Reversing silenced AR signal with demethylating agents - A promising treatment option?

Therapeutic Efforts Pharmaceutical
#241

nature.com/emboj/journal/v19/n3/abs/7592146a.html

The control of target gene expression by nuclear receptors requires the recruitment of multiple cofactors. However, the exact mechanisms by which nuclear receptor–cofactor interactions result in tissue-specific gene regulation are unclear. Here we characterize a novel tissue-specific coactivator for the androgen receptor (AR), which is identical to a previously reported protein FHL2/DRAL with unknown function. In the adult, FHL2 is expressed in the myocardium of the heart and in the epithelial cells of the prostate, where it colocalizes with the AR in the nucleus. FHL2 contains a strong, autonomous transactivation function and binds specifically to the AR in vitro and in vivo. In an agonist- and AF-2-dependent manner FHL2 selectively increases the transcriptional activity of the AR, but not that of any other nuclear receptor. In addition, the transcription of the prostate-specific AR target gene probasin is coactivated by FHL2. Taken together, our data demonstrate that FHL2 is the first LIM-only coactivator of the AR with a unique tissue-specific expression pattern.

#242

goldjournal.net/article/S0090-4295(9800468-3/abstract

Objectives. Shorter CAG repeat lengths in exon 1 of the androgen receptor (AR) gene are associated with a stronger transcriptional activity of the AR and with a higher risk of prostate cancer. Because benign prostatic hyperplasia (BPH) is an androgen-dependent condition, we examined the hypothesis that men with shorter AR gene CAG repeat lengths have an increased risk of developing BPH.

Methods. Using data from the Health Professionals Follow-up Study (HPFS), we evaluated the relationship between AR gene CAG repeat length and prevalent BPH, as defined by BPH surgery, by enlarged prostate gland detected by digital rectal examination, and by urinary symptoms as determined by the American Urological Association Symptom Index.

Results. The odds ratio for BPH surgery or enlarged prostate gland was 1.92 (95% confidence interval [CI] 1.22 to 3.03; P [trend] = 0.0002), comparing AR gene CAG repeat length of 19 or less to 25 or more. Results were similar for the end points of BPH surgery (P [trend] = 0.002) and for enlarged prostate gland (P [trend] = 0.001). For a six-repeat decrease in CAG repeat length, the odds ratio for having moderate or severe urinary obstructive symptoms from an enlarged prostate gland was 3.62 (95% CI 1.51 to 8.67; P = 0.004).

Conclusions. Variability in the AR gene CAG repeat influences the development of symptomatic BPH, particularly in predicting obstructive urinary symptoms. Our findings support further study to establish the appropriate clinical relevance.

#243

Reduction of ventral prostate weight by finasteride is associated with suppression of insulin-like growth factor I (IGF-I) and IGF-I receptor genes and with an increase in IGF binding protein 3.

Finasteride, a competitive and specific inhibitor of 5alpha-reductase, is widely used in the treatment of symptomatic benign prostatic hyperplasia. We demonstrate here that finasteride, when administered in an in vivo experimental system, caused ventral prostate regression. Intraprostatic dihydrotestosterone levels decreased, whereas testosterone levels increased in a dose-dependent manner following finasteride treatment. Finasteride also inhibited the expression of insulin-like growth factor (IGF)-I and IGF-I receptor genes in the ventral prostate. Finasteride significantly increased IGF binding protein-3 and slightly decreased IGF binding protein-2, -4, and -5 gene expression. Because IGFs are potent mitogens for prostate epithelial cells, this newly described activity of finasteride may contribute to its antiproliferative properties, particularly with regard to the inhibition of prostate growth seen clinically and in animal models.

ncbi.nlm.nih.gov/pubmed/9443394

#244

Androgen receptor gene alterations and chromosomal gains and losses in prostate carcinomas appearing during finasteride treatment for benign prostatic hyperplasia.

Finasteride is commonly used for the treatment of benign prostatic hyperplasia and has been suggested to prevent prostate cancer development. To gain insight to the molecular effects of finasteride on prostate cancer development, we studied six prostate cancers diagnosed during finasteride treatment for benign prostatic hyperplasia. Comparative genomic hybridization detected genetic alterations in four tumors (1-5 changes/tumor). Xq gains and 6q losses were the most common alterations. The recurrent Xq gains motivated us to study the involvement of the androgen receptor (AR) gene. One tumor with Xq gain had a 3-fold amplification of the AR gene, suggesting that tumor development in finasteride-treated patients may require increased AR copy number and expression, as has previously been shown for prostate cancers recurring during hormonal therapy. Furthermore, in another tumor, an Arg726Leu mutation of the AR gene was found. This mutation was also present in the germ-line DNA of the patient. Arg726Leu mutation has previously been reported to affect the transactivational properties of the AR. In summary, prostate cancers developing during finasteride therapy may have distinct biological properties, such as a low number of chromosomal alterations and frequent involvement of the AR gene. Further studies are needed to explore the role of germ-line AR mutations in these patients.

ncbi.nlm.nih.gov/pubmed/10589774

#245

eblue.org/article/S0190-9622(0300777-1/abstract

The expression of insulin-like growth factor 1 in follicular dermal papillae correlates with therapeutic efficacy of finasteride in androgenetic alopecia

In a small uncontrolled study of 9 patients with AGA, an increased expression of IGF-1 messenger RNA levels in the DP was associated with patient response to finasteride.

#246

onlinelibrary.wiley.com/doi/10.1111/j.1365-2605.2009.00970.x/full

Finasteride treatment alters MMP-2 and -9 gene expression and activity in the rat ventral prostate

The safety of using finasteride as a prevention of prostate cancer is still under debate. In this study, we investigated the effects of finasteride on the location, gene expression and activities of matrix metalloproteinases -2 and -9, which are involved in the degradation of extracellular matrix components during tissue remodelling and prostate cancer progression, invasion and metastasis. Ventral prostates (VP) from Wistar rats treated with finasteride (25 mg/kg/day) for 7 and 30 days and age-matched controls were evaluated using histology, immunohistochemistry, semi-quantitative RT-PCR and gelatin zymography. Finasteride treatment reduced the epithelial immunostaining of MMP-2 but increased MMP-9 immunostaining in the epithelial cells and in the stroma. The mRNA expression of both MMP-2 and MMP-9 were significantly increased on day 7 of finasteride treatment, mainly for MMP-9 and returned to the control levels by day 30. However, gelatin zymography showed that MMP-9 activity was significantly increased on day 7 of finasteride treatment and remained elevated on day 30 (p < 0.05), while MMP-2 activity was reduced after 30 days of treatment. Finasteride increases MMP-9 and reduces MMP-2 activities in the prostate, which may affect negatively and positively both normal and tumoural prostatic cell behaviour during the treatment. Studies on expression of MMPs in the prostate during different androgen manipulation or cancer chemoprevention strategies can contribute to understand the tissue’s overall response and clinical data.

#247

ncbi.nlm.nih.gov/pubmed/16382684

Finasteride is not necessarily effective on all of the male pattern baldness (MPB) patients. To know any factor which correlates with the effectiveness of finasteride, the polymorphism of androgen receptor (AR) gene was analyzed. Symptoms of the 488 MPB patients (18-62 y) before and after treatment with total dose of 10 mg or more of finasteride was typed by photographic method. The number of CAG and GGC repeats in AR gene of MPB patients was determined by DNA sequencing. When the number of the triplet repeats (CAG + GGC) was plotted against the degree of symptom improvement after treatment with this drug, a broad correlation between these variables was observed. The smaller the repeat number, the higher the improvement with finasteride. The group of patients with shorter repeat region in AR gene responded better to this drug than that with longer repeat region, although the former patients tended to reveal severe initial symptoms. Determination of such polymorphism is thought to be useful in the drug choice for MPB patients.

#248

sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-4D4R5P7-4&_user=10&_coverDate=10%2F01%2F2004&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1596463404&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c23762ebb1b87df0c164d786a93966ef&searchtype=a

Modulation of GABAA receptor gene expression by allopregnanolone and ethanol

Expression of specific γ-aminobutyric acid type A (GABAA) receptor subunit genes in neurons is affected by endogenous modulators of receptor function such as neuroactive steroids. This effect of steroids appears to be mediated through modulation of GABAA receptor signalling mechanisms that control the expression of specific receptor subunit genes. Furthermore, the specific outcomes of such signalling appear to differ among neurons in different regions of the brain. Neuroactive steroids such as the progesterone metabolite allopregnanolone might thus exert differential effects on GABAA receptor plasticity in distinct neuronal cell populations, likely accounting for some of the physiological actions of these compounds. Here we summarise experimental data obtained both in vivo and in vitro that show how fluctuations in the concentration of allopregnanolone regulate both the expression and function of GABAA receptors and consequently affect behaviour. Such regulation is operative both during physiological conditions such as pregnancy and lactation as well as in pharmacologically induced states such as pseudopregnancy and long-term treatment with steroid derivatives or anxiolytic-hypnotic drugs. Accordingly, long-lasting exposure of GABAA receptors to ethanol, as well as its withdrawal, induces marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and ethanol in modulating the functional activity of specific neuronal populations.

#249

eje-online.org/cgi/reprint/138/4/421.pdf

3a-Androstanediol glucuronide (3a-diol G) is con- sidered to be an excellent marker of peripheral androgen action and especially of 5a-reductase activity (11, 12).

The clinical use of 3a-diol G as a marker of peripheral androgen action is, however, controversial because many authors deduce that the origin of 3a-diol G, and therefore its plasma concentrations, reflect adrenal androgen production and hepatic metabolism (14, 15).

Our results have shown that higher levels of 3a-diol G are found only in hirsute patients, and are independent of androgen levels (hyperandrogenic subjects n 1⁄4 45, normal androgenic subjects n 1⁄4 35) and of BMI. Even values for 3a-diol G in PCOS-NH were higher compared with the controls although significantly lower than those in hirsute women.

It is known that the activity of 5a-reductase can be stimulated not only by circulating levels of androgens, but also by genetic factors (19), insulin and the insulin- like growth factor-I/insulin-like growth factor-binding protein (IGF-I/IGFBP) system (20).

Hirsutism only appears when plasma levels of 3a-diol G are very elevated, giving evidence of maximum 5a- reductase activity and of an elevated formation of DHT in the hair follicle. The levels of 3a-diol G in IH and in PCOS-H, compared with PCOS-NH, suggests the importance of genetic factors in the regulation of 5a-reductase and the key role of peripheral events in the determination of hirsutism.

#250

The correlation between 3a-diol G and hirsutism, and the values of 3a-diol G in controls and in PCOS-NH, suggests a cutaneous origin of 3a-diol G. Our results, obtained from a broad series, confirm the clinical usefulness of 3a-diol G as a marker of the peripheral metabolism of androgens. The 3a-diol G dosage can be employed to monitor various therapies for hirsutism.

What I find interesting is that levels of 3a-diol G are independent of androgen levels meaning one can have high levels of testosterone but a low 3a-diol G. Also if one bumps up the testosterone you may not bump up the 3a-diol G. Having said that this

jcem.endojournals.org/cgi/reprint/85/4/1648.pdf says that increasing androgens does increase it.

If you look at maracatu’s results however - viewtopic.php?f=4&t=2763&start=100 - testosterone didn’t make much difference.

It should be noted Adiol 17-G is important too.

endo.endojournals.org/cgi/content/abstract/123/6/2788

jcem.endojournals.org/cgi/content/abstract/66/1/212

These results indicate that Adiol 17-G is the predominant circulating form of Adiol G in normal men and women and that it is also the major Adiol G isomer derived from DHT.

epirev.oxfordjournals.org/cgi/reprint/23/1/42

However, in studies of men treated with finasteride, a 5a-reductase type 2 inhibitor, serum levels of 3a-diol G decrease concomitantly with finasteride treatment, suggesting that 3a-diol G levels predominantly reflect the activity of the type 2 enzyme

cebp.aacrjournals.org/cgi/content/full/12/6/578

The circulating A-diol-g concentration is believed to be a more accurate serum marker of 5 -reductase type II than serum DHT itself, because A-diol-g is the direct metabolite of DHT formed in the prostate gland. However, circulating DHT is largely derived from 5 -reductase type I activity in the skin and is therefore not an accurate marker of intraprostatic 5 -reductase type II activity.

Also the consensus on its function is not confirmed.

nature.com/jid/journal/v119/ … 1659a.html

“Clinically, it is still controversial if serum levels of 3alpha-Adiol conjugates (3alpha-Adiol glucuronide or 3alpha-Adiol sulfate) serve as reliable indicator for cutaneous 5alpha-DHT formation (see later,Lookingbillet al, 1988a;Horton, 1992;Vogt et al, 1992), or are just a marker of adrenal steroid production and metabolism”

So “maybe” its saying serum DHT is a better marker for type 1 activity and type 2 - adiol-g. Most likely adiol 17 g. We should be testing this as well as Adiol-3g.

Now I propose that it could be that due to alterations in gene expression type 2 activity is decreased. DHT produced by type 2 activity has paracrine effects on the immediate tissues surrounding it and exerts its function. However again it could be the androgen receptor not responding to DHT therefore peripheral action of androgens decreases - decreasing Adiol-G. This seems more likely to me as direct DHT replacement would help (although probably not as much as normal production due to the paracrine effects) in the broken 5 alpha reductase type 2 theory.

Just trying to make sense of Adiol-G and its relationship with our systems.

The idea of IGF1 stimulating 5 alpha reductase is interesting too as JN had some benefit on GH - also Xyrem increases IGF1.

#251

endo.endojournals.org/cgi/content/abstract/145/5/2253

Androgens Regulate Phosphodiesterase Type 5 Expression and Functional Activity in Corpora Cavernosa

endo.endojournals.org/cgi/content/abstract/126/2/1165

Testosterone at High Concentrations Interacts with the Human Androgen Receptor Similarly to Dihydrotestosterone*

I think my journal searching is coming to an end.

#252

A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer.

Abstract
In addition to the classical activation by ligands, nuclear receptor activity is also regulated by ligand-independent signalling. Here, we unravel a novel signal transduction pathway that links the RhoA effector protein kinase C-related kinase PRK1 to the transcriptional activation of the androgen receptor (AR). Stimulation of the PRK signalling cascade results in a ligand-dependent superactivation of AR. We show that AR and PRK1 interact both in vivo and in vitro. The transactivation unit 5 (TAU-5) located in the N-terminus of AR suffices for activation by PRK1. Thus, TAU-5 defines a novel, signal-inducible transactivation domain. Furthermore, PRK1 promotes a functional complex of AR with the co-activator TIF-2. Importantly, PRK signalling also stimulates AR activity in the presence of adrenal androgens, which are still present in prostate tumour patients subjected to testicular androgen ablation therapy. Moreover, PRK1 activates AR even in the presence of the AR antagonist cyproterone acetate that is used in the clinical management of prostate cancer. Since prostate tumours strongly overexpress PRK1, our data support a model in which AR activity is controlled by PRK signalling.

ncbi.nlm.nih.gov/pubmed/12514133

Activation of PRK1 by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. A comparison with protein kinase C isotypes.

Abstract
As potential targets for polyphosphoinositides, activation of protein kinase C (PKC) isotypes (beta 1, epsilon, zeta, nu) and a member of the PKC-related kinase (PRK) family, PRK1, has been compared in vitro. PRK1 is shown to be activated by both phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P2) as well as phosphatidylinositol 3,4,5-trisphosphate (PtdIns-3,4,5-P3) either as pure sonicated lipids or in detergent mixed micelles. When presented as sonicated lipids, PtdIns-4,5-P2 and PtdIns-3,4,5-P3 were equipotent in activating PRK1, and, furthermore, sonicated phosphatidylinositol (PtdIns) and phosphatidylserine (PtdSer) were equally effective. In detergent mixed micelles, PtdIns-4,5-P2 and PtdIns-3,4,5-P3 also showed a similar potency, but PtdIns and PtdSer were 10-fold less effective in this assay. Similarly, PKC-beta 1, -epsilon, and -nu were all activated by PtdIns-4,5-P2 and PtdIns-3,4,5-P3 in detergent mixed micelles. The activation constants for PtdIns-4,5-P2 and PtdIns-3,4,5-P3 were essentially the same for all the kinases tested, implying no specificity in this in vitro analysis. Consistent with this conclusion, the effects of PtdIns-4,5-P2 and PtdIns-3,4,5-P3 were found to be inhibited at 10 mM Mg2+ and mimicked by high concentrations of inositol hexaphosphate and inositol hexasulfate. The similar responses of these two classes of lipid-activated protein kinase to these phosphoinositides are discussed in light of their potential roles as second messengers.

ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=7673228&dopt=b

#253

ncbi.nlm.nih.gov/pubmed/15049965

IGF-I and testosterone levels as predictors of bone mineral density in healthy, community-dwelling men.

OBJECTIVE: Age-related decline in IGF-I and gonadal hormones have been postulated to play an important role in the pathogenesis of age-related bone loss in men. In this cross-sectional study, the relation between serum IGF-I and gonadal hormones with bone mineral density (BMD) was examined in community-dwelling men.

CONCLUSION: These data support the hypothesis that the age-related decline in bone mass in men is associated with declining levels of IGF-I and testosterone.

I know this doesn’t relate directly to gene expression but if one becomes androgen resistant then that is the equivalent of a lower testosterone may lead to bone problems.

ncbi.nlm.nih.gov/pubmed/20050857

Association of vitamin D status with serum androgen levels in men.

OBJECTIVE: Studies in rodents indicate a role of vitamin D in male reproduction, but the relationship between vitamin D and androgen levels in men is largely unexplored. We aimed to investigate the association of 25-hydroxyvitamin D [25(OH)D] levels with testosterone, free androgen index (FAI) and SHBG. Moreover, