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Immunohistochemical distribution of aromatase and 3B-hydroxysteriod dehydogenase in human hair follicle and sebaceous gland
Abstract
Human hair follicles (HF) and sebaceous glands (SG) were assessed for the presence and distribution of the cytochrome P-450-aromatase (AR) and 3B-hydroxysteroid dehydrogenase (3B-HSD) enzymes. Immunohistochemical methods were used to examine both enzymes in male and female human skin specimens at various ages and different body sites. AR was found in the external root sheath of anagen, terminal HF, and in SG, whereas the 3B-HSD was found only in the SG. AR was rarely found in telogen HF. The expression of both enzymes, AR and 3B-HSD, did not vary with body site or sex. Localizing AR in the external root sheath of anagen HF suggests that AR may have a function in the HF cycle. We hypothesize that AR may be one of many enzymes or factors that play a role in the HF cycle by regulating the level of androgens formed locally, whereas 3B-HSD is localized in SG, converting weak androgen precursors to potent androgens, stimulating lipogenesis.
... Aromatase (CYP19A1), which is required to convert androgens to estrogens, has been detected in scalp HFs [13] and may also play a major role in AGA, as previously reported by our group in women with female pattern hair loss (FPHL) [10]. ...
... AR is a member of the nuclear receptor superfamily that functions as a liganddependent transcription factor, and AR gene overexpression has been described in 30-50% of castration-resistant prostate cancer (CRPC) patients, indicating that AR plays an important role in the development of PCa [35,36]. Significantly higher expression of AR was also observed in balding versus non-balding scalp follicles from men with AGA [13], in line with the present results. In this regard, Hayes et al. [37] described a variant in the AR gene (AR-E211 A allele) associated with a lower risk of metastatic PCa and AGA. ...
Androgenic alopecia (AGA) is the most prevalent type of progressive hair loss and has psychological repercussions. Nevertheless, the effectiveness of current pharmacological treatments remains limited, in part because the molecular basis of the disease has not been fully elucidated. Our group previously highlighted the important roles of aromatase and 5α-reductase (5α-R) in alopecia in young women with female pattern hair loss. Additionally, an association has been proposed between AGA and prostate cancer (PCa), suggesting that genes implicated in PCa would also be involved in AGA. A low-invasive, sensitive, and precise method was used to determine mRNA levels of aromatase, 5α-R isozymes, and 84 PCa-related genes in samples of plucked hair from young men with AGA and controls. Samples were obtained with a trichogram from the vertex scalp, and mRNA levels were quantified using real-time RT-PCR. The men with AGA had significantly higher 5α-R2 mRNA levels in comparison to controls; interestingly, some of them also showed markedly elevated mRNA levels of 5α-R1 or 5α-R3 or of both, which may explain the varied response to 5α-R inhibitor treatments. The men with AGA also showed significant changes versus controls in 6 out of the 84 genes implicated in PCa. This study contributes greater knowledge of the molecular bases of AGA, facilitating early selection of the most appropriate pharmacological therapy and opening the way to novel treatments.
... In addition, the skin expresses all necessary enzymes to convert dehydroepiandrosterone sulfate (DHEAS) to dihydrotestosterone [25]. Aromatase also exists in sebaceous glands and the outer root sheath of hair follicles and can diminish local androgen action through aromatization [25,26]. ...
... Androgen metabolism within the pilosebaceous unit is further modified by several other steroid enzymes (sulfotransferase, 3β-hydroxysteroid dehydrogenase, and 17β-hydroxysteroid dehydrogenase) [25][26][27]. Sebaceous glands also possess receptors for several growth factors, including epidermal growth factor, insulin-like growth factor I, and keratinocyte growth factor, which further modify sebum production [25]. ...
In endocrine and reproductive endocrine literature, adult female acne is considered as a possible clinical expression of hyperandrogenism, with most polycystic ovary syndrome (PCOS) guidelines considering acne as a condition of androgen excess. Adult female acne, however, in the dermatological literature is considered as an inflammatory skin disease and new guidelines on adult female acne have been produced by dermatological societies, with little perspective from any endocrine or reproductive endocrine points of view. An expert task force was appointed by the AE-PCOS society to determine the current state of knowledge and provide evidence-based recommendations that could be valid for all specialists taking care of female adult acne. The following are the recommendations (level of evidence A or B): (1) diagnosis of female adult acne is mainly clinical, but a grading tool is needed for optimizing the treatment; (2) measurement of serum androgen values (total testosterone, free testosterone, and dehydroepiandrosterone sulfate) by high-quality assays is recommended in all women with adult acne; (3) in women with adult acne and proven hyperandrogenism, oral combined estroprogestins should be added to the topical or systemic treatment of acne, independently of severity of acne; (4) all second- and third-generation estroprogestins may be used, independently of the estrogen dose and progestin component; (5) spironolactone may be added to estroprogestins in women with moderate or severe hyperandrogenic adult acne, not responding to usual treatments; (6) estroprogestins may be used in nonhyperandrogenic patients with adult acne as second-line therapy.
... Oestrogens may also play a role in scalp hair growth, [30]. Thus, aromatase, the key enzyme required to convert androgens to oestrogens, has been localized in scalp hair follicles [41]. ...
... However, other authors have shown androgen receptor, 5α-R1 and 5α-R2 expression in the root sheath of hair follicle pointing that it plays an important role in androgen regulation [42]. Besides, aromatase has also been located in root sheath of hair follicles [41]. Plucked anagen hairs are lacking of DP, however they are mainly constituted by keratinocytes cells forming both outer and inner root sheaths [31]. ...
Female pattern hair loss (FPHL) is an important hair disorder, especially when young women are affected. However, pharmacological treatments are not successful in all women. Androgens, especially dihydrotestosterone (DHT), may play a role in FPHL, but many women with this disorder have normal serum androgen levels. It therefore appears that hair follicle levels of DHT depend on in situ testosterone (T) metabolism. Because T can be converted to DHT or estradiol (E2) by 5α-reductase (5α-R) and aromatase, respectively, these enzymes would determine DHT and E2 concentrations and their ratio. We propose and apply a low-invasive, sensitive and precise method for the absolute quantification of mRNA levels of aromatase and 5α-R isozymes (type 1, type 2 and type 3) in plucked hair from young women with FPHL. Normoandrogenic women with FPHL and controls were studied. Plucked hair samples were obtained by trichogram from vertex scalp and mRNA levels quantified by real-time RT-PCR. We revealed for the first time the presence of 5α-R3 mRNA in human hair. Interestingly, one, two, or even three 5α-R isozymes were increased in some women with FPHL but not in others, which may explain the lack of response to 5α-R inhibitors in some FPHL cases. Aromatase mRNA levels were significantly lower in women with FPHL than in controls. It may therefore produce a reduction in oestrogen levels and an increase in the androgen/oestrogen ratio in hair. The proposed low-invasive technique offers a molecular aetiologic diagnosis of FPHL for the selection of more appropriate pharmacological treatments with early predicted effectiveness.
... Interestingly, the androgen receptor (AR) is also expressed in dermal papilla cells but is not detected in keratinocytes (35,36). Aromatase, which breaks down DHT, is highly expressed in the outer root sheath of hair follicles during the anagen phase and in sebaceous glands (37). ...
Androgenetic alopecia (“AGA”) is the most prevalent type of progressive hair loss, causing tremendous psychological and social stress in patients. However, AGA treatment remains limited in scope. The pathogenesis of androgenetic alopecia is not completely understood but is known to involve a hair follicle miniaturization process in which terminal hair is transformed into thinner, softer vellus-like hair. This process is related to the dysregulation of the Wnt/β-catenin signaling pathway, which causes premature termination of the anagen growth phase in hair follicles. Historically used for wound healing, platelet rich plasma (“PRP”) has recently been at the forefront of potential AGA treatment. PRP is an autologous preparation of plasma that contains a high number of platelets and their associated growth factors such as EGF, IGF-1, and VEGF. These factors are known to individually play important roles in regulating hair follicle growth. However, the clinical effectiveness of PRP is often difficult to characterize and summarize as there are wide variabilities in the PRP preparation and administration protocols with no consensus on which protocol provides the best results. This study follows the previous review from our group in 2018 by Cervantes et al. to analyze and discuss recent clinical trials using PRP for the treatment of AGA. In contrast to our previous publication, we include recent clinical trials that assessed PRP in combination or in direct comparison with standard of care procedures for AGA such as topical minoxidil and/or oral finasteride. Overall, this study aims to provide an in-depth analysis of PRP in the treatment of AGA based on the evaluation of 17 recent clinical trials published between 2018 and October 2021. By closely examining the methodologies of each clinical trial included in our study, we additionally aim to provide an overall consensus on how PRP can be best utilized for the treatment of AGA.
... In IHC staining, P450arom was present in follicular dermal papilla cells, in hair keratinocytes of internal and external root sheaths, and in sebocytes in control rats. This localization of P450arom expression is consistent with other studies [48,49]. We did not observe immunopositive fibroblasts in the examined specimens, which may be due to dermal fibroblasts converting androgens into estrogens [10]. ...
Skin is a target for hormones and a site of hormone production. Aromatase inhibitors such as letrozole reduce circulating estrogen. The aim of the study was to investigate the morphology of the dermis and immunoexpression of androgen receptor (AR), estrogen receptor α and β (ERα, ERβ), luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), and cytochrome P450 aromatase (P450arom) in male rats with a deficit of estradiol. Experiments were performed on skin of 12 male rats. Rats in the experimental group received per os letrozole for 6 months. For morphological analysis, van Gieson, Sirius Red and orcein staining of sections was performed. In immunohistochemistry, reactions with specific antibodies (anti-P450arom, LHR, FSHR, ERα, ERβ) were used. In morphometric analysis, sections were stained with hematoxylin and eosin. Differences between groups were assessed by Mann-Whitney U-test. There were no differences in the diameter of collagen fibers. The dermis of letrozole-treated animals showed areas without collagen fibers, and expression of P450arom, ERα and ERβ was diminished in the skin of these animals. This study indicates that estrogens exert an effect via ERs that has a role in maintaining proper skin morphology in males, together with androgen. This is also the first documented expression of FSHR in the skin of male rats.
