Keywords
Androgenetic, alopecia, follicle
Androgenetic, alopecia, follicle
Androgenetic alopecia (AGA) affects both genders and is characterised by hair loss in a distinctive and reproducible pattern from the scalp1. Bitemporal recession affects 98.6% of men and 64.4% of women, whereas mid-frontal hair loss (Figure 1) affects nearly two thirds of women over the age of 80 years, and three quarters of men over 80 years have mid-frontal and vertex hair loss2. Local and systemic androgens transform large terminal follicles into smaller vellus-like ones3. Follicular miniaturization is the histological hallmark of AGA4,5.
Diffuse hair thinning and sometimes increased hair shedding (Figure 2) precede the clinical appearance of baldness by a number of years6. This is because the process of follicular miniaturization which occurs in AGA does not simultaneously affect all follicles within a follicular unit (FU). Instead, there is a hierarchy of follicular miniaturization within FUs, and secondary follicles are affected initially and primary follicles are miniaturized last7.
Scalp hairs arise from FUs that are best seen on horizontal scalp biopsy. FUs comprise a primary follicle that gives rise to an arrector pili muscle (APM), a sebaceous gland, and multiple secondary follicles that arise distal to the APM (Figure 3). Hairs from secondary follicles commonly emerge from a single infundibulum (Figure 4). In contrast, hairs over the beard, trunk, and limbs do not give rise to secondary hairs and exist singly or in groups of three, known as Mejeres trios (Figure 5). Miniaturization occurs initially in the secondary follicles, leading to the reduction in hair density that precedes visible baldness (Figure 6). Baldness ensues when all of the hairs within an FU are miniaturized.
One intriguing question is that identical hair follicle miniaturization is seen histologically in lesions of alopecia areata. In this condition, miniaturization of all follicles occurs simultaneously, and unlike AGA, miniaturization occurring in alopecia areata is potentially fully reversible.
This apparent paradox may be explained by examination of the APM and in particular its proximal attachment to the hair follicle bulge8. The APM is a small band of smooth muscle that runs from the hair follicle to the adjacent upper dermis and epidermis. This muscle contributes to thermoregulation and sebum secretion. The APM arises proximally at the hair follicle at the bulge, which is an epithelial stem cell niche. Three-dimensional reconstructions of scalp biopsy specimens demonstrate that preservation of the APM predicts reversible hair loss (Figure 7) and that, conversely, loss of attachment between the APM and hair follicle bulge is associated with irreversible or partially reversible hair loss (Figure 8).
The APM plays a significant role in maintaining hair follicle integrity. Restoration of the APM in transplanted hair follicle units has been shown to induce the regeneration of the neurofollicular and neuromuscular junction in the follicle bulge in single FU transplants in patients with AGA9.
The discovery that progressive muscle volume loss and fat infiltration of the APM leading to total or near total loss of the muscle attachment to the primary follicle bulge in AGA samples10 led to the hypothesis that maintenance of the attachment between the APM and the bulge might differentiate between reversible and irreversible hair follicle miniaturization. These features were exclusive to AGA and not seen in alopecia areata, a disorder associated with reversible hair follicle miniaturization11. The finding that the APM is preserved in telogen effluvium and alopecia areata supports this view.
It appears likely that the interaction between the mesenchyme-derived APM and the follicle bulge epithelium is essential for the integrity of the pilosebaceous unit, much in the same way as the interaction between the mesenchymal-derived dermal papilla and the epithelial hair follicle matrix.
Follicle cycling is associated with the movement of cells between the dermal papilla and dermal sheath12. It is thought that disruption of this process in AGA causes a loss of cells from the dermal sheath and then the dermal papilla that leads to hair follicle miniaturization (Figure 9). Cells from the dermal papilla and dermal sheath are capable of undergoing both smooth muscle and adipose differentiation in vitro. Cells from the follicle mesenchyme might also contribute to maintenance of the APM, and the muscle degeneration seen in AGA could be caused by the loss of a progenitor cell population that maintains both the APM and the dermal papilla.
In conclusion, we propose a new model for AGA (Figure 10). In early stages of hair loss, the APM remains attached to the primary follicle but loses its attachment to some of the regressing secondary follicles in some FUs. Miniaturization of secondary follicles and detachment of the APM from these follicles extend to the rest of the FUs. At this stage, patients may complain of hair thinning and loss of volume in their pony tail without visible baldness.
With further progression, miniaturization continues and the muscle loses attachment to the secondary follicles in affected FUs completely. Primary follicles eventually miniaturize and this leads to visible baldness. When primary follicles lose muscle attachment, the hair loss becomes irreversible. Hopefully, this model facilitates a clearer understanding of normal physiological hair growth and also alterations to hair growth in hair loss conditions.
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Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
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Version 1 19 Aug 15 |
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