Change in hair growth-related gene expression profile in human isolated hair follicles induced by 5-alpha reductase inhibitors - dutasteride and finasteride - in the presence of testosterone.
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ABSTRACT:
SUBMITTER: Hatanaka T
PROVIDER: S-EPMC9678139 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Change in hair growth-related gene expression profile in human isolated hair follicles induced by 5-alpha reductase inhibitors - dutasteride and finasteride - in the presence of testosterone.
Hatanaka Toshiki T Lulic Zrinka Z Mefo Tim T Booth Cath C Harrison Elliott E Ong Gary G
Singapore medical journal 20210122 9
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Project description:BackgroundPreviously, we studied the effect of finasteride- or dutasteride-containing diets in male C57BL/6 TRAMP x FVB mice. Pre (6 weeks of age) and post (12 weeks of age) groups received finasteride or dutasteride to determine the efficacy of these pharmaceuticals on prostate cancer (PCa) development in male C57BL/6 TRAMP x FVB mice. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment, and dutasteride treatments were more effective than finasteride treatments in decreasing prostatic intraepithelial neoplasia (PIN) progression and PCa development. Finasteride and Pre-Dutasteride treatments significantly decreased high-grade PIN incidence, but increased poorly differentiated PCa incidence. In this study, molecular changes in prostates of these mice were characterized in an effort to elucidate the discordant response in Pre-Dutasteride and finasteride groups, and determine why Post-Dutasteride treatment was more effective.Method/principal findingsKi-67 (proliferation marker) and androgen receptor (AR) protein, apoptotic DNA fragmentation (TUNEL assay), 5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) mRNA were quantified in male TRAMP mice prostate tissues with genitourinary weight < 1 and > 1 gram. Overall, proliferation and AR were decreased and apoptosis was increased in most tumors versus prostate epithelium and hyperplasia. Proliferation and AR were increased notably in hyperplasia versus prostate epithelium and tumor. There were no clear trends or differences in 5α-reductase 1 and 5α-reductase 2 levels between large and small tumors. The discordant response in Pre-Finasteride and Pre-Dutasteride groups may be due to upregulated 5αR1 levels in large versus small tumors. It is not clear what the mechanism is for the different response in the Post-Finasteride group. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment in decreasing 5αR1 in large tumors. Therefore, this may be why this treatment was more effective in decreasing PIN progression and PCa development.ConclusionThe effect of finasteride and dutasteride on these biomarkers did not clearly elucidate their mechanism of action, but tumor 5αR1 levels were significantly positively correlated with adjusted prostate severe lesion score.
| S-EPMC5526468 | biostudies-literature
Project description:Oral testosterone undecanoate (TU) is used to treat testosterone deficiency; however, oral TU treatment elevates dihydrotestosterone (DHT), which may be associated with an increased risk of acne, male pattern baldness and prostate hyperplasia. Co-administration of 5α-reductase inhibitors with other formulations of oral testosterone suppresses DHT production and increases serum testosterone. We hypothesized that finasteride would increase serum testosterone and lower DHT during treatment with oral TU. Therefore, we studied the steady-state pharmacokinetics of oral TU, 200 mg equivalents of testosterone twice daily for 7 days, alone and with finasteride 0.5 and 1.0 mg po twice daily in an open-label, three-way crossover study in 11 young men with experimentally induced hypogonadism. On the seventh day of each dosing period, serum testosterone, DHT and oestradiol were measured at baseline and 1, 2, 4, 8, 12, 13, 14, 16, 20 and 24 h after the morning dose. Serum testosterone and DHT were significantly increased into and above their normal ranges similarly by all three treatments. Co-administration of finasteride at 0.5 and 1.0 mg po twice daily had no significant effect on either serum testosterone or DHT. Oral TU differs from other formulations of oral testosterone in its response to concomitant inhibition of 5α-reductase, perhaps because of its unique lymphatic route of absorption.
| S-EPMC4269219 | biostudies-literature
Project description:PurposeCo-administration of the 5α-reductase inhibitor dutasteride increases the oral testosterone bioavailability in men with experimentally induced hypogonadism. We examined oral testosterone with and without dutasteride administration in hypogonadal men for 28 days.Materials and methodsWe randomly assigned 43 hypogonadal men to twice daily oral doses of 150, 250 or 400 mg testosterone with 0.25 mg dutasteride, 400 mg testosterone alone or 0.25 mg dutasteride alone for 28 days in a multicenter study. Subjects underwent pharmacokinetic profiling of serum hormones on days 1 and 28. A total of 32 men completed all study procedures.ResultsSerum testosterone increased in all groups on testosterone compared with that in the dutasteride only group. At the 400 mg dose the combination of testosterone and dutasteride resulted in average testosterone concentrations that were 2.7 and 4.6 times higher than in the testosterone only group on days 1 and 28, respectively (p <0.01). On day 28 average testosterone was 20% to 30% lower in all groups on testosterone and dutasteride, and 50% lower in the testosterone only group compared with day 1. Serum dihydrotestosterone was suppressed in all groups on dutasteride and increased in the testosterone only group.ConclusionsOral testosterone administration resulted in a therapeutic serum testosterone concentration in hypogonadal men. Dutasteride improved the oral bioavailability of testosterone while suppressing dihydrotestosterone. Compared with day 1, testosterone was decreased after 28 days of administration. Additional study is warranted of oral testosterone with dutasteride for testosterone deficiency.
| S-EPMC4267472 | biostudies-literature
Project description:BACKGROUND:Dutasteride is a potent inhibitor of 5-alpha reductase enzymes that reduces concentrations of dihydrotestosterone to a greater extent than finasteride. Whether this has adverse implications for bone health is unknown. We compared the risk of osteoporosis and fractures in older men treated with dutasteride or finasteride. METHODS:We conducted a population-based retrospective cohort study with high-dimensional propensity score matching of Ontario men aged 66 years or older who started treatment with dutasteride or finasteride between January 1, 2006 and December 31, 2012. The primary outcome was a diagnosis of osteoporosis within 2 years of treatment initiation. A secondary outcome was osteoporotic or fragility fractures. RESULTS:We studied 31,615 men treated with dutasteride and an equal number of men treated with finasteride. Dutasteride-treated patients had a lower incidence of osteoporosis than those receiving finasteride [2.2 versus 2.6 per 100 person years; hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.72 to 0.93]. This effect was no longer statistically significant following adjustment for specialty of prescribing physician (HR 0.90; 95% CI 0.78 to 1.02)]. There was no differential risk of fractures with dutasteride (HR 1.04; 95% 0.86 to 1.25). CONCLUSIONS:Despite differential effects on 5-alpha reductase, dutasteride is not associated with an increased risk of osteoporosis or fractures in older men relative to finasteride. These findings suggest that dutasteride does not adversely affect bone health.
| S-EPMC5964967 | biostudies-literature
Project description:Development of an oral testosterone therapy has proven extremely challenging because of extensive and variable first-pass metabolism. We investigated the in vivo metabolism of testosterone with increasing oral doses of testosterone, both alone and with the co-administration of dutasteride (5α-reductase inhibitor) by liquid-chromatography tandem mass spectrometry (LC-MS/MS). In eugonadal men prior to dosing, the circulating concentration of testosterone, androstenedione, etiocholanolone-glucuronide, and androsterone-glucuronide was 8.6, 20.9, 9.1, and 55.3%, respectively, of the total testosterone-related species, whereas testosterone-glucuronide was ∼1%. When testosterone was dosed orally to men with experimental hypogonadism, a proportion of testosterone-glucuronide increased to 13%. Dutasteride treatment significantly decreased levels of androsterone and its metabolites. This work reveals extensive metabolism of orally dosed testosterone to androsterone glucuronide via androstenedione, with testosterone-glucuronide appearing to be the second most important metabolite. This information is of importance in the development of an effective oral testosterone therapy and may have implications for testosterone doping research.