... the steroid metabolizing enzymes needed to convert DHEA sulfate (DHEAS) to the mid potent androgen, DHT including 3β -hydroxysteroid dehydrogenase 9 and 5α-reductase. 10 11. ...
Acne is one of the most commonest dermatological disorders in young patients. 1. It is a disease of the pilosebaceous follicular unit. 2. Endocrine mechanisms control the components of sebocyte function—namely lipid synthesis, proliferation and differentiation. 3. Androgens upregulate the sebaceous glandular function by binding to the nuclear androgen receptors (ARs). Highest density of these androgen receptors have been demonstrated in sebaceous glands.
The mechanisms suggested in acne include: Increased circulating levels of androgens, Increased free androgen levels, Increased local metabolism of androgens in skin and increased tissue sensitivity to androgens.
This case control study was conducted In the department of dermatology, venerology and leprosy, shadan institute of medical sciences, Hyderabad from February 2019-february-2020. A total of 50 patients (25 males and 25 females) of moderate to severe acne vulgaris resistant to conventional treatment were included in the study A total of 50 patients (25 males and 25 females) of moderate to severe acne vulgaris resistant to conventional treatment were included in the study
Age range: 14 to 35 years
patients who were receiving any systemic drugs, oral contraceptives or hormonal therapy, pregnant and lactating. 50 age and sex matched healthy acne free subjects were also part of the study.
Venous blood samples were collected for the assay of serum testosterone, dehydroepiandrosterone-sulfate (DHEA-S) and androstenedione (A4A) between 0800-0900 hours. For testosterone assay three samples were collected at 20 minute intervals and pooled together. Immediately after collection the red cells were separated and the sera were stored at - 20°C till assay. In females, the samples were collected only in the first half of the follicular phase of the menstrual cycle. All hormones were measured by radioimmunoassay using standard techniques with commercially obtained kits.
All patients included in the study had moderate to severe acne. The commonest lesions encountered were pustules and nodules while cysts were present in 10/25 males and 11/25 females. 32/50 patients had acne lesions also on the trunk. The mean duration of acne was 2.6 years (range 1 to 6 years). A history of partial or no response to conventional treatment was present in all the patients. Mild to moderate degree of hirsutism was present in 7/25 female patients; of whom 4 also had oligomenorrhea. No other sign of virilisation was observed in any female patient. In males with acne the mean serum testosterone levels were only marginally elevated but their DHEA-S levels were significantly higher than in controls.
... Although, the expression was not uneven among body sites and gender, aromatase activity in women with AGA showed to be 2-fold higher in occipital compared to frontal hair follicles, and 6 to 3-fold higher in frontal and occipital sites, respectively, compared to men with AGA. Frontal follicles of women had almost twice aromatase activity than frontal hair follicles of men with AGA (Sawaya and Price, 1997;Sawaya and Penneys, 1992). Therefore aromatase activity in the skin can serve to fine tune the regulation of androgens and estrogens levels in target cells (Ohnemus et al., 2006). ...
Beyond sexual functions, androgens exert their action in skin physiology and pathophysiology. Skin cells are able to synthesize most of active androgens from gonadal or adrenal precursors and the enzymes involved in skin steroidogenesis are implicated both in normal or pathological processes. Even when the role of androgens and androgen receptor (AR) in skin pathologies has been studied for decades, their molecular mechanisms in skin disorders remain largely unknown. Here, we go over recent studies of androgens and AR roles in several skin-related disorders, focusing in the current understanding of its molecular mechanisms in androgenetic alopecia (AGA). We review on the molecular pathophysiology of type 2 5α-reductase, AR coactivators, the paracrine factors deregulated in dermal papilla (such as TGF-β, IGF 1, WNTs and DKK-1) and the crosstalk between AR and Wnt signaling in order to shed some light on new promising treatments.
... Once formed, testosterone and DHT can be removed by conversion back to the weaker 17ketosteroids or can be metabolized via other enzymatic pathways into estrogens via cytochrome P450 aromatase. Aromatase activity is detectable in hair follicles [42], and its expression in the outer root sheath of terminal hair follicles in the anagen phase and in sebaceous glands [43] suggests a local balance system for androgens and estrogens and that hair follicles function as both targets and sources of estrogen [44]. ...
Purpose:
Androgenetic alopecia, commonly known as male pattern baldness, is the most common type of progressive hair loss disorder in men. The aim of this paper is to review recent advances in understanding the pathophysiology and molecular mechanism of androgenetic alopecia.
Methods:
Using the PubMed database, we conducted a systematic review of the literature, selecting studies published from 1916 to 2016.
Results:
The occurrence and development of androgenetic alopecia depends on the interaction of endocrine factors and genetic predisposition. Androgenetic alopecia is characterized by progressive hair follicular miniaturization, caused by the actions of androgens on the epithelial cells of genetically susceptible hair follicles in androgen-dependent areas. Although the exact pathogenesis of androgenetic alopecia remains to be clarified, research has shown that it is a polygenetic condition. Numerous studies have unequivocally identified two major genetic risk loci for androgenetic alopecia, on the X-chromosome AR?EDA2R locus and the chromosome 20p11 locus.
Conclusions:
Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms at different genomic loci are associated with androgenetic alopecia development. A number of genes determine the predisposition for androgenetic alopecia in a polygenic fashion. However, further studies are needed before the specific genetic factors of this polygenic condition can be fully explained.
... Každé z androgen-senzitivních kožních adnex (potní žláza, vlasový folikul a mazová žláza) metabolizuje androgeny dle charakteristického modelu, avšak mazové a potní žlázy jsou pro svoji nesmírnou převahu odpovědné za metabolismus androgenů v kůži (62). Enzym 3βhydroxysteroid-dehydrogenáza (HSD) je obzvlášť významný v mazových žlázách (63). Exprese Biologická aktivita testosteronu v cílových tkáních je výrazně ovlivněna jeho konverzí na DHT pomocí 5α-reduktázy, což je mikrozomální nukleotidreduktáza (NADPH) dependentní enzym (66). ...
... Many attempts have been made to localize the expression of the major enzymes and receptors of the androgen system in the pilosebaceous apparatus. Enzymes that reduce androgenicity, by aromatizing testosterone and androstenedione to estrogens localize immunologically to the ORS (P-450 aromatase complex, Ref. 494). Enzymes that convert the relatively inactive testosterone to the highly active dihydrotestosterone (DHT), the 5␣-reductases (5␣-R type 1 and 5␣-R type 2), localize to the papilla and ORS (109,495). ...
Despite more than a hundred years of professinal hair research, and substantial recent progress in unravelling the molecular controls of hair follicle morphogenesis, the chronobiological control system that cyclically drives the hair follicle through dramatic remodelling processes between phases of growth (anagen), regression (catagen), and relative resting (telogen) have remained disappointingly obscure. In view of the vast literature that has become available over the past decades on numerous genetic, biochemical, cellular and pharmacological aspects of hair growth control under physiological and pathological conditions, it is astounding how comparatievely few researchers in the field have published theoretical concepts that explore how hair follicle cycling might be controlled. Since this question is at the very heart of basic and clinically applied hair biology, it deserves a much more systematic and serious public exploration, which the following contributions are designed to stimulate.
... This therefore explains less severity of hair loss in women who have 2-5-folds greater in aromatase than men confirming frontal hairline sparing in women accordingly. 33 Thus, overall causes of hair loss are androgen, genetic, and age. The readers would find more details regarding molecular mechanism of androgenetic alopecia that had been presented elsewhere. ...
Baldness:
or androgenetic alopecia directly distresses self-confidence affecting the individual's quality of life. Hair loss is therefore a significant psychosocial manifestation that worth much expense on treatment. Androgenetic alopecia is noticed as a slow transformation of large scalp terminal hair follicles to shorter, thinner, and less deep vellus hair with a much shorter anagen. Although minoxidil, finasteride, and dutasteride including other synthetic therapeutic agents are mostly used for alopecia treatment, their adverse effects encourage sorting of alternative efficient treatment agent with a limited side effect particularly herbs. Thus, this review briefly summarized causes of hair loss and emphasized on active ingredients for treatment in particular currently used herbs and the potential candidates. Treatment choices will be further wider and conclusively select herbs that fitting the consumers' preference.
... Those factors can be divided into several classifications, such as hormones, growth factors, enzymes and transcription factors. Examples of enzymes include urokinase [1], ornithine decarboxylase [2], γ-glutamyl transpeptidase [3], alkaline phosphatase [4], hydroxysteroid dehydrogenase [5], adenyl-cyclase [6], aryl hydrocarbon hydroxylase [7], aromatase [8], glutathione s-transferase [9] and nexin 1, a serine protease inhibitor [10]. Since the hair cycle might be considered as a process of tissue regeneration, we thought that regulation of the extracellular matrix (ECM) could well affect the hair cycle. ...
In most mammals, each hair follicle undergoes a cyclic process of growing, regressing and resting phases (anagen, catagen, telogen, respectively) called the hair cycle. Various biological factors have been reported to regulate or to synchronize with the hair cycle. Some factors involved in the extracellular matrix, which is a major component of skin tissue, are also thought to regulate the hair cycle. We have focused on an enzyme that degrades elastin, which is associated with skin elasticity. Since our previous study identified skin fibroblast elastase as neprilysin (NEP), we examined the fluctuation of NEP enzyme activity and its expression during the synchronized hair cycle of rats. NEP activity in the skin was elevated at early anagen, and decreased during catagen to telogen. The expression of NEP mRNA and protein levels was modulated similarly. Immunostaining showed changes in NEP localization throughout the hair cycle, from the follicular epithelium during early anagen to the dermal papilla during catagen. To determine whether NEP plays an important role in regulating the hair cycle, we used a specific inhibitor of NEP (NPLT). NPLT was applied topically daily to the dorsal skin of C3H mice, which had been depilated in advance. Mice treated with NPLT had significantly suppressed hair growth. These data suggest that NEP plays an important role in regulating the hair cycle by its increased expression and activity in the follicular epithelium during early anagen.
... Cytochrome P450 aromatase is required for bioconversion of androgens to oestrogens. Aromatase activity is detectable in hair follicles (27,28), and its expression in the outer root sheath of anagen hair follicles and in sebaceous glands (29), suggesting the presence of a local balance system for androgens and oestrogens and that hair follicles function as oestrogen targets and sources (30). A comparison of aromatase content in frontal hair follicles from men and women with pattern baldness has shown that it is six times greater in women (27), which has led to speculation that this difference may account for the difference in clinical presentations of pattern baldness. ...
Androgens stimulate beard growth but suppress hair growth in androgenetic alopecia (AGA). This condition is known as 'androgen paradox'. Human pilosebaceous units possess enough enzymes to form the active androgens testosterone and dihydrotestosterone. In hair follicles, 5α-reductase type 1 and 2, androgen receptors (AR) and AR coactivators can regulate androgen sensitivity of dermal papillae (DP). To regulate hair growth, androgens stimulate production of IGF-1 as positive mediators from beard DP cells and of TGF-β1, TGF-β2, dickkopf1 and IL-6 as negative mediators from balding DP cells. In addition, androgens enhance inducible nitric oxide synthase from occipital DP cells and stem cell factor for positive regulation of hair growth in beard and negative regulation of balding DP cells. Moreover, AGA involves crosstalk between androgen and Wnt/β-catenin signalling. Finally, recent data on susceptibility genes have provided us with the impetus to investigate the molecular pathogenesis of AGA.
... In the brain, aromatase cytochrome P450 is involved in the neuronal development of sexual dimorphism in a few nuclei of the hypothalamus, as well as in sexual behavior and reproduction in the adult (Lephart, 1996). In the epidermis, human hairs and sebaceous glands are influenced by androgens (Schweikert and Wilson, 1974;Sawaya and Penneys, 1991). It is possible that the circumanal glands of the dog are, as a whole, under gonadal control and that a small population of polyhedral cells in each lobule produces sex steroid hormones and is responsible for local regulation within lobules or for regulation of cellular metabolism in the polyhedral cells themselves. ...
Background
The circumanal glands of the dog are thought to be a glandular tissue, but there is some controversy as to whether they should be classified as exocrine or endocrine. In this study, we examined the nature of the circumanal glands to determine whether they should be described as exocrine, endocrine, or something else altogether. In addition, we investigated the cell degeneration in lobules of the circumanal glands in relation to the apocrine glands.Methods
Light microscopic observations were made of paraffin sections stained with hematoxylin and eosin, and after immunohistochemical staining with antibodies against -smooth muscle actin, keratin, filaggrin, and 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD). Samples were also examined by electron microscopy after fixation by aldehyde perfusion.ResultsThe lobules of circumanal glands could be divided into two types on the basis of the presence or absence of cysts. Four layers (I–IV) were detected in the lobules with cysts. The outermost layer (layer I or the basal layer) consisted of flattened cells that contained bundles of tonofilaments and were stained immunohistochemically with the antibody against keratin. Layer II (the polyhedral or “spinous” layer) consisted of polyhedral cells that contained bundles of tonofilaments. These cells were connected to adjacent cells by desmosomes, interdigitations, and gap junctions, and they were immunopositive for keratin. A small number of polyhedral cells were immunopositive for 3β-HSD. Layer III (the granular layer) was composed of flattened cells that contained hematoxylin-stainable granules and were moderately immunopositive for filaggrin. The innermost layer (layer IV or the horny layer) consisted of keratin. Lobules without cysts consisted only of layer I (the basal layer) and layer II (the polyhedral layer). Lobules of the circumanal glands were not directly connected to apocrine glands. Polyhedral cells degenerated and were phagocytosed by basal cells at a periphery of lobules. Then, basal cells phagocytosing degenerated polyhedral cells escaped from lobules, moved into the walls of apocrine glands, and, finally, dropped into the lumen of apocrine glands.Conclusions
Lobules of the circumanal glands have many characteristics of epidermis (a basal layer, a polyhedral or “spinous layer,” a granular layer, and a horny layer) and they should not be classified as glandular tissue. The cysts in lobules can be interpreted as “closed hair canals.” We suggest that steroid metabolism might occur in the polyhedral cells of the lobules. Anat. Rec. 250:251–267, 1998. © 1998 Wiley-Liss, Inc.
... In reality, the skin is not only an estrogen target, but also a major synthetic organ with the capacity to release and produce a wide range of hormones, including estrogens. Skin cells are able to synthesise locally acting estrogens from the precursors cholesterol and DHEA (Fig. 2) (Simpson et al. 1997; Bulun et al. 1999; Chen et al. 2002; Chen et al. 1998; Thiboutot et al. 1998; Hughes et al. 1997; Sawaya and Penneys 1992; Dumont et al. 1992; Eicheler et al. 1995; Thiboutot et al. 2000). Additionally, local production of 11b-HSD by epidermal keratinocytes, dermal fibroblasts and hair follicles (Tiganescu et al. 2011) increases cortisol conversion and has been speculated to control the inflammatory response (Vukelic et al. 2011). ...
The links between hormonal signalling and lifespan have been well documented in a range of model organisms. For example, in C. elegans or D. melanogaster, lifespan can be modulated by ablating germline cells, or manipulating reproductive history or pregnenolone signalling. In mammalian systems, however, hormonal contribution to longevity is less well understood. With increasing age human steroid hormone profiles change substantially, particularly following menopause in women. This article reviews recent links between steroid sex hormones and ageing, with special emphasis on the skin and wound repair. Estrogen, which substantially decreases with advancing age in both males and females, protects against multiple aspects of cellular ageing in rodent models, including oxidative damage, telomere shortening and cellular senescence. Estrogen's effects are particularly pronounced in the skin where cutaneous changes post-menopause are well documented, and can be partially reversed by classical Hormone Replacement Therapy (HRT). Our research shows that while chronological ageing has clear effects on skin wound healing, falling estrogen levels are the principle mediator of these effects. Thus, both HRT and topical estrogen replacement substantially accelerate healing in elderly humans, but are associated with unwanted deleterious effects, particularly cancer promotion. In fact, much current research effort is being invested in exploring the therapeutic potential of estrogen signalling manipulation to reverse age-associated pathology in peripheral tissues. In the case of the skin the differential targeting of estrogen receptors to promote healing in aged subjects is a real therapeutic possibility.
... The former has been supported by the increased expression and enzyme activity of StAR, 3β-HSD, 17β-HSD and 5α-reductase leading to high follicular levels of DHT. 75,86,87 Moreover, studies of the cutaneous expression of sex-determining genes in regulating steroidogenesis showed significantly higher protein levels of DAX-1, SRY and WT-1 in the bald fronto-parietal scalp as compared to the occipital scalp, in which only the SRY expression displayed a positive correlation with the baldness severity in Norwood-Hamilton classification. 88 On the other hand, higher levels of AR were found in the balding hair follicle DPC than those from non-balding scalp, 80 and AR polymorphism was suggested to confer susceptibility to AGA. 89 Highly interesting are regional differences in cutaneous hyperandrogenism, in which (1) people with acne may not have AGA and vice versa; (2) AGA involves almost exclusively the frontoparietal scalp sparing the occipital scalp; (3) acne lesions tends to move from forehead/cheeks in pubertal acne to lower face/submandibular regions in acne tarda. ...
Hormones can exert their actions through endocrine, paracrine, juxtacrine, autocrine and intracrine pathways. The skin, especially the pilosebaceous unit, can be regarded as an endocrine organ meanwhile a target of hormones, because it synthesizes miscellaneous hormones and expresses diverse hormone receptors. Over the past decade, steroid hormones, phospholipid hormones, retinoids and nuclear receptor ligands as well as the so-called stress hormones have been demonstrated to play pivotal roles in controlling the development of pilosebaceous units, lipogenesis of sebaceous glands and hair cycling. Among them, androgen is most extensively studied and of highest clinical significance. Androgen-mediated dermatoses such as acne, androgenetic alopecia and seborrhea are among the most common skin disorders, with most patients exhibiting normal circulating androgen levels. The "cutaneous hyperandrogenism" is caused by in stiu overexpression of the androgenic enzymes and hyperresponsiveness of androgen receptors. Regulation of cutaneous steroidogenesis is analogous to that in gonads and adrenals. More work is needed to explain the regional difference within and between the androgn-mediated dermatoses. The pilosebaceous unit can act as an ideal model for studies in dermato-endocrinology.
