FRI378 Estetrol Prolongs Anagen In Healthy Female Scalp Hair Follicles By Positively Modulating Dermal Papilla Functions And Generation Of Progenitor Stem Cells Ex Vivo

Abstract Disclosure: C. Gerard: None. A. La Riche: None. S. Altendorf: None. V. Dion: None. L. Epping: None. T. Bíro: None. G. Dixon: None. M. Bertolini: None. The human hair follicle (HF) is a neuroendocrine mini-organ that responds to, but also generates, a wide range of hormones, which affect hair cycle and HF biology. HF functions are profoundly regulated by several intrafollicular neuroendocrine axes like the HF-equivalent of the hypothalamic-pituitary-adrenal and thyroid axes, as well as by local prolactin secretion. In this regard, estrogens exert a direct role in hair cycle regulation, since estrogen receptors are prominently expressed in the epithelium of scalp HFs. It has been shown that postmenopausal women increasingly experience female pattern hair loss (FPHL) due to the decrease in ovarian estrogen secretion. Conversely, elevated estrogen levels were found to correlate with enhanced numbers of anagen HFs during pregnancy. Estetrol (E4) is a natural estrogen produced by the fetal liver during pregnancy. E4 was recently approved as the estrogenic component of a new combined oral contraceptive and is currently in the late stage of clinical development for its use as a menopausal hormone therapy. In this study, we aimed to assess the capacity of E4 to regulate hair growth.Frontotemporal, full-length microdissected HFs from 4 healthy female donors (> 50 years) were exposed to different concentrations of E4 (300nM, 3µM and 30µM) ex vivo. Subsequently, hair cycle staging, hair matrix keratinocyte proliferation (Ki-67), dermal papilla (DP) inductivity (versican expression and alkaline phosphatase activity), fibroblast emigration (cell density in the DP, the dermal cup (DC) and the DP stalk), and the percentage of HFs stem cell (HFSC) progenitors (CD34+) was assessed by quantitative (immuno-)histomorphometry. E4 treatment led to a tendential (300nM and 30µM) or significant (3µM) increase in the number of anagen (growing) HFs, further supported by enhanced hair matrix keratinocyte proliferation. Although neither size nor cell density of DP was affected by the treatment with E4, a significant lower number of cells was detected in the DP stalk and DC, indicating less DP fibroblast emigration. Additionally, E4 treatment stimulated DP fibroblast inductivity as evidenced by a tendential up-regulation of versican expression and alkaline phosphatase activity in the DP, the latter even significantly in only anagen HFs. Moreover, application of 3µM E4 positively affected the generation of stem cell progeny by significantly increasing the percentage of CD34+ cells in the suprabulbar outer root sheath. Taken together, our data suggest that treatment with E4 boosts anagen maintenance, reduces DP fibroblast emigration, stimulates DP inductivity and promotes the expansion of HFSC progeny. Thus, these findings point at a potential role of E4 to prevent catagen development and changes known to be involved in HF miniaturization, and further encourage the exploration of E4 as possible treatment strategy for hair loss disorders such as FPHL. Presentation: Friday, June 16, 2023