| S-EPMC6132360 | biostudies-literature
Project description:Finasteride, a 5α-reductase inhibitor used in benign prostatic hyperplasia and androgenetic alopecia, has been associated with an increased suicidal risk, whereas it is unclear whether such risk is similar to that for another 5α-reductase inhibitor, dutasteride. We aimed to assess the risk of suicidal behaviours with finasteride relative to dutasteride. A nationwide cohort study was conducted using the French National Health Data System (SNDS). Men aged 50 years or older initiating finasteride 5 mg or dutasteride 0.5 mg in France between 01-01-2012 and 30-06-2016 were included and followed until outcome (suicide death identified from death certificate or self-harm hospitalisation), treatment discontinuation or switch, death, or 31-12-2016. Self-harm by violent means or resulting in admission to an intensive care unit were also examined. Cox proportional hazards models controlled for age and psychiatric and non-psychiatric conditions by inverse probability of treatment weighting (IPTW). Analyses were stratified according to psychiatric history. The study compared 69,786 finasteride new users to 217,577 dutasteride new users (median age: 72.0 years [Q1-Q3 = 64.5-80.2] vs. 71.1 [Q1-Q3 = 65.0-79.2]). During follow-up, 18 suicide deaths (0.57/1000 person-years) and 34 self-harm hospitalisations (1.08/1000) occurred among finasteride users versus 47 deaths (0.43/1000) and 87 hospitalisations (0.79/1000) among dutasteride users. Overall, finasteride was not associated with an increased risk of any suicidal outcome (IPTW-adjusted Hazard Ratio = 1.21 [95% Confidence Interval .87-1.67]), suicide death or self-harm hospitalisation. However, among individuals with a history of mood disorders, finasteride was associated with an increased risk of any suicidal outcome (25 versus 46 events; HR = 1.64 [95% CI 1.00-2.68]), suicide death (8 versus 10 events; HR = 2.71 [95% CI 1.07-6.91]), self-harm by violent means (6 versus 6 events; HR = 3.11 [95% CI 1.01-9.61]), and self-harm with admission to an intensive care unit (7 versus 5 events; HR = 3.97 [95% CI 1.26-12.5]). None of these risks was significantly increased among individuals without a psychiatric history. These findings do not support an increased risk of suicide with finasteride used in the treatment of benign prostatic hyperplasia. However, an increased risk cannot be excluded among men with a history of mood disorder, but this result based on a limited number of events should be interpreted with caution.
| S-EPMC10066399 | biostudies-literature
Project description:Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with the interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene, Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell-autonomous responses in the epidermis. Third, deleting Abca12 in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing IL-17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.
| S-EPMC11317994 | biostudies-literature
Project description:We have previously studied mouse whisker follicles in Gelfoam® histoculture to determine the role of nestin-expressing plutipotent stem cells, located within the follicle, in the growth of the follicular sensory nerve. Long-term Gelfoam® whisker histoculture enabled hair follicle nestin-expressing stem cells to promote the extensive elongation of the whisker sensory nerve, which contained axon fibers. Transgenic mice in which the nestin promoter drives green fluorescent protein (ND-GFP) were used as the source of the whiskers allowing imaging of the nestin-expressing stem cells as they formed the follicular sensory nerve. In the present report, we show that Gelfoam®-histocultured whisker follicles produced growing pigmented and unpigmented hair shafts. Hair-shaft length increased rapidly by day-4 and continued growing until at least day-12 after which the hair-shaft length was constant. By day-63 in histoculture, the number of ND-GFP hair follicle stem cells increased significantly and the follicles were intact. The present study shows that Gelfoam® histoculture can support extensive hair-shaft growth as well as hair follicle sensory-nerve growth from isolated hair follicles which were maintained over very long periods of time. Gelfoam® histoculture of hair follicles can provide a very long-term period for evaluating novel agents to promote hair growth.
| S-EPMC4589329 | biostudies-literature
Project description:Cortisol concentrations in hair are used increasingly as a biomarker of long-term stress in free-ranging wildlife. Cortisol is believed to be integrated into hair primarily during its active growth phase, typically occurring over weeks to months or longer periods, depending on latitude. Cortisol concentrations in hair thus reflect the activity of the hypothalamic-pituitary-adrenal axis over this time. However, local, independent cortisol secretion within the skin, which includes hair follicles, may also contribute to cortisol levels in growing hair. Methodological differences between studies include the measurement of cortisol in only the hair shaft (i.e. follicle absent, as with shaved hair) versus the whole hair (i.e. follicle present, as with plucked hair). If the concentration of cortisol in the follicle is high enough to influence the overall hair cortisol concentration (HCC), this could confound comparisons between studies using different types of hair samples (hair shafts vs. whole hair) and collection methods. Here, we test the hypothesis that cortisol present in follicles influences HCC. We compared HCC in paired subsamples of hair with and without follicles from 30 free-ranging Scandinavian brown bears (Ursus arctos) and observed significantly greater HCC in samples with follicles present. The effect of follicles remained significant also with sex and age of sampled bears taken into account in a linear mixed model. Finally, we provide an overview of collection methods and types of hair samples used for HCC analysis in 77 studies dealing with stress in wild mammal species. Our findings highlight the need to unify methods of hair collection and preparation to allow for valid comparisons, and to optimize labour input in ecophysiological studies.
| S-EPMC6994724 | biostudies-literature
Project description: Not available
| S-EPMC8137337 | biostudies-literature