrated by comparison of the hair parameters in 9 men with frontal balding which were treated for 6 months with 5% minoxidil. Even in this small cohort of patients, we noticed after 3 months of treatment compared to baseline a significant increase in hair density (+21.3 hairs/cm2; p = 0.047) and cumulative hair thickness (+0.61 mm; p = 0.008) and after 6 months a significant increase in hair density (+34 hairs/cm2; p = 0.011) and cumulative hair thickness (+0.88 mm; p = 0.010). The study shows that the Trichoscan has many advantages. It can be used for clinical studies to compare placebo versus treatment or to compare the relative potencies of different hair-growth-promoting substances. It can be used for studying AGA or other forms of diffuse hair loss, and it can be adopted to study the effect of drugs or laser treatment on hypertrichosis or hirsutism. The drawbacks, however, are that the Trichoscan still needs a hair dye for contrast enhancement and the measurement area must be clipped before analysis. This mini-review summarizes recent attempts to optimize the technique and shows new options such as the calculation of follicular units or the 'anagen hair count'.
Since mammalian skin expresses the enzymatic apparatus for melatonin synthesis, it may be an extrapineal site of melatonin synthesis. However, evidence is still lacking that this is really the case in situ. Here, we demonstrate melatonin-like immunoreactivity (IR) in the outer root sheath (ORS) of mouse and human hair follicles (HFs), which corresponds to melatonin, as shown by radioimmunoassay and liquid chromatography/tandem mass spectrometry (LC/MS/MS). The melatonin concentration in organ-cultured mouse skin, mouse vibrissae follicles, and human scalp HFs far exceeds the respective melatonin serum level and is significantly increased ex vivo by stimulation with norepinephrine (NE), the key stimulus for pineal melatonin synthesis. By real-time PCR, transcripts for the melatonin membrane receptor MT2 and for the nuclear mediator of melatonin signaling, retinoid orphan receptor alpha (ROR)alpha, are detectable in murine back skin. Transcript levels for these receptors fluctuate in a hair cycle-dependent manner, and are maximal during apoptosis-driven HF regression (catagen). Melatonin may play a role in hair cycle regulation, since its receptors (MT2 and RORalpha) are expressed in murine skin in a hair cycle-dependent manner, and because it inhibits keratinocyte apoptosis and down-regulates ERalpha expression. Therefore, the HF is both, a prominent extrapineal melatonin source, and an important peripheral melatonin target tissue. Regulated intrafollicular melatonin synthesis and signaling may play a previously unrecognized role in the endogenous controls of hair growth, for example, by modulating keratinocyte apoptosis during catagen and by desensitizing the HF to estrogen signaling. As a prototypic neuroectodermal-mesodermal interaction model, the HF can be exploited for dissecting the obscure role of melatonin in such interactions in peripheral tissues.
Melatonin exerts oncostatic effects on different kinds of tumors, especially on endocrine-responsive breast cancer. The most common conclusion is that melatonin reduces the incidence and growth of chemically induced mammary tumors, in vivo, and inhibits the proliferation and metastatic behavior of human breast cancer cells, in vitro. Both studies support the hypothesis that melatonin oncostatic actions on hormone-dependent mammary tumors are mainly based on its anti-estrogenic actions.
Two different mechanisms have been proposed to explain how melatonin reduces the development of breast cancer throughout its interactions with the estrogen-signaling pathways: (a) the indirect neuroendocrine mechanism which includes the melatonin down-regulation of the hypothalamic-pituitary reproductive axis and the consequent reduction of circulating levels of gonadal estrogens and (b) direct melatonin actions at tumor cell level. Melatonin's direct effect on mammary tumor cells is that it interferes with the activation of the estrogen receptor, thus behaving as a selective estrogen receptor modulator. Melatonin also regulates the activity of the aromatases, the enzymes responsible for the local synthesis of estrogens, thus behaving as a selective estrogen enzyme modulator.
The same molecule has both properties to selectively neutralize the effects of estrogens on the breast and the local biosynthesis of estrogens from androgens, one of the main objectives of recent antitumor pharmacological therapeutic strategies. It is these action mechanisms that collectively make melatonin an interesting anticancer drug in the prevention and treatment of estrogen-dependent tumors, since it has the advantage of acting at different levels of the estrogen-signaling pathways.
In addition to the well-known hormonal influences of testosterone and dihydrotestosterone on the hair cycle, melatonin has been reported to have a beneficial effect on hair growth in animals. The effect of melatonin on hair growth in humans has not been investigated so far.
To examine whether topically applied melatonin influences anagen and telogen hair rate in women with androgenetic or diffuse hair loss.
A double-blind, randomized, placebo-controlled study was conducted in 40 women suffering from diffuse alopecia or androgenetic alopecia. A 0.1% melatonin or a placebo solution was applied on the scalp once daily for 6 months and trichograms were performed to assess anagen and telogen hair rate. To monitor effects of treatment on physiological melatonin levels, blood samples were taken over the whole study period.
Melatonin led to a significantly increased anagen hair rate in occipital hair in women with androgenetic hair loss compared with placebo (n=12; P=0.012). For frontal hair, melatonin gave a significant increase in the group with diffuse alopecia (n=28; P=0.046). The occipital hair samples of patients with diffuse alopecia and the frontal hair counts of those with androgenetic alopecia also showed an increase of anagen hair, but differences were not significant. Plasma melatonin levels increased under treatment with melatonin, but did not exceed the physiological night peak.
To the authors' knowledge, this pilot study is the first to show that topically applied melatonin might influence hair growth in humans in vivo. The mode of action is not known, but the effect might result from an induction of anagen phase.