1. Sebaceous gland enlargement 2. Sebocyte proliferation 3. Lipid metabolism 2,3 Majority of the circulating androgens are produced by gonads and the adrenal gland, but they are also locally produced, in sebocyte from dehydroepiandrosterone (DHEA) sulfate, an adrenal precursor hormone. Androgen receptors are expressed in the basal layer of the sebaceous gland and in the outer root sheath keratinocytes of the hair follicle. 4,5 When free testosterone enters the cell. It is quickly reduced to 5-dihydrotestosterone (5-DHT) by the 5α-reductase enzyme. The activity of 5α-reductase is increased in the sebaceous gland in proportion to the size of the gland. 6 DHT is ~5-10 times more potent than testosterone in its interaction with the androgen receptor. On binding to its receptor protein, DHT is translocated to the nucleus and initiates the transcription of androgen-responsive genes. DHT increases the mRNA of proteins involved in fatty acid, triglyceride squalene, and cholesterol synthesis. This effect is mediated by sterol response element binding proteins (SREBP's). By inhibiting SREBP's effect with 25-hydroxy cholesterol, there was a 50% decrease in lipid synthesis increase by DHT alone. 7 Androgens exert their effect on sebaceous glands by increasing the proliferation of sebocytes and increasing lipid production through SREBP's.
Female pattern hair loss (FPHL), a type of hair disease common in pre- and postmenopausal women, is characterized by thinning of hair to O-type, mainly at the crown. Although a mouse model of this disease has recently been established, its details are still unknown, and thus, warrants further analysis. In this study, 3 week-old and 7- to 8 week-old C57BL/6 female mice were divided into two groups: one group underwent ovariectomy (OVX), while the other underwent sham surgery. In the 3 week-old mice, the dorsal skin was collected at seven weeks of age, while in the 7- to 8 week-old mice, it was collected at 12 and 24 weeks of age. In the former group, both the pore size of the hair follicles (HFs) and diameter of the hair shaft of telogen HFs decreased upon OVX; while in the latter group, these factors increased significantly. Notably, the thickness of the dermis and subcutis increased significantly in the OVX group. It needs to be further elucidated whether OVX mouse could serve as an ideal mouse model for FPHL, but our results upon evaluation of skin thickness indicate that it could be used to establish a novel treatment for non-hair-related diseases, such as post-menopause-related skin condition.
Androgenetic Alopecia (AGA) is by far the most common cause of hair loss in men, and its high prevalence has been reported in detail for many decades [1]. Several different terms in international medical bibliography have been suggested by several authors, such as androgenic alopecia, male pattern baldness, androgen-dependent alopecia, common baldness, and genetic hair loss. However, the term “Androgenetic Alopecia” is considered the most appropriate since it summarizes the etiology of the condition, with the term “andro-” referring to the hormonal and “-genetic”, implying the inherited parameter of its pathogenesis.
The sebaceous gland almost always accompanies a hair follicle, vellus or terminal, and the resulting complex is called pilosebaceous unit; independent sebaceous glands freely secreting on the skin surface are rare.
Topical 17-beta-estradiol (E2) regulates the hair cycle, hair shaft differentiation, and sebum production. Vitamin A also regulate sebum production. Vitamin A metabolism proteins localized to the pilosebaceous unit (PSU; hair follicle and sebaceous gland); and were regulated by E2 in other tissues. This study tests the hypothesis that E2 also regulates vitamin A metabolism in the PSU. First, aromatase and estrogen receptors localized to similar sites as retinoid metabolism proteins during mid-anagen. Next, female and male wax stripped C57BL/6J mice were topically treated with E2, the estrogen receptor antagonist ICI 182,780 (ICI), letrozole, E2 plus letrozole, or vehicle control (acetone) during mid-anagen. E2 or one of its inhibitors regulated most of the vitamin A metabolism genes and proteins examined in a sex dependent manner. Most components were higher in females and reduced with ICI in females. ICI reductions occurred in the premedulla, sebaceous gland, and epidermis. Reduced E2 also reduced RA receptors in the sebaceous gland and bulge in females. However, reduced E2 increased the number of retinal dehydrogenase 2 positive hair follicle associated dermal dendritic cells in males. These results suggest that estrogen regulates vitamin A metabolism in the skin. Interactions between E2 and vitamin A have implications in acne treatment, hair loss, and skin immunity.
Emerging evidence suggests that sex steroids are important for human skin health. In particular, estrogen improves skin thickness, elasticity and moisture of older women.
The major source of circulating estrogen is the ovary; however, local estrogen synthesis and secretion have important roles in, for example, bone metabolism and breast cancer development. We hypothesized that infiltrated peripheral monocytes are one of the
sources of estrogen in skin tissues. We also hypothesized that, during atopic dermatitis under stress, a decline in the hypothalamus–pituitary–adrenal axis (HPA) and facilitation
of the (hypothalamus)–sympathetic–adrenomedullary system (SAM) attenuates estrogen secretion from monocytes. Based on this hypothesis, we tested aromatase expression in the human peripheral monocyte-derived cell line THP-1 in response to the synthetic glucocorticoid dexamethasone (Dex), the synthetic β-agonist isoproterenol (Iso) and the β-antagonist propranolol (Pro). Dex mimics glucocorticoid secreted during excitation
of the HPA, and Iso mimics catecholamine secreted during excitation of the SAM. We found that aromatase activity and the CYP19A1 gene transcript were both upregulated in THP-1 cells in the presence of Dex. Addition of Iso induced their downregulation
and further addition of Pro rescued aromatase expression. These results may suggest that attenuation of estrogen secretion from peripheral monocytes could be a part of the pathology of stress-caused deterioration of atopic dermatitis. Further examination
using an in vitro human skin model including THP-1 cells might be a valuable tool for investigating the therapeutic efficacy and mechanism of estrogen treatment for skin health.
Androgens, in combination with a genetic susceptibility, have been demonstrated to be required for the development of androgenetic alopecia. Disturbances in androgen metabolism or target organ sensitivity are thought to underlie the pathophysiology of the condition. Observations of patients with disorders of androgen metabolism or function have determined the basic physiology involved in regulation of hair growth by androgens at selective body sites. More recently, in vitro studies of scalp skin and hair follicles have begun to define specifc alterations in androgen metabolism at the local level that may play a key role in pathogenesis. The prominent role of 5a-reductase in these studies suggested that inhibitors of this enzyme could provide new therapeutic opportunities for patients with androgenetic alopecia, and clinical trials have confirmed the use of this class of compounds in the treatment of men with this disorder.
This chapter reviews the structure and function of the pilosebaceous unit and the controlling influences on the pilosebaceous unit and sebum secretion. The chapter is divided into three sections. Section I gives an account of the structure and function of the normal pilosebaceous unit; Section II describes the biochemistry and regulation of pilosebaceous unit biology; and finally, Section III deals briefly with the biochemical changes occurring in the pilosebaceous duct in acne. SECTION ONE: ANATOMY Structure of the Pilosebaceous Unit In humans, pilosebaceous units or pilosebaceous follicles are found on all skin surfaces, apart from the palms of the hands and soles of the feet. Essentially, they are invaginations of the epidermis into the dermis. Each comprises a duct, which ends in the dermal papilla, a hair fiber (or pilus) produced by the dermal papilla, a sebaceous gland and its associated sebaceous duct. The duct supports and protects the hair fiber and also drains sebum produced by the sebaceous gland and carries it to the skin surface. In addition, in split thickness wounds, the cells of the ductal epithelium are a source of proliferating keratinocytes, which migrate to re-epithelialize the wound (1). A specialized population of epithelial cells called stem cells, located in the bulge region situated below the sebaceous gland, are believed to be crucial for this (2). These cells are pluripotent and can also differentiate in some circumstances to produce ductal keratinocytes and sebocytes (3,4). Both the hair and sebum are products of pilosebaceous follicles, emerging onto the skin surface. Sebum is a holocrine secretion from the sebaceous gland cells or sebocytes, which means that the cells are destroyed when sebum is released. The function of sebum in humans is unclear, but as will be discussed later it may play a role in several skin functions (5,6).
Hormones, regulatory molecules synthesized in specialized cells, interact with specific extra- or intracellular receptors and are responsible for homeostasis. Homeostasis may be disturbed by numerous diseases of the endocrine system or inevitable aging. Aging is a progressive process of impairing the function of many organs, including the skin. An outer protective barrier, lipid coating, created by lipids synthesized in sebaceous glands and keratinocytes, plays an important role in skin aging. The amount of lipids begins to decrease significantly during the menopause. It is strictly connected with cessation of the ovarian function. Lack of estrogens in the skin causes dryness, wrinkles, healing impairment, flaccidity, excessive sweating and decreased sebum secretion.
The skin is one of the organs, which is influenced by sex steroids, especially estrogen and testosterone. Estrogen receptors are found in the whole skin, with the density of receptors being highest on the face, pubic region, genitalia and lower limbs. Pregnancy, menstruation and menopause modulate the skin appearance and properties, especially during menopause the skin undergoes profound changes. Postmenopausal women often complain of dry, atrophic, slack skin with increased wrinkling. The altered biomechanical properties of the skin in climacteric women cause certain disorders, such as atrophic vulvovaginitis, dysaesthetic vulvodynia, vulval lichen sclerosus, facial hirsutism, frontal fibrosing alopecia and recurrent menopausal flushing. Although skin aging is certainly no indication for the hormone replacement therapy the beneficial effect of estrogen supplementation on the skin appearance is a positive side aspect of such treatment.
