DHEA and frontal fibrosing alopecia: molecular and physiopathological mechanisms

The transforming growth factor-beta 1 (TGFβ1) promotes fibrosis, differentiating epithelial cells and quiescent fibroblasts into myofibroblasts and increasing expression of extracellular matrix. Recent investigations have shown that PPAR (peroxisome proliferator-activated receptor*) is a negative regulator of fibrotic events induced by TGFβ1. Dehydroepiandrosterone (DHEA) is an immunomodulatory hormone essential for PPAR functions, and is reduced in some processes characterized by fibrosis. Although scarring alopecia characteristically develops in the female biological period in which occurs decreased production of DHEA, there are no data in the literature relating its reduction to fibrogenic process of this condition. This article aims to review the fibrogenic activity of TGFβ1, its control by PPAR and its relation with DHEA in the frontal fibrosing alopecia.


INTRODUCTION
The frontal fibrosing alopecia (FFA) is a form of alopecia manifested in women, very rarely in men, and it begins in frontal hairline, progressing in the lateral and posterior direction, with permanent loss of hair follicles and may reach also the eyebrows and other areas. 1 Of unknown etiology and treatment with unsatisfactory results, it was recently compared to a similar type of hair loss found in mutant animals presenting changes in functions of specific intranuclear receptors.
The occurrence of this event almost exclusively in women, and those in the pre or post-adrenopause period, raises the need to relate the hormonal changes concerning the development of alopecia.
Even maintaining the present article under "review article" designation, only the essential facts to the current conceptualization of the disease are presented, leaving more space for the aspects that are considered relevant: a) Is the reduction of the local activity of dehydroepiandrosterone (DHEA) responsible for fibrosis and loss of hair follicles? b) May DHEA for topical use be useful in its treatment?

HISTORY
In 1994, Steven Kossard described a new and peculiar hair loss called the frontal fibrosing alopecia of women (FFA). 1 Its histology was similar to lichen planopilaris (LPP), without the occurrence of signs of lichen planus in the rest of the tegument.
Sixteen years before Josefowicz identified a mutant species of mouse, named Asebia, with alopecia and atrophy of sebaceous glands. 2 Genetic aspects related to alopecia in these mice were mapped in a second mutant animal, the Asebia 2, spontaneously developed in laboratory and with extreme atrophy of sebaceous glands and hair follicles progressing to fibrosis. 3 The genotype of these animals, with changes resulting from chromosome 11 mutations, was identified, evidencing the entire follicular degeneration process. 4 The fact that the activity of PPAR α and γ was essential for the differentiation and functions of sebocytes was followed by identification of malfunctions of these receptors in Asebia 2. 5 It has been shown that deletion of PPARγ in the follicular bulge generated changes similar to LPP. 6

EPIDEMIOLOGICAL AND CLINICAL ASPECTS
Re-evaluating 355 cases in a multicenter study, only 12 were men, 49 were women with early menopause and 49 were premenopausal women. In 37% patients, alopecia was found to be severe.
Mean age was 61 years (between 23 and 86 years). 10 FFA is characterized in its early stages by retraction of the previous limit of hairline, with evolution in lateral and posterior direction, and may present erythema, micropapules and hyperkeratosis in the follicles. Mild skin atrophy, itching and burning sensation may occur in some patients, as well as partial and even total loss of eyebrows. The final result is a scarring aspect in the affected area. The progression of the process is slow and spontaneous remission may occur. Lesions in other areas of the scalp have been described.
Loss of eyebrows occurred in 73% of patients, of eyelashes in 3%, and of hair body in 25% of 60 patients. 11 In a series of 16 cases, 8 presented loss in eyebrows and 6 presented axillary alopecia. 12

DERMATOSCOPIC DIAGNOSIS
Dermoscopy can indicate the area of biopsy and should be performed where there is perifollicular concentric scales that are less scaly than LPP. Perifollicular erythema is indicative of disease progression and may be present in other scarring alopecia, such as discoid lupus erythematous and LPP. Keratosis pilaris is also common to discoid lupus erythematosus. [13][14][15] In the lesions of 79 women, 72.1% showed hyperkeratosis, 66.3%, perifollicular erythema, and 44.8%, follicular plugs. 16 Erythema and perifollicular scales indicate progressive disease activity. 14 There is progressive loss of follicles with perifollicular erythema with and without scales. The absence of follicular ostia is the ultimate characteristic feature. 17

HISTOPATHOLOGICAL DIAGNOSIS
Biopsy reveals the presence of lymphocytic infiltrate involving the bulge and the infundibulum. Apoptotic cells in the outer sheath of the rod and concentric fibrosis around the follicle with decrease in the follicle number, replaced by fibrous tissue, are present. 19 The location of the infiltrate is centered in the bulge region. 20 These aspects occur in LPP and although there is no clear tissue difference between LPP and FFA, there is milder inflammation and apoptosis in FFA than in LPP. 20,21 TREATMENT Stabilization of the anterior limit of the implant can be achieved with intralesional corticosteroids in most patients. 22 Stand-alone topical corticosteroids are not effective. 23  Antimalarials, intralesional steroids and antiandrogens are the most often cited as being able to stop the progression of FFA. 10,[26][27][28] In The importance of the effect of DHEA on mitochondrial oxidative metabolism was stabilished by administration of this hormone in rats. These animals showed increased liver and brain metabolism with elevated brain weight without concurrent increase in body weight. 52 The results observed in the topographic response is demonstrative of the variation in distribution of DHEA receptors in the body of these animals.
Tests with radioactive DHEA administered to dogs confirmed their higher metabolism in fibroblasts derived from dermal follicles and, among these, in dermal fibroblasts derived from the follicles of the skulls of the animals, accentuating the topographic differences of their receptors. 53 The relation between the activity of DHEA and FFA is also Having found that the essential fact in FFA is the dysfunction of PPARγ and that the function of this receptor is linked to stimulation of DHEA, it is vital to define its participation in the development of fibrosis in this alopecia. However, in the medical literature, there is no information on the relation between the fibrogenic process of FFA and endocrine changes of adrenopause regarding DHEA.

DISCUSSION
The exposed aspects that relate to fibrogenic activity to reduction of PPARs function and their dependence of the activation by DHEA, lead us to suppose that the reduced activity of this hormone, characteristic of the phase in which this alopecia occurs, correlates directly to fibrogenic inflammatory process of FFA.
Knowing that the activity of a hormone depends on both its blood content as the functional integrity of specific cellular receptors, and that these are presented in topographic and individual