Local Androgen Metabolism Research Articles

Idiopathic hirsutism: Is it really idiopathic or is it misnomer?

Hirsutism, which is characterized by excessive growth of terminal hair in a male pattern, may result from various causes including polycystic ovary syndrome (PCOS), non-classic congenital adrenal hyperplasia, adrenal or ovarian tumors or it may be idiopathic. Idiopathic hirsutism is currently defined as hirsutism associated with normal ovulatory function, normal serum androgen levels and normal ovarian morphology, however, the pathogenesis of idiopathic hirsutism is not clear. The androgens are the main hormones to stimulate growth of body hair, therefore, there should be any form of increased androgen effect irrespective of normal serum androgen levels in any patient with hirsutism. In accordance to this scientific truth, we have previously shown that, although within normal limits, patients with idiopathic hirsutism have relatively higher serum androgen levels (relative hyperandrogenemia) in comparison to healthy subjects which let as to think that is idiopathic hirsutism really idiopathic? In addition to relative hyperandrogenemia, we have previously shown that, in comparison to healthy subjects, women with idiopathic hirsutism demonstrated higher expression of steroid sulphatase and 17-beta hydroxysteroid dehydrogenase mRNA both in the subumbilical region and arm skin, which contributes to local androgen metabolism. Those results support the idea that, in some patients, although the adrenals or ovaries do not secrete increased amount of androgens leading to hyperandrogenemia, pilocebaceous unit locally produce increased amount of androgens leading to hirsutism without ovulatory dysfunction. Upon the demonstration of relative hyperandrogenemia and possible increase in local androgen synthesis in patients with idiopathic hirsutism, we think that idiopathic hirsutism is not idiopathic and it may be named as "normoandrogenic hirsutism". Furthermore, it may not be a different entity but may be an early stage of hyperandrogenic disorders such as PCOS. Clinically, this can be find out by following-up patients with idiopathic hirsutism prospectively.

Sex-specific differences in the effects of local androgen metabolism in the heart as an indicator for the risk of myocardial infarction

Aim Testosterone influences cardiovascular risk and disease in a sex-specific manner. The more potent androgen 5α-dihydrotestosterone (DHT) can be formed through conversion of testosterone by the enzyme 5α-reductase. We hypothesized that, because of the presence of DHT in coronary and myocardial tissues, a sexually dimorphic effect can be observed if differences exist in genetics or mRNA expression in androgen-metabolizing enzymes. Materials and methods mRNA levels of steroidogenic enzymes and the androgen receptor (AR) were investigated in human myocardial tissue samples. Subsequently, all participants in the baseline cohort of the Rotterdam Study (RSI) with successful genotyping and without prevalent myocardial infarction (MI, N=5199) were recruited to study the association between single nucleotide polymorphisms (SNPs) within SRD5A1, SRD5A2, and AKR1C3 and incident MI using Cox regression models. Significant results were replicated within the Atherosclerosis Risk in Communities cohort and the second cohort of the RSII. Results The expression of SRD5A1, AKR1C3, and AR was found in all myocardial samples, whereas HSD17B3 and SRD5A2 expression levels were low and undetectable, respectively. Myocardial SRD5A1 expression was higher in women than in men. Within SRD5A1, SNP rs248805G>A was significantly associated with incident MI in western European women (hazard ratio 1.49; 95% confidence interval 1.19-1.87). This SNP is tightly linked to the HinfI polymorphism in SRD5A1 (rs248793G>C), of which the minor allele has been associated with a higher DHT/T ratio. Conclusion Genetic variation in SRD5A1 is associated with an increased risk of MI in western European women, possibly because of the sex-specific potential of local androgen conversion and effect.

Androgen Glucuronidation: An Unexpected Target for Androgen Deprivation Therapy, with Prognosis and Diagnostic Implications

Androgen deprivation therapy (ADTh) remains a mainstay of prostate cancer treatment, but its efficacy is bypassed by mechanisms that are not fully understood. In human prostate cancer cells, androgen glucuronidation, catalyzed by the two UDP-glucuronosyltransferase (UGT) enzymes UGT2B15 and UGT2B17, is the major androgen inactivation pathway. In this study, we investigated the effect of ADTh on androgen glucuronidation to evaluate its potential clinical utility for prostate cancer prognosis or therapy. UGT2B15 and UGT2B17 expression was evaluated in prostate cancer specimens from untreated or treated patients and in cell models of prostate cancer exposed to clinically relevant antiandrogens. UGT2B15 and UGT2B17 protein levels in prostate were increased after 5 months of ADTh when compared with specimens from untreated patients. UGT2B15 expression remained elevated for up to 12 months, but UGT2B17 returned to initial levels as soon as after 6 months. Several androgen receptor (AR) antagonists tested caused a dose- and time-dependent stimulation of UGT2B15 and UGT2B17 expression and androgen glucuronidation in prostate cancer cell lines. The role of AR in these regulatory events was confirmed using AR-deficient LNCaP cells, in which UGT2B attenuation reduced the antiproliferative effects of AR pharmacologic antagonists. Through this combination of clinical and functional investigations, our work revealed that ADTh stimulates a local androgen metabolism in prostate cells, establishing a foundation to evaluate the potential of UGT2B15 and UGT2B17 as drug targets and/or molecular markers for ADTh responsiveness and maintenance in prostate cancer.