The skin is one of the organs affected by sex hormones, with oestrogens produced in the granular cells of ovarian follicles having the strongest effect on what happens to the female skin. While the sex hormones operate mainly through the receptors for sex steroids, they can also merge with the target cell by a cell membrane bond. The number of receptors is different for different parts of the skin, but they are most abundant on the face and near the reproductive organs and lower limbs. They are found on the keratinocytes of the epidermis stratum basale, on melanocytes, dendritic cells and the endothelium of vessels, fibroblasts and macrophages. Apart from oestrogen receptors the skin also has androgen and progesterone receptors. Oestrogens affect all layers of the skin. The epidermis benefits from their stimulating effect on proliferation processes and keratinocyte differentiation; they help with the generation of keratohyalin granulations, stimulate fibroblasts for collagen production and have an effect on skin colouring. With the ovarian follicles becoming less active, oestrogen receptors are no longer excited in the skin and as a result negative menopausal symptoms appear. The epidermis suffers from atrophy, the boundary between the cuticle and epidermis is levelled off and the overall number of collagen and elastic fibres in the dermis drops following reduced fibroblast activity and synthesis. In clinical terms the skin is thin, inelastic, with parallel grooves and wrinkles of varying depth, and the skin becomes dry and at times even androgenic. Menopausal aging runs parallel to chronological and aging and photoaging. By applying active substances designed to slow down the menopausal aging of the skin, we can reduce the clinical symptoms and delay the process.
The neuroendocrine theory of aging, first proposed over 50 years ago, states that naturally occurring changes in hormone levels drive organismal aging and subsequent age-associated pathology. In practice, changes in the endocrine hormone estrogen have been widely linked to age-associated changes in numerous tissues. The skin is particularly important in this respect as macromolecular structural changes are both immediately visible and functionally important. Estrogen deficiency following menopause (or in advanced male aging) negatively influences multiple skin cell types, including keratinocytes, fibroblasts, immune cells and melanocytes. Physiologically, a lack of estrogen accelerates age-associated atrophic skin changes. Skin becomes wrinkled due to reduced dermal matrix and altered elastic fibre structure, changes to sebaceous glands increase dryness, while vascularity is reduced. Crucially, cutaneous estrogen deficiency following menopause both increases susceptibility to damage and hinders the ability of damaged skin to repair. Extensive studies in rodent models have revealed the complexity of estrogen signalling and identified estrogen receptor-specific functions. Selective estrogen receptor modulators now hold great therapeutic promise for the treatment of skin aging and promotion of skin repair.
Talgdrüsen entwickeln sich ontogenetisch aus den primitiven Haar-Talgdrüsen-Einheiten der Haarbündel, welche beim Menschen überwiegend aus einem Haupt- und zwei Beihaaren bestehen [66, vgl. 85]. Prinzipiell gelten ähnliche Verhältnisse auch für den Vellushaarfollikel [7]. Aus einem epithelialen Follikelkragen bildet sich die Anlage, aus welcher Talgdrüsen entstehen können [106]. Die funktionelle Intaktheit der Talgdrüsen ist an die physiologische Ausprägung des Haares geknüpft. Kommt es zur sekundären Degeneration der Haarfollikel, bilden sich auch Talgdrüsen zurück [74].
The enzyme 3β -hydroxysteroid dehydrogenase/isomerase (3β -HSD) is essential for the biosynthesis of all active steroid hormones, such as those secreted from the adrenal gland, testis, ovary, skin and placenta. The 3β-HSD enzymes exist in multiple isoforms in humans and rodents. To date, six different isoforms have been identified in the mouse, and these isoforms are speculated to play different roles in different tissues. We previously showed that the murine type VI 3β -HSD isoform (Hsd3b6) is expressed specifically in the aldosterone- producing zona glomerulosa cells within the adrenal gland and that its overexpression causes abnormally increased aldosterone synthesis, revealing a crucial (or rate-limiting) role of this enzyme in steroidogenesis. However, potential contributions of this enzyme to the steroid hormone synthesis outside the adrenal glands are poorly understood. This paucity of knowledge is partly because of the lack of isoform-specific antibody that can be used for immunohistochemistry. Here, we report the development and characterization of specific antibody to Hsd3b6 and show the results of immunohistochemistry for the adrenal gland, testis, ovary, skin and placenta. As expected, Hsd3b6 immunoreactivities within the adrenal gland were essentially confined to the zona glomerulosa cells, where aldosterone is produced. By contrast, no immunopositive cells were observed in the zona fasciculata, which is where corticosterone is produced. In the gonads, while the ovaries did not show any detectable immunoreactivity to Hsd3b6, the testes displayed intense immunoreactivities within the interstitial Leydig cells, where testosterone is produced. In the skin, positive immunoreactivities to Hsd3b6 were only seen in the sebaceous glands, suggesting a specific role of this enzyme in sebaceous function. Moreover, in the placenta, Hsd3b6 was specifically found in the giant trophoblast cells surrounding the embryonic cavity, which suggests a role for this enzyme in local progesterone production that is required for proper embryonic implantation and/or maintenance of pregnancy. Taken together, our data revealed that Hsd3b6 is localized in multiple specific tissues and cell types, perhaps thereby involved in biosynthesis of a number of tissue-specific steroid hormones with different physiological roles.
Complementary DNA (cDNA) clones encoding equine testicular steroidogenic enzyme 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (3β-HSD) have been isolated from equine testicular cDNA library. Polymerase chain reaction (PCR) with 3β-HSD specific primers was performed with equine testicular cDNA, and PCR fragment was used as a probe for screening of equine testicular λ ZAP II phage cDNA library. Positive clones were excised into plasmid vector pBluescript and determined their nucleotide sequences. Total 1651 bp of the cDNA sequence was consisted with 112 bp of 5' flanking untranslated sequence, 1122 bp open reading frame encodes 373 amino acids, and putative poly-adenylation signal "AATAAA" at 385 bp downstream of the stop codon. The nucleotide and the deduced amino acid sequence of equine 3β-HSD were very similar to the known mammalian 3β-HSD sequences. From the deduced amino acid sequence, equine testicular 3β-HSD may be concluded to catalyze 3β-dehydrogenation and Δ-isomerization, but 3-ketoreduction as well as murine isoforms. As the clone was used in Northern blot analysis of equine tissues, the expression of equine 3β-HSD mRNA was prominent in the classical steroidogenic tissues including placenta.
Our study was designed to measure the transcutaneous Po-2 of the scalp to determine if there was a relative microvascular insufficiency and associated tissue hypoxia in areas of hair loss in male pattern baldness. A controlled prospective study was performed at Butterworth Hospital, Grand Rapids, Michigan. Eighteen nonsmoking male volunteers aged 18 years and older were studied. Nine men had male pattern baldness (Juri degree II or III), and nine were controls (no male pattern baldness). Scalp temperature and transcutaneous Po-2 were obtained at frontal and temporal sites in each subject. Peripheral circulation was assessed from postocclusive transcutaneous Po-2 recovery time by means of maximum initial slope measurements. Statistical significance was assessed at p < 0.05. There was no significant difference in scalp temperature between male pattern baldness subjects and controls. Temporal scalp blood flow was significantly higher than frontal scalp blood flow in male pattern baldness subjects; however, there was no significant difference in controls. Transcutaneous Po-2 was significantly lower in bald frontal scalp (32.2 +/- 2.0 mmHg) than in hair-bearing temporal scalp (51.8 +/- 4.4 mmHg) in men with male pattern baldness. In controls, there was no significant difference in transcutaneous Po-2 of frontal scalp (53.9 +/- 3.5 mmHg) and temporal scalp (61.4 +/- 2.7 mmHg). Transcutaneous Po-2 also was significantly lower in the frontal scalp of male pattern baldness subjects (32.2 +/- 2.0 mmHg) than in either frontal or temporal scalp of controls (53.9 +/- 3.5 mmHg and 61.4 +/- 2.7 mmHg, respectively). There is a relative microvascular insufficiency to regions of the scalp that lose hair in male pattern baldness. We have identified a previously unreported tissue hypoxia in bald scalp compared with hair-bearing scalp.
Aromatase is a key enzyme for estrogen formation in human tissues. Although ovarian aromatase expression is shut down after the menopause, age-related increases in aromatase expression in peripheral tissues (adipose and skin) modify the severity of estrogen deficiency by elevating plasma estradiol. In fact, circulating estradiol may persist at sufficient levels to cause postmenopausal uterine bleeding, endometrial hyperplasia, and even cancer. Local expression of aromatase in other tissues (brain and bone) may also have physiologically significant consequences, such as maintenance of cognitive function and bone mass. Finally, clinical relevance of estrogen formation via aberrant aromatase expression in breast cancer and postmenopausal endometriosis has been exemplified by the successful treatment of these estrogen-dependent conditions using aromatase inhibitors [62,63].
Recently, the search for new and effective agents for the treatment of alopecia has become significantly more intense. The increase in hair biology research worldwide seen in both academic institutions and pharmaceutical companies stems from the desire to profit from the marketing of drugs that have been termed cosmeceuticals. Millions of men and women from every ethnic group suffer from various forms of alopecia, the most common being androgenetic alopecia (AGA), where the target tissue active androgen, 5α-dihydrotestosterone (DHT) aggravates genetically programmed scalp hair follicles, resulting in hair loss. Currently available drugs indicated for other disease processes are still commonly used to treat the various forms of alopecia because no other agents are available; some of these compounds have severe side-effects and many also exhibit minimal efficacy. These prescription drugs were not originally indicated for alopecia and have not been adequately tested in controlled clinical trials to assess for efficacy, safety and toxicity. Despite this, these agents continue to be used clinically for the treatment of patients with various forms of alopecia. To combat the problems associated with the currently prescribed drugs a variety of new agents have emerged in patent applications. This report reviews nearly 70 patent applications submitted since 1995 for AGA, immunomodulatory related hair diseases and antichemotherapeutic alopecia agents (preventing hair loss during chemotherapy) and discusses the mechanisms of action targetted by research and their implications regarding efficacy.
Introduction and scopeProtein synthesis and organisation during epidermal differentiationLipid synthesis and organisation during epidermal differentiationLipid classes in the stratum corneumStratum corneum turnoverBiotransformations in skinSummaryReferences
Introduction:
Breast cancer is a common, life-threatening disease among women. Contemporary hormonal therapy with third-generation aromatase inhibitors for estrogen-receptor-positive breast cancers in postmenopausal women is still facing the challenge of interpatient variability in therapeutic response and intensity of adverse effects.
Areas covered:
This review highlights up-to-date literature regarding genomic findings in the literature pertaining to anastrozole, exemestane and letrozole metabolism, as well as the drug target aromatase. Genetic polymorphisms in phase I and II aromatase inhibitor metabolizing enzymes that contribute to altered responses among different patient genotypes are discussed. Similarly, aromatase CYP19A1 functional genetic polymorphisms are presented in correlation to altered aromatase activity, disease prognosis and severity of aromatase inhibitor adverse effects.
Expert opinion:
The field of pharmacogenomics has shown remarkable progress over the last few years, notably in cancer. However, large comprehensive genotyping studies, evaluated under clinical settings, are still needed to unravel the potential impact of aromatase inhibitor pharmacogenomics on breast cancer treatment, monitoring and predicting adverse effects.
National Natural Science Foundation of China (NSFC) [30872806, 30872809]; Ministry of Public Health of China; Ministry of Science and Technology of China [2006AA02A131]; Natural Science Foundation of Fujian Province [2009J06023]
Although estrogens have long been known to accelerate healing in females, their roles in males remain to be established. To address this, we have investigated the influence of 17beta-estradiol on acute wound repair in castrated male mice. We report that sustained exposure to estrogen markedly delays wound re-epithelialization. Our use of hairless mice revealed this response to be largely independent of hair follicle cycling, whereas other studies demonstrated that estrogen minimally influences wound inflammation in males. Additionally, we report reduced collagen accumulation and increased gelatinase activities in the wounds of estrogen-treated mice. Increased wound matrix metalloproteinase (MMP)-2 activity in these animals may i) contribute to their inability to heal skin wounds optimally and ii) stem, at least in part, from effects on the overall levels and spatial distribution of membrane-type 1-MMP and tissue inhibitor of MMP (TIMP)-3, which respectively facilitate and prevent MMP-2 activation. Using mice rendered null for either the alpha or beta isoform of the estrogen receptor, we identified estrogen receptor-alpha as the likely effector of estrogen's inhibitory effects on healing.
Human sebaceous glands (SG) and hair follicles (HF) are target structures in the skin for androgen action. They contain steroid enzymes, capable of transforming weak androgens into the target-tissue-active androgens testosterone (T) and dihydrotestosterone (DHT), which bind to the androgen receptor (AR) to regulate cellular transcription. The AR from HF and SG from human scalp tissue has been purified greater than 86,000 times by phenyl-sepharose, DEAE-sephacel, gel filtration chromatography, and ultrafiltration. Sucrose density gradient analysis and non-denaturing gradient polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate (SDS)-PAGE revealed two molecular species of AR, an active form called monomer, capable of binding DHT with great specificity (4S, m = 62,000 Da, Kd = 0.6 nM, Bmax 8260 fmol/micrograms protein), and the other, an inactive form of the monomer called tetramer (10.8S, m = 252,000 Da, Kd = 2.9 nM). The two species are interconvertible, and after purification each appeared as a single band on SDS-PAGE. The conversion of the monomer to the tetramer AR form is influenced by reduced and oxidized glutathione, and possibly by an endogenous disulfide converting factor (DCF). Furthermore, biochemical events in the androgenic signal transduction sequence were shown to be stimulated by androgens via the AR. These include the total nuclear AR content, chromatin binding of AR complexes, and stimulation of RNA polymerase II, thus influencing gene expression, which is important in understanding regulation of HF growth and SG proliferation.
Human hair follicles contain several steroid enzymes capable of transforming weak androgens, such as dehydroepiandrosterone, into more potent target tissue androgens, such as testosterone and dihydrotestosterone. Kinetic constants have been evaluated for the 3-alpha, 3-beta, and 17-beta hydroxysteroid dehydrogenase enzymes, 5a-reductase, and the aromatase enzyme in isolated human HF from scalp of men and women with androgenetic alopecia. The apparent Km values did not differ for each enzyme whether present in bald, receded HF or thick, anagen HF of men or women. However, levels of specific activity varied greatly in the frontal versus occipital HF analyzed. The androgen receptor content and activation factors also differ between men and women. The steroid mechanisms influencing AGA in men and women may be similar, but differences in the specific activity/amounts of enzymes, receptors, and activation factors differ between men and women. These findings may explain the varied clinical presentations of men and women with AGA, and may shape treatment options for the future.
Structures of cDNA clones encoding three members of the rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) family were characterized. To search for potential new types of 3 beta-HSD, rat types I and II 3 beta-HSD cDNAs were used as probes to screen a rat genomic DNA library. Among the clones isolated, one encodes a novel predicted rat 3 beta-HSD isoenzyme, chronologically designated type IV. The corresponding full-length cDNA was thereafter isolated by selective polymerase chain reaction amplification from rat ovary and day-15 placenta cDNA libraries. The rat type IV 3 beta-HSD cDNA encodes a predicted 372-amino acid protein of 41,854 daltons, which shares 90.9, 87.9, and 78.8% sequence identity with rat types I, II, and III proteins, respectively. Ribonuclease protection assay reveals that type IV 3 beta-HSD is the sole 3 beta-HSD mRNA species detectable in the skin and represents the predominant species in the placenta while being also detectable in the ovary and, to a lower degree, in the adrenal gland. Transient expression of type IV cDNA in SW-13 cells indicates 3 beta-HSD activity similar to that of rat type I 3 beta-HSD. The presence of multiple 3 beta-HSD genes should permit differential and tissue-specific regulation of this rate-limiting enzymatic activity essential in the biosynthesis of all classes of steroid hormones in both classical steroidogenic and intracrine peripheral tissues.
A hereditary, androgen-driven disorder, androgenetic alopecia is the most common form of alopecia in humans: its prevalence is 23-87%. Central alopecia is more severe in men; women are more likely to experience diffuse thinning. The acute onset of alopecia in those with inflammatory diseases of the scalp suggests a variety of etiologies, including the impact of inflammatory cells, release of cytokines, presence of growth factors, and increased interaction of stromal cells. Therapeutic modalities, which are most effective when used in combinations, utilize hair growth promoters, antiandrogens, and androgen blockade agents.
In this review we tabulated molecules which have been experimentally identified to be associated with, or play a role in, hair follicle growth. While compiling these data we were impressed by the fact that this field is only now beginning to be developed in terms of molecular analysis. Ironically, hair was used in some of the earliest molecular approaches to biologic structure (e.g. Astbury and Street, 1931), but the field did not develop from there. From our review we have come to the following conclusions. (1) As indicated by the growing number of reports dealing with follicle-associated molecules in the past 3 years, the field of hair biology has entered a new molecular era. (2) In many reported hair biology studies not enough emphasis has been placed on the fact that the follicle is a dynamic structure. All too often a study is limited to follicles of one particular phase of the cycle or one phase of development. Students in the field have to be more sensitive to the remarkable changes that this deceptively simple structure can undergo during its cycle. (3) Although we have not been able to find any molecules unique to the follicle, some of the structural molecules come close to an ideal tool. It is our impression that even more specific molecule tags will be found. Whether this requires a subtraction library approach or gene mapping of specific mutants is not yet clear. It would appear that the large, diverse family of intermediate filament-associated proteins will prove to be an excellent source of unique follicle-labeling molecules. (4) There is an acute need for molecules which distinguish the phases of the cycle, e.g. telogen from early anagen. Telogen is by far the most difficult phase to identify morphologically since the earliest phase of anagen and the latest phase of catagen may appear structurally like telogen. That these phases are functionally distinguishable must imply a molecular difference. As the number of recognized hair follicle-associated molecules and their interactions increase, it will be essential to assemble libraries of highly specific RNA and antibody probes for localization and mapping studies. We recognize that this review, as written, is imperfect. It is particularly deficient in making any effort towards identifying unifying principles of structure and function. We look forward to returning to this subject within 3 years.(ABSTRACT TRUNCATED AT 400 WORDS)
The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.
Using human adipose stromal cells in monolayer culture as a model system for study of the regulation of aromatase activity, as well as polyclonal antibodies raised in this laboratory against aromatase cytochrome P-450 (cytochrome P-450AROM), it was found that the rate of synthesis of cytochrome P-450AROM was stimulated by dibutyryl cyclic AMP. This stimulation was attenuated by epidermal growth factor and was potentiated by phorbol esters. These changes in cytochrome P-450AROM synthesis were associated with comparable changes in the levels of translatable cytochrome P-450AROM mRNA, as well as with changes in the activity of aromatase of these cells. By contrast, there was little change in the synthesis of the reductase component of the aromatase enzyme complex in response to these factors. The increase in mRNA was blocked by cycloheximide, indicative of a requirement for protein synthesis in mediating this inductive response. It is concluded that aromatase activity is regulated primarily by changes in the level of mRNA encoding cytochrome P-450AROM, and that such changes are likely a reflection of changes in the rate of transcription of the gene encoding this enzyme. Increases in the levels of cytochrome P-450AROM mRNA are apparently mediated by a regulatory protein(s), similar to that found for other steroidogenic forms of cytochrome P-450.
3[beta]-Hydroxysteroid dehydrogenase (3[beta]-HSD), which converts pregnenolone to progesterone, was localized immunohistochemically in 18 thecomas, 23 fibromas, 5 granulosa-cell tumors, 5 sclerosing stromal tumors, and 2 steroid-cell tumors. Immunohistochemical study of estrogen, progesterone, and testosterone was also performed in serial sections of thecomas and fibromas. In thecomas, immunoreactivity of 3[beta]-HSD was observed only in luteinized theca cells and thecomatous tumor cells with abundant pale to vacuolated cytoplasm but not in spindled tumor cells and thecomatous tumor cells with small to moderate amounts of pale to vacuolated cytoplasm. Immunoreactivity of steroids was not observed in thecomas except for testosterone immunoreactivity in one case. No immunoreactivity of steroids or the enzyme was present in fibromas. No tumor cells were positive for 3[beta]-HSD in any of the cases of granulosa-cell tumor examined. Immunoreactivity of 3[beta]-HSD was present in cells in steroid-cell tumors and polygonal tumor cells with prominent cytoplasmic vacuoles in two cases of sclerosing stromal tumor. Thus, 3[beta]-HSD can be a good immunohistochemical marker of steroidogenesis in functioning ovarian neoplasms.
(C)1990International Society of Gynecological Pathologists
Sebaceous glands were isolated by manual dissection using a stereomicroscope from skin specimens of bald scalp of men with male-pattern baldness undergoing hair transplant or scalp reduction surgery and also from specimens taken from hairy and bald areas of scalp at autopsy of adult male victims of accidental death within 3 h post mortem. Homogenates of the isolated glands exhibited activities of Δ5-3β-hydroxysteroid dehydrogenase (3βHSD), 17β-hydroxysteroid dehydrogenase and testosterone 5α-reductase by the conversion of [3H]dehydroepiandrosterone (DHA) to 3H-Δ4-androstenedione (AD), [3H]testosterone, and [3H]dihydrotestosterone. Homogenates of glands from bald (B) scalp had greater 3βHSD activity than homogenates of glands from hairy (H) scalp. After differential centrifugation, 3βHSD activity was found mainly in the microsomal and 105,000 × g supernatant fractions. Specific activity of the enzyme based on protein mass was highest in the microsomal fraction; however, the total 3βHSD activity in the 105,000 × g supernatent of B glands was significantly (p < .01) greater than that of H glands. 3βHSD activity in sebaceous glands isolated from autopsy specimens did not differ from that of glands isolated from surgical specimens in apparent Km(0.13- 0.14 μM), pH optima (8.0), or coenzyme requirement for NAD. Since substantial 3βHSD activity was present in the cytosol, and cytosol of B glands showed increased 3βHSD activity, the increased conversion of DHA to AD may be a critical step for androgenic action and may be responsible for excessive androgenicity in male-pattern baldness.
In human pregnancy, placental 3β-hydroxy-5-ene-steroid dehydrogenase and steroid 5 → 4-ene-isomerase produce progesterone from pregnenolone and metabolize fetal dehydroepiandrosterone sulfate to androstenedione, an estrogen precursor. The enzyme complex was solubilized from human placental microsomes using the anionic detergent, sodium cholate. Purification (500-fold, 3.9% yield) was achieved by ion exchange chromatography (Fractogel-TSK DEAE 650-S) followed by hydroxylapatite chromatography (Bio-Gel HT). The purified enzyme was detected as a single protein band in sodium dodecylsulfate-polyacrylamide gel electrophoresis (monomeric Mr = 19,000). Fractionation by gel filtration chromatography at constant specific enzyme activity supported enzyme homogeneity and determined the molecular mass (Mr = 76,000). The dehydrogenase and isomerase activities copurified. Kinetic constants were determined at pH 7.4, 37°C for the oxidation of pregnenolone (Km = 1.9 μM, Vmax = 32.6 nmol/min/mg) and dehydroepiandrosterone (Km = 2.8μM, Vmax = 32.0 nmol/min/mg) and for the isomerization of 5-pregnene-3,20-dione (Km = 9.7 μM, Vmax = 618.3 nmol/min/mg) and 5-androstene-3,17-dione (Km = 23.7μM, Vmax = 625.7 nmol/min/mg). Mixed substrate analyses showed that the dehydrogenase and isomerase reactions use the appropriate pregnene and androstene steroids as alternative, competitive substrates. Dixon analyses demonstrated competitive inhibition of the oxidation of pregnenolone and dehydroepiandrosterone by both product steroids, progesterone and androstenedione. The enzyme has a 3-fold higher affinity for androstenedione than for progesterone as an inhibitor of dehydrogenase activity. Based on these competitive patterns of substrate utilization and product inhibition, the pregnene and androstene activities of 3β-hydroxy-5-ene-steroid dehydrogenase and steroid 5 → 4-ene-isomerase may be expressed at a single catalytic site on one protein in human placenta.
The formation of (3-H) estrone has been demonstrated in human anagen scalp hair roots incubated with (1, 2, 6, 7-3H) androstenedione, and approximate rates of formation of 0.2 pmol of estrone/mg DNA/h were observed. Thus, hair is a potential site for the extraglandular formation of estrogen in man.
Although testosterone (T) stimulates aggressive and reproductive behaviors in males of many vertebrate species, it is now known that the full expression of T action in the brain requires aromatization to estradiol (E2) and subsequent interaction of locally formed E2 with nuclear estrogen receptors. In experiments reported here, we used a behavioral test which quantifies the response of an individual male Japanese quail (Coturnix coturnix japonica) to the visual stimulus of a conspecific. We have called this behavior aggression because it shares many features in common with traditional measures of aggression, e.g., predicting dominance and subordinance. Nevertheless, the behavior probably also combines a complex steroid-sensitive masculine behavior. The advantage of this test is that it allows the discrimination of individual differences in masculine behavior but avoids fighting and sexual encounters per se, thereby reducing effects of learning, a problem with previous tests of avian aggression. In addition, this test has been applied usefully to identify neuroendocrine correlates to male behavior. Using this test, the arousal of reproductively inactive males (hereafter referred to as aggression) is activated by administration of T or estradiol benzoate (EB), but not by 5 alpha-dihydrotestosterone (DHT). T-induced aggression was blocked by the aromatase inhibitor 4-hydroxyandrostenedione (OHA), an effect partially reversed by treatment with EB. In addition, OHA or the estrogen receptor blocker CI-628 reduced aggressiveness of reproductively active males whereas the androgen receptor blocker flutamide had no effect. Results with the 5 alpha-reductase inhibitor N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 alpha-carboxyamide (4-MA) were equivocal. Additionally, treatment of reproductively inactive quail with T or E2 but not DHT increased aromatase activity in the hypothalamus-preoptic area (HPOA). We conclude, therefore, that T to E2 conversion is essential for the activation of aggressiveness in this species. Although locally formed estrogen exerts its effects on aggression in part by increasing activity of aromatase per se, analysis of the time course of behavioral induction or suppression by the various treatments suggests that the response has multiple components, including both short latency, receptor-independent and long latency, receptor-dependent events.
Immunocytochemical localization of aromatase cytochrome P-450 was examined in immature rat ovaries treated with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG), and in pregnant rat ovaries. It is well known that PMSG and hCG treatments induce ovulation about 12 h after hCG injection. At 24 h after hCG injection, many antral follicles were recognized in immature rat ovaries and only the granulosa cells in the antral follicles were stained weakly with the anti-aromatase antibody. At 0 to 9 h after hCG injection, in addition to the antral follicles, some large Graafian follicles could be observed in the rat ovaries, and the granulosa cells of these follicles were positively stained for aromatase. Each follicle was surrounded by the basal lamina which shows lineally distinct positive reaction against anti-laminin antibody. At 12 h after hCG injection, some large Graafian follicles without oocyte were weakly positive to the anti-aromatase antisera, and the outline of their basal lamina stained with anti-laminin antibody became irregular in shape and fragmentous. At 15 to 18 h after hCG injection, the luteinized cysts could be seen, and the granulosa-lutein cells of these cysts were almost negative for aromatase. Fragmentous reaction to the anti-laminin antibody was observed around the luteinized cysts. In the ovaries of day 4 in pregnancy, only the granulosa cells of the large antral follicles were weakly stained, but corpora lutea negatively reacted to the anti-aromatase antibody. At 7 to 19 days in gestation, both the granulosa cells of antral follicles and pregnant luteal cells were positively stained against aromatase antisera.(ABSTRACT TRUNCATED AT 250 WORDS)
An immunocytochemical peroxidase-antiperoxidase procedure using a purified polyclonal antibody raised against human placental aromatase was used to localize aromatase-containing cells in the Japanese quail brain. Immunoreactive cells were found only in the preoptic area and hypothalamus, with a high density of positive cells being present in the sexually dimorphic medial preoptic nucleus, in the ventromedial nucleus of the hypothalamus and in the infundibulum. The positive material was localized in the perikarya and in adjacent cytoplasmic processes. Aromatase-containing cells were a specific marker for the sexually dimorphic preoptic nucleus. Treatment with testosterone produced a 6-fold increase in the aromatase activity of the preoptic area and a 4-fold increase in the number of immunoreactive cells in the medial preoptic nucleus. Thus, the increase in aromatase activity observed after testosterone administration is caused by a change in enzyme concentration.
In previous studies we have shown that aromatase cytochrome P450 (P450arom) mRNA and protein increase markedly in luteal tissue between days 10-19 of gestation, whereas cholesterol side-chain cleavage cytochrome P450 (P450scc) appears to be constitutively maintained regardless of hormonal changes occurring during pregnancy. To identify pituitary and placental hormones that regulate these two P450 enzymes in the rat corpus luteum, serum LH activity and pituitary PRL release were selectively inhibited by administration of LH antiserum (LH-Ab) or CB-154, respectively. Placental hormones were removed by hysterectomy. Hormonal activities were replaced by the administration of hCG, PRL, testosterone (T), or estradiol (E), given individually or in combination. Induction of aromatase mRNA transcripts (3.3, 2.6, and 1.9 kilobases) and protein (54,000 mol wt) between days 10-15 of gestation was blocked by either surgical hysterectomy or LH-Ab treatment. Hysterectomy on day 10 combined with CB-154 abolished not only aromatase mRNA, but also markedly reduced P450scc mRNA (2.0 kilobases) by day 12. Induction of aromatase was partially restored in the day 10-15 hysterectomized rats by treatment with PRL plus E (most effective), PRL plus T, or PRL alone, but not by either T or E alone. Similar results were observed 2 days after hysterectomy (day 12), except that hysterectomy alone caused a transient 3.5-fold increase in P450arom mRNA and protein, most likely due to a transient release of pituitary LH. Aromatase mRNA and protein were also increased in intact pregnant rats treated with hCG between days 10-12. However, no effect of hCG was observed before (days 8-10) or after (days 13-19) midgestation. Likewise, LH-Ab had no effect if given after day 13. Despite hormone-specific regulation of the content of aromatase protein, E biosynthesis in vitro was not strictly related to aromatase enzyme content. We conclude that aromatase mRNA and protein are maintained by PRL at a low level of expression in the first half of pregnancy, can be modulated by LH at midgestation, and are subsequently induced to high levels in the second half of gestation by placental factors (rat placental lactogen-1 and T) and the conversion of T to E in the corpus luteum. P450scc appears to be constitutively maintained. Thus, two P450 genes known to be regulated by LH/cAMP in the rat follicle are controlled by diverse peptide and steroid signal transduction mechanisms in the corpus luteum.
Sebaceous glands were isolated by manual dissection using a stereomicroscope from skin specimens of bald scalp of men with male-pattern baldness undergoing hair transplant or scalp reduction surgery and also from specimens taken from hairy and bald areas of scalp at autopsy of adult male victims of accidental death within 3 h post mortem. Homogenates of the isolated glands exhibited activities of delta 5-3 beta-hydroxysteroid dehydrogenase (3 beta HSD), 17 beta-hydroxysteroid dehydrogenase, and testosterone 5 alpha-reductase by the conversion of [3H]dehydroepiandrosterone (DHA) to 3H-delta 4-androstenedione (AD), [3H]testosterone, and [3H]dihydrotestosterone. Homogenates of glands from bald (B) scalp had greater 3 beta HSD activity than homogenates of glands from hairy (H) scalp. After differential centrifugation, 3 beta HSD activity was found mainly in the microsomal and 105,000 X g supernatant fractions. Specific activity of the enzyme based on protein mass was highest in the microsomal fraction; however, the total 3 beta HSD activity in the 105,000 X g supernatent of B glands was significantly (p less than .01) greater than that of H glands. 3 beta HSD activity in sebaceous glands isolated from autopsy specimens did not differ from that of glands isolated from surgical specimens in apparent Km (0.13-0.14 microM), pH optima (8.0), or coenzyme requirement for NAD. Since substantial 3 beta HSD activity was present in the cytosol, and cytosol of B glands showed increased 3 beta HSD activity, the increased conversion of DHA to AD may be a critical step for androgenic action and may be responsible for excessive androgenicity in male-pattern baldness.
In 20 patients with a newly diagnosed type I diabetes mellitus a cytotoxic effect of blood lymphocytes against beta cells of the pancreas of neonatal rats could be demonstrated. This effect remained nearly unchanged during the first 12 months of control. During the course up to 18 months, the cytotoxicity decreased significantly. After stimulation with glucose and glucagon, a C-peptide secretion was demonstrated in all patients during the first 12 months but it decreased thereafter. The follow-up study showed cell-mediated immune reactions against beta cells in type I diabetics as long as the existence of beta cells can be assumed on the basis of functional tests. Thus the immune process seems to depend on the presence of the specific antigen.
I. Sexual Dimorphism in Feather Morphology NO ASPECT of sexual dimorphism is more striking or more variable among species than is the feathering pattern of birds. One such sexual difference involves the morphology of feathers. For example, in some birds the feathers of the male are longer and more deeply fringed than those of the female.1 Species in which such sexual differences are extreme include the lyre bird, the peacock, some types of hummingbird, and the domestic chicken (1). Owing to their accessibility, chickens have been the favored subjects for the study of relationships between gonadal function and feather structure, and it is customary to characterize the plumage of adult chickens as either henny or cocky (Fig. 1) (3). In the hen most feathers are short and straight and have a solid vane with many barbules and hence little fringing. In the rooster, in contrast, the neck hackle feathers, the feathers of the saddle (the median tail coverts), and the major tail coverts and great sickle feathers o...
Two androstenedione derivatives, 10-propargylestr-4-ene-3,17-dione and its 17-propionated form, were administered to normal cycling rats, and both compounds led to an inhibition of ovarian aromatase. Under in vitro conditions, only the former compound exhibited high potency as an inhibitor of rat ovarian and human placental microsomal aromatase. At 1 mg/kg/day both compounds were effective in promoting regression of 9,10-dimethyl-1,2-benzanthracene-induced mammary tumors in rats without terminating their estrous cycle. PED also inhibited growth of a human ovarian carcinoma in athymic mice. The results with the 17-propionated compound testify to the necessity of in vivo assays in screening antitumor agents. In summary, PED and its propionated derivative inhibited ovarian aromatase in vivo and inhibited the growth of hormone-responsive tumors.
[1,2 3H] Androstenedione metabolism has been measured under standardized conditions in growing and resting hair roots from varying anatomical sites from 5 women and 12 men, 6 of whom had male pattern baldness. 5α Reduced and 17β hydroxy steroids were the major metabolites of androstenedione. Hairs from all body regions have the capacity to transform androstenedione into testosterone, but the rate of the reduction of 17 ketosteroids is less than the rate of oxidation so that the 17 keto rather than 17β hydroxysteroids tend to accumulate in the cell. Since the 5α reduction is irreversible and conditions favor the formation of 17 ketosteroids, androstenedione is the principal intracellular androgen in the hair root.
3 beta-hydroxysteroid dehydrogenase delta 4-5-isomerase (delta 5-3 beta-HSD) catalyzes an early step in the synthesis of testosterone from dehydroepiandrosterone (DHA). We compared enzyme activity in back skin biopsies with sebum excretion rate (SER) in 14 individuals. The rate of conversion of [7 alpha-3H]DHA into [3H]-4-androstene-3,17-dione was measured in cryostat sections of skin and compared with the sebaceous gland content of the same biopsies. Reaction rate was proportional to the volume of sebaceous gland tissue in the sections. Enzyme activity was absent from sections without histologically identifiable sebaceous gland tissue. This suggests that the delta 5-3 beta-HSD is localized in sebaceous glands. SER, measured by a modified photometric technique at the biopsy site, correlated highly with sebaceous gland volume and with the rate of conversion of DHA into androstenedione in the biopsy. For each biopsy, specific activity of delta 5-3 beta-HSD in sebaceous glands was calculated by dividing the rate of formation of [3H]-4-androstene-3,17-dione by sebaceous gland volume. Specific activity of delta 5-3 beta-HSD did not correlate significantly with SER, suggesting that variations in concentration of delta 5-3 beta-HSD in sebaceous glands probably do not underlie variations in sebaceous gland activity.
Aromatase activity of human genital skin fibroblasts grown in cell culture was studied using both [1,2,6,7-3H] androstenedione (A) and [1-3H]A as substrates. With the former substrate the generation of [3H]estrogens was determined, whereas with the latter substrate, the formation of [3H]H2O was measured. Our results showed that the release of [3H]H2O from [1-3H]A provides an accurate and sensitive method for determining aromatase activity in cultured human skin fibroblasts. Because genital skin fibroblasts also possess marked 5 alpha-reductase activity, we found that addition of an alternate substrate for 5 alpha-reductase was necessary to prevent shunting of A from the aromatase pathway. Hence, all aromatase assays were carried out in the presence of 5 microM progesterone. Under these experimental conditions, no correlation was found between levels of 5 alpha-reductase and aromatase activities. The Michaelis-Menten constant (Km) of the aromatase in cultured genital skin fibroblasts measured in the presence of A and added progesterone ranged between 10 and 39 nM, and the maximum velocity (Vmax) ranged between 0.14 and 1.46 pmol product/mg protein/h. These values are in good agreement with those previously described for adipose tissue stromal-vascular cells, suggesting that the aromatase complexes are similar in skin and adipose tissue. We conclude that skin may be an important site for aromatization of androgens to estrogens in men.
The formation of estrogens in mammals via aromatase involves the relatively unique capacity to form an aromatic ring de novo in contrast to most other aromatic substances (essential amino acids) which are obtained only in the diet. The reaction is the only example of a cytochrome P450 system which resides in both the mitochondrial and microsomal fractions of the cell. It occurs widely throughout the body in diverse tissues and functions via both de novo synthesis and transformation of prehormones (androstenedione and testosterone). It is found widely in animal species in both the brain and gonads even in phylogenetically primitive species. Placental aromatase appears to be associated with the evolution of viviparity and an extended gestational period in utero. Follicular aromatase which is dependent upon follicle-stimulating hormone stimulation appears to be essential for oogenesis, ovulation, and normal luteal functions while central nervous system aromatase serves to determine sexual behavior and the neurohormonal link to the hypothalamus and pituitary for ovarian cyclicity. While estrogens are the key to pituitary, breast, and endometrial growth and development, this hormone is one of the few examples of an endogenous steroid that has been implicated as a carcinogen or a stimulant for carcinogenesis.
Regulation of estrogen biosynthesis in human adipose stromal cells
- Evans CT
Comparison between sebaceous lipogenesis and androgen metabolism in skin from acne patients
- Hay JR