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

Abstract

In this study, it was investigated how estrogens (17-beta-estradiol, E2) affect the estrogen receptor (ER) expression and gene regulation of male versus female human scalp hair follicles in vitro. Anagen VI follicles from frontotemporal scalp skin were microdissected and organ-cultured for up to 9 d in the presence of E2 (1-100 nm). Immunohistochemistry was performed for ERbeta-expression, known to be predominant in human scalp hair follicles, and for TGF-beta2-expression (as negative key hair growth modulator), and E2-responsive genes in organ-cultured human scalp hair follicles (48 h, 10 nM) were explored by cDNA microarray, using a commercial skin focus chip (Memorec, Cologne, Germany). The distribution pattern of ERbeta and TGF-beta2-immunoreactivity differed between male and female hair follicles after 48 h culture. Of 1300 genes tested, several genes were regulated sex-dependent differently. The study reveals substantial sex-dependent differences in the response of frontotemporal human scalp hair follicles to E2. Recognition and systematic dissection of the E2-dependent gene regulation will be crucial for the development of more effective, gender-tailored management strategies for female versus male pattern balding.

The Hair Follicle as an Estrogen Target and Source

“…Recently, it was reported that in cultured dermal papilla cells from nonbalding male donors, both ER␣ and ER␤ showed a consistently higher expression, both at the RNA and protein levels, in occiput dermal papilla cells compared with vertex dermal papilla cells (258). With respect to ER␤ immunoreactivity, we found that, in anagen VI follicles microdissected from frontotemporal skin, there was a remarkable distribution difference between male and female hair follicles from frontotemporal scalp skin: ER␤ immunoreactivity was found in male scalp hair follicles predominantly in the matrix keratinocytes, whereas in female hair follicles, ER␤ immunoreactivity was predominantly found in the dermal papilla fibroblasts (10). These data not only highlight substantial, previously underappreciated sex-dependent differences in ER␤ expression of an important peripheral E2 target organ, but also underscore the importance of investigating whether E2 effects on the human hair follicle are location-dependent, as is well-recognized for the paradoxical hair growth effects of androgens (64, 259, 260).…”

“…Several genes were modulated equidirectionally in both sexes (e.g., down-regulation of osteopontin and hevin ϭ highly expressed endothelial venule protein; up-regulation of cytokeratin type II and bone morphogenetic protein 7). Intriguingly, however, several genes showed distinct regulatory responses in male and female hair follicles: e.g., downregulation of filaggrin and FGF receptor 2 in males; upregulation of nuclear receptor subfamily 4, group A, member 1 in females; whereas cysteine-rich 61, fos-like antigen 2, and collagen IV A6 were up-regulated in males, yet down-regulated in females (10). This reveals that terminal human scalp hair follicles from one defined region show strikingly different, sex-dependent biological responses to stimulation with the same ER ligand, strongly advocating gender-tailored management of female vs. male pattern balding (androgenetic alopecia) (10).…”

“…In pregnant women, the scalp hair shaft diameter reportedly increases compared with nonpregnant women, although it remains to be determined which pregnancy-associated factors are responsible for this phenomenon (278). In view of the complex, multiple concomitant endocrine changes during and after pregnancy and lactation (including dramatic fluctuations in gestagen and prolactin levels), it clearly is very difficult to dissociate strictly E2-based hair growth effects from those that other hormones might exert on the human scalp hair follicle in vivo during this time (10,12).…”

“…Due to different activities of key enzymes in dermal, epidermal, or sebaceous compartments like aromatase, 17␤-hydroxysteroid dehydrogenase, or steroid sulfatase (57, 69,123), there may indeed be important regional differences in the extrafollicular estrogen metabolism of/in hair follicle in different integumental locations that must be carefully taken into account when estrogens are applied topically. However, possibly more important than such differences in local intracutaneous estrogen metabolism are gender-associated differences in the hair follicle response to E2 stimulation: frontotemporal female scalp hair follicles display most of their ER␤-associated immunoreactivity inside the (mesenchymal) dermal papilla, whereas ER-like immunoreactivity in male frontotemporal scalp hair follicles is located in the (epithelial) hair matrix and outer root sheath (10).…”

Distinct mechanisms underlie pattern formation in the skin and skin appendages

“…As a result, the type of hairs that form and the region of hair growth (hairline) change at different ages. The mechanism controlling how scalp and occipital hairs respond differently to sex hormones is not known but appears to be mediated by differences in dermal papillae which respond differently to stimulation with androgens or estrogens (Inui et al 2002, Randall et al, 2001Conrad et al 2005). Thus, hormonally based skin lesion patterns are also the consequence of region-specific developmental programming.…”