DHEA Administration Activates Local Bioactive Androgen Metabolism in Cancellous Site of Tibia of Ovariectomized Rats

It is not known whether local androgen metabolism is involved in the mechanisms underlying the dehydroepiandrosterone (DHEA) administration-induced improvement of bone mineral density (BMD) in an estrogen-deficiency state. The aim of the present study was to clarify whether DHEA administration would improve local androgen metabolism and BMD in cancellous site of tibia of ovariectomized (OVX) rats. Twenty-two female rats, 6weeks old, were randomized into three groups: sham-operated rats, OVX control rats, and OVX rats that received DHEA treatment. DHEA was administered intraperitoneally at 20mg/kg body weight for 8weeks. The concentrations of free testosterone and dihydrotestosterone (DHT) in cancellous site of tibia did not change as a result of ovariectomy, while the DHT concentration increased following DHEA administration. We revealed that DHEA administration improved the reduction of 17β- and 3β-hydroxysteroid dehydrogenases and clearly reversed the reduction of 5α-reductase types 1 and 2 and androgen receptor in the cancellous site of tibia of OVX rats. DHEA administration suppressed estrogen deficiency relative to the decrease in the cancellous BMD, which was positively associated with local DHT concentration. These findings indicate that DHEA administration enhances local bioactive androgen metabolism in the cancellous tibia of young OVX rats, suggesting that local DHT may play a part in the DHEA administration-induced improvement of cancellous BMD.

Abstract 4906: A systems approach into studying the changes in genetic regulation during prostate cancer progression

Abstract Prostate cancer (PC) is a complex disease that is currently the most common malignancy in males, and the second most frequent cause of cancer-related mortality in developed countries. Despite its high prevalence, the molecular mechanisms that induce PC progression are not well understood. The most common alterations affecting genetic regulation in PC are TMPRSS2:ERG gene fusions, 8q24 amplifications (including MYC-oncogene), and androgen receptor (AR) mutations and amplifications in castration-resistant (late stage) tumors. In normal prostatic tissue, local androgen metabolism maintains a balance between the proliferation and apoptotic cell death of prostatic epithelial cells. However in PC, androgen metabolism drives malignant transformation. The exact mechanisms which cause the imbalance in proliferation and apoptosis are not known, but likely include dysregulation of AR/MYC/ERG-regulated transcription factors (TFs) and/or microRNAs. Using a systems biology approach, we jointly studied the accumulation of expression and copy number differences of TFs and microRNAs during PC progression. We first established a generic regulatory network consisting of transcription factors and microRNAs using three sets of sequence-based binding site predictions. First, TF binding sites were predicted by scanning the sequences upstream from gene transcription start sites for binding motifs from Transfac database, second, TF binding to microRNA promoters was predicted with ProbTF, and third, microRNA binding sites were obtained from Targetscan predictions. The inferred generic network was then adapted for studying PC by pruning it based on a set of publicly available gene expression, microRNA expression data. That is, we only considered those hypothetical regulatory connections that were supported by the data. By dividing these data into normal prostate tissue, primary PC's of different grade, and metastatic tumors, we were able to study the changes in regulation during different stages of the disease. We uncovered putative regulatory motifs consisting of differentially expressed TFs and microRNAs. Another level of regulatory information was added by integrating copy number information to the regulatory motifs. We concentrated on the motifs that could be associated to AR-, ERG-, or MYC-signaling, due to their relevance in prostate cancer, or to molecules that are known to be regulated by these TFs. We found previously unknown microRNAs and TFs that may directly bound to the promoters of the TFs and therefore may have a critical effect to the malignancy of prostate cancers. The experimental validations of the most promising new candidate TF/microRNA regulatory connections are currently underway. We demonstrated here an application of a systems biology based method to prostate cancer which was used to gain insights into the changes in genetic regulation during progression of the disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4906. doi:10.1158/1538-7445.AM2011-4906

Type 2 and 5 17β-hydroxysteroid dehydrogenases and androgen receptor in human fetal lungs

Androgens delay fetal lung maturation through an androgen receptor (AR)-dependent mechanism. Type 2 and 5 17beta-hydroxysteroid dehydrogenases (17betaHSD) are involved in androgen inactivation and synthesis, respectively. We aimed to further characterize the human fetal lung potential for androgen metabolism and response. 17betaHSD2, 17betaHSD5, and AR mRNA levels were determined in lungs of mid-late gestation and in adult lungs, while protein detections were performed at mid-gestation. Relationships between levels of each mRNA and gestational age were observed. AR protein levels showed important differences among individuals of the same gestational window. 17betaHSD2 and AR were co-localized in epithelial and mesenchymal cells. AR was detected in both, cytoplasm and nucleus, which suggests fine-tuning of AR occupancy. In contrast, 17betaHSD5 was localized in a few epithelial cells of conducting zones. Our results support the existence of a local androgen metabolism in male and female human fetal lungs during the period of high-risk premature birth.

Mechanisms of androgenic action in adipose tissue

Androgens are involved in the modulation of adipose tissue function and body fat distribution in humans. The mechanisms involved include signaling through the androgen receptor and its coregulators as well as the crosstalk of several intracellular signaling pathways. Local modulation of androgen concentrations by steroid-converting enzymes, such as aldo–keto reductases 1C is associated with visceral fat accumulation and omental adipocyte enlargement. A recent study suggested that local androgen metabolism may be regulated by glucocorticoids in preadipocytes. Together, the available literature suggests that androgens possibly affect human body fat distribution through several potential mechanisms. This review article summarizes in vitro and in vivo findings on androgenic effects in adipose tissue, with a specific emphasis on signaling and pre-receptor regulation of androgen availability.

Pathophysiologie und Therapie der benignen Prostata-Hyperplasie

Benign prostatic hyperplasia (BPH) and benign prostatic enlargement (BPE) are among the most frequent medical disorders of elderly men and cause a number of annoying symptoms of the lower urinary tract (LUTS), leading to reduced quality of life and severe complications, including acute urinary retention. Nodular overgrowth of the epithelium and in particular the fibromuscular tissue is observed in the transition zone and periurethral areas. In particular, functional and phenotypic transdifferentiation of fibroblasts into myofibroblasts is a hallmark of the tissue remodeling in the benign hyperplastic prostate. BPH/BPE have a complex pathophysiology with a multitude of endocrine and local factors involved. Two risk factors, namely aging and circulating androgens, contribute significantly to risk of BPH/BPE. One of the primary initiating mechanisms appears to be a consequence of age-related changes in systemic sex steroid hormone levels accompanied by alterations in local androgen metabolism. This results in the disruption of the delicate balance of interacting growth factor signaling pathways and stromal/epithelial interactions generating a growth promoting and tissue remodeling microenvironment that leads to an increase in prostate volume. Secondarily, altered cytokine and chemoattractant production by the remodeled stroma promotes local inflammation that may further contribute to disease progression via lymphocyte-derived inflammatory cytokines and reactive oxygen/nitrogen species. Local hypoxia as a result of increased oxygen demands of proliferating cells may induce low levels of reactive oxygen species promoting neovascularization and fibroblast-to-myofibroblast transdifferentiation. Medical therapies for LUTS due to BPH/BPE have changed little over the past 15 years with mainstay treatments being alpha-adrenoreceptor blockade and 5alpha-reductase inhibitors. We provide an in depth view of the mechanisms underlying BPH/BPE and relate new research findings to the clinical picture with the prospect of novel therapeutic targets, including selective hormone antagonists/agonists, anti-stromal therapy, vitamin-D analogues and approaches to redress the redox imbalance.

Managing Cutaneous Manifestations of Hyperandrogenic Disorders

Cutaneous manifestations of hyperandrogenic disorders (acne, seborrhea, hirsutism and androgenetic alopecia) can be caused by elevated levels of free testosterone or androgen precursors. In women with normal serum levels of testosterone or androgen precursors, enhanced local conversion to testosterone, or to the more potent androgen dihydrotestosterone, may lead to increased androgen activity in the pilosebaceous unit. Large individual variations in the response to normal or elevated androgens suggests considerable differences in local androgen metabolism and androgen receptor-mediated activities, which may partly be related to genetic disposition. Androgens cause opposite effects on hair follicles in the scalp compared with the face and body, and there are large differences in the length of anagen phase. Androgens enhance sebum production and keratinization, prolong the growth phase of face and body hair, stimulate the transformation of vellus to terminal hair, and shorten the anagen phase of scalp hair. Estrogens may antagonize the androgen-induced actions on sebaceous glands and hair follicles. Treatment with oral contraceptives (OCs) reduces the production of androgens and androgen precursors and increases sex hormone-binding globulin, resulting in a decrease of free testosterone levels. According to type and dose, the estrogen and progestogen components of OCs may directly reduce the effect of androgens within sebaceous glands and hair follicles. Therefore, OCs with a predominant estrogen effect may improve mild to moderate forms of acne and seborrhea, hirsutism and androgenetic alopecia, in a time-dependent manner. In women who do not respond satisfactorily, treatment with OCs containing a progestogen with antiandrogenic activity is recommended. In many women with severe acne or hirsutism, a considerable increase in the local concentration of the antiandrogenic progestogen is required to reduce the androgenic interaction with the androgen receptor. For this therapy, an OC containing cyproterone acetate can be used. If necessary, the dose of cyproterone acetate can be increased in a stepwise manner. While androgenetic alopecia is best treated with a low-dose OC containing cyproterone acetate (optimal effect occurs after at least 12 months of therapy), severe acne and hirsutism are significantly improved after 6-12 months of regimens containing high doses of cyproterone acetate (25-100 mg/day). After termination of treatment the disorders may reappear, therefore treatment with suitable low-dose formulations is recommended to maintain the therapeutic effect.

Androgen effects on bone metabolism: recent progress and controversies.

Androgens have beneficial effects on skeletal development and maintenance in women and men. The detection and functional characterization of androgen receptors in bone cells has implicated bone tissue as a potential target tissue for androgens. Gonadal and adrenal androgens directly regulate various aspects of osteoblastic lineage cells, including proliferation, differentiation, mineralization, and gene expression. These effects may differ depending on the stage of differentiation, the number of androgen receptors, and other inherent characteristics (species, site, cell biology) of the osteoblastic cell system. In addition, recent studies have suggested that some of the anabolic and anti-resorptive effects of androgens on bone may be mediated by regulation of autocrine and paracrine factors in the bone microenvironment, including transforming growth factor-beta, insulin-like growth factors (and their binding proteins), and interleukin-6. This review summarizes the recent progress made in our knowledge of androgen receptor action, local androgen metabolism in bone, and direct and indirect effects of gonadal and adrenal androgens as well as androgen receptor antagonists on bone cells.

Post-adolescent acne: a review of clinical features

Acne is usually recognized as a disorder of adolescence. However, the referral of patients over the age of 25 years with acne has significantly increased over the past 10 years. The clinical features of 200 patients over the age of 25 years, referred to our department for treatment of acne, were evaluated with a view to establishing possible aetiological factors. There were 152 (76%) women and 48 (24%) men. The mean age of the patients was 35.5 years (range 25-55 years). The acne was mild or moderate in severity, consisting principally of inflammatory lesions, with mean total acne grade (Leeds Grading Scale) of 1.125 for men and 0.75 for women. Most patients had persistent acne; but true late-onset acne (onset after the age of 25 years) was seen in 28 (18.4%) of women and four (8.3%) of men. Thirty-seven per cent of women had features of hyperandrogenicity. One hundred and sixty-four patients (82%) had failed to respond to multiple courses of antibiotics, and 64 (32%) had relapsed after treatment with one or more courses of isotretinoin. External factors, such as cosmetics, drugs and occupation, were not found to be significant aetiological factors. A family history revealed that 100 (50%) of patients had a first-degree relative with post-adolescent acne. Patients with post-adolescent acne appear to represent an increasingly important population of acne sufferers. External factors do not seem to have a significant aetiological role. Two main clinical groups were identified: those with persistent acne and those with late-onset acne. A minority of women also had features of hyperandrogenicity. These patients, and those with late-onset acne, may represent a subgroup who have underlying abnormalities of ovarian, adrenal or local androgen metabolism, and require separate investigation.

Hormonal Parameters in Androgenetic Hair Loss in the Male

Alopecia in the male is considered as a genetically determined disorder. Increased local androgen metabolism and androgen receptor binding in the balding areas confirm the importance of the target organ hair follicle as regulative of androgen influences. In our study the hormonal parameters of 65 male patients with male pattern hair loss with a mean age of 24.31 years were compared with those of 58 age-matched controls. Determinations of the androgens, sex-hormone-binding globulin, the hypophyseal hormones luteinizing hormone, follicle-stimulating hormone and prolactin, 17 beta-estradiol and cortisol were performed by standard radioimmunoassay. Significant differences in serum levels of androstenedione, cortisol, 17 beta-estradiol and luteinizing hormone were noted between hair loss patients and control subjects. Suprarenal stimulation as well as hypophyseal feedback mechanisms therefore seem to be involved in male pattern alopecia.