Hair has been used in many studies as a bioindicator of mercury exposure for human populations. At the time of hair formation, mercury from the blood capillaries penetrates into the hair follicles. As hair grows approximately 1 cm each month, mercury exposure over time is recapitulated in hair strands. Mercury levels in hair closest to the scalp reflect the most recent exposure, while those farthest from the scalp are representative of previous blood concentrations. Sequential analyses of hair mercury have been useful for identifying seasonal variations over time in hair mercury content, which may be the result of seasonal differences in bioavailability of fish and differential consumption of piscivorous and herbivorous fish species. Knowledge of the relation between fish-eating practices and hair mercury levels is particularly important for adequate mitigation strategies. Methyl mercury is well absorbed, and because the biological half-life is long, the body burden in humans may reach high levels. People who frequently eat contaminated seafood can acquire mercury concentrations that are potentially dangerous to the fetus in pregnant women. The dose-response relationships have been extensively studied, and the safe levels of exposure have tended to decline. Individual methyl mercury exposure is usually determined by analysis of mercury in blood and hair. The objective of the present review was to examine variations in hair mercury levels from different populations with respect to fish-eating practices.
To evaluate the association of androgenetic alopecia (AGA) with smoking and to estimate its prevalence among Asian men.
Population-based cross-sectional survey.
Tainan County, Taiwan.
The eligible population consisted of all male residents 40 years or older in Tainan County. A total of 740 subjects aged 40 to 91 years participated in the survey between April 10, 2005, and June 12, 2005.
Norwood and Ludwig classifications were used to assess the degree of hair loss. Information on smoking, together with other possible risk factors and age at onset of AGA, was collected using a questionnaire interview.
After controlling for age and family history, statistically significant positive associations were noted between moderate or severe AGA (Norwood types > or =IV) and smoking status (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.14-2.76), current cigarette smoking of 20 cigarettes or more per day (OR, 2.34; 95% CI, 1.19-4.59), and smoking intensity (OR, 1.78; 95% CI, 1.03-3.07). The OR of early-onset history for AGA grades increased in a dose-response pattern. Risk for moderate or severe AGA increased for family history of first-degree and second-degree relatives, as well as for paternal relatives.
The age-specific prevalence of AGA in Taiwan was compatible to that among Korean men but was lower than that among persons of white race/ethnicity. Smoking status, current amount of cigarette smoking, and smoking intensity were statistically significant factors responsible for AGA after controlling for age and family history. Patients with early-onset AGA should receive advice early to prevent more advanced progression.
Melatonin, the chief secretory product of the pineal gland, has long been known to modulate hair growth, pigmentation and/or molting in many species, presumably as a key neuroendocrine regulator that couples coat phenotype and function to photoperiod-dependent environmental and reproductive changes. However, the detailed effects and mechanisms of this surprisingly pleiotropic indole on the hair follicle (HF) regarding growth control and pigmentation have not yet been completely understood. While unspecific melatonin binding sites have long been identified (e.g., in goat and mouse HFs), specific melatonin membrane MT2 receptor transcripts and both protein and mRNA expression for a specific nuclear melatonin binding site [retinoid-related orphan receptor alpha (RORalpha)] have only recently been identified in murine HFs. MT1, known to be expressed in human skin cells, is not transcribed in mouse skin. After initial enzymologic data from hamster skin related to potential intracutaneous melatonin synthesis, it has recently been demonstrated that murine and human skin, namely human scalp HFs in anagen, are important sites of extrapineal melatonin synthesis. Moreover, HF melatonin production is enhanced by catecholamines (as it classically occurs in the pineal gland). Melatonin may also functionally play a role in hair-cycle control, as it down-regulates both apoptosis and estrogen receptor-alpha expression, and modulates MT2 and RORalpha expression in murine skin in a hair-cycle-dependent manner. Because of melatonin's additional potency as a free radical scavenger and DNA repair inducer, the metabolically and proliferatively highly active anagen hair bulb may also exploit melatonin synthesis in loco as a self-cytoprotective strategy.
Melatonin is a recognized antioxidant with high potential as a protective agent in many conditions related to oxidative stress such as neurodegenerative diseases, ischemia/reperfusion syndromes, sepsis and aging. These processes may be favorably affected by melatonin through its radical scavenging properties and/or antiapoptotic activity. Also, there is increasing evidence that these effects of melatonin could be relevant in keratinocytes, the main cell population of the skin where it would contribute to protection against damage induced by ultraviolet radiation (UVR). We therefore investigated the kinetics of UVR-induced apoptosis in cultured keratinocytes characterizing the morphological and mitochondrial changes, the caspases-dependent apoptotic pathways and involvement of poly(ADP-ribose) polymerase (PARP) activation as well as the protective effects of melatonin. When irradiated with UVB radiation (50 mJ/cm(2)), melatonin treated, cultured keratinocytes were more confluent, showed less cell blebbing, more uniform shape and less nuclear condensation as compared to irradiated, nonmelatonin-treated controls. Preincubation with melatonin also led to normalization of the decreased UVR-induced mitochondrial membrane potential. These melatonin effects were followed by suppression of the activation of mitochondrial pathway-related initiator caspase 9 (casp-9), but not of death receptor-dependent casp-8 between 24 and 48 hr after UVR exposure. Melatonin down-regulated effector caspases (casp-3/casp-7) at 24-48 hr post-UV irradiation and reduced PARP activation at 24 hr. Thus, melatonin is particularly active in UV-irradiated keratinocytes maintaining the mitochondrial membrane potential, inhibiting the consecutive activation of the intrinsic apoptotic pathway and reducing PARP activation. In conclusion, these data provide detailed evidence for specific antiapoptotic mechanisms of melatonin in UVR-induced damage of human keratinocytes.
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