Gene expression of type 2 17β hydroxysteroid dehydrogenase in scalp hairs of hirsute women☆
Introduction
The presence of hirsutism can signal conditions associated with hyperandrogenism, such as polycystic ovary syndrome (PCOS), androgen-secreting tumors, non-classic adrenal hyperplasia (NCAH) and syndromes of severe insulin resistance [1], [2]. Hirsutism can also result from peripheral hypersensitivity to circulating androgens, namely idiopathic hirsutism (IH) [3], [4]. Although, in general, this condition is not life-threatening, it is greatly distressing to patients and has a significant negative psychosocial impact. Investigating the effect of androgens on human hair follicle biology may lead to improved treatments for hirsutism.
It is well known that hair follicles from different body sites have different responses to androgens [5]. Despite this difference, the effect of all active androgens on target cells is mediated by their binding to the same nuclear androgen receptor (AR). In the 1960s and 1970s, studies on androgen resistance syndromes revealed the importance of the AR for androgen-dependent growth of axillary, pubic, and beard hair [6], [7]. More recently, an increased androgen binding capacity was observed in scalp cells of balding men [8] as well as in dermal papilla cells cultured from balding scalp [9]. However, until the present moment, a consistent difference has not been found in the number or function of AR in hirsute patients in relation to normal subjects [10], [11], [12], [13], [14].
The dissimilar androgen sensitivity of hair follicles in different body sites may be explained by variations in intracellular androgen metabolism. Hair follicles have autonomous control over androgen metabolism, adjusting the production and degradation of steroid hormones according to local requirements.
5α-Reductase was the first steroidogenic enzyme suspected of playing a key role in the action of androgen in hair follicles [6]. An increase in 5α-reductase activity was demonstrated in genital and pubic skin fibroblasts from hirsute patients, but this is not sufficient to completely explain the pathogenesis of hirsutism [4], [11], [15], [16]. Therefore, we decided to focus our attention on another steroidogenic enzyme present in the pilosebaceous unit, type 2 17β hydroxysteroid dehydrogenase (17β-HSD), which catalyzes both the formation of testosterone and estradiol (via reduction) and the back-conversion of these hormones to less active precursors (via oxidation).
To date, 11 types of 17β-HSD have been described, which differ in terms of tissue distribution, catalytic preference, substrate specificity, sub-cellular location, and regulation mechanisms. In addition, many isoforms of 17β-HSD have been shown to be involved in the pathogenesis of human disorders such as pseudo-hermaphroditism (type 3 17β-HSD), bi-functional enzyme deficiency (type 4 17β-HSD), polycystic kidney disease (type 8 17β-HSD) and Alzheimer’s disease (type 10 17β-HSD) [17]. Hair follicle keratinocytes express very high levels of type 2 17β-HSD (17β-HSD) [18], [19], which inactivates both estradiol and testosterone to estrone and Δ4-androstenedione, respectively. The presence of type 2 17β-HSD in the root sheath cells of hair follicle has been associated with maintenance of androgen homeostasis in these cells [20]. Therefore, the aims of the present study were (1) to analyze the gene expression of the AR and type 2 17β-HSD in keratinocyte cells of plucked scalp hairs from hirsute patients in comparison to normal subjects of both sexes, and (2) to evaluate the associations between type 2 17β-HSD mRNA levels and clinical and hormonal data.
Section snippets
Subjects
The study population included women consulting for hirsutism seen consecutively during a 6-month period at the Gynecological Endocrinology Unit at Hospital de Clı́nicas de Porto Alegre, Brazil. During this period, 31 women were diagnosed at the Unit as having PCOS and 27 as having IH. The diagnosis of PCOS was based on the physical features of hyperandrogenism, disturbed menstrual cycles, elevated serum LH levels or LH/FSH ratio, increased levels of total testosterone (TT) and/or free
Results
Fig. 1 shows AR mRNA levels in the plucked hair cells from the scalp of men (0.79±0.09), normal women (0.63±0.05), and hirsute patients (PCOS: 0.71±0.03 and IH: 0.79±0.07). Plucked scalp hair AR expression was similar in all groups.
The gene expression of type 2 17β-HSD was significantly lower in untreated hirsute patients as compared to normal women (2.1±0.10 and 3.1±0.17, respectively, at P<0.05) and similar to that of normal men (1.8±0.22) (Fig. 2). However, in the 25 hirsute patients who
Discussion
Androgens are the main hormonal regulators of human hair growth, and they are associated with clinical hair growth conditions such as hirsutism. In the present paper, we focused on aspects related to the AR and androgen metabolism in keratinocytes from plucked anagen scalp hairs from hirsute patients. Plucked anagen hairs contain mainly keratinocytes, which form both the outer and inner root sheaths. Since it is non-invasive, the plucked hair technique may be advantageous in relation to
Acknowledgements
This study was supported by grants from Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS), and Programa de Apoio aos Núcleos de Excelência em Pesquisa (PRONEX 26/98).
We thank for the editorial support provided by the Graduate Research Group (GPPG) at Hospital de Clı́nicas de Porto Alegre.
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Presented in part, as free communication, at the 84th Annual Meeting of the Endocrine Society, San Francisco, USA, June 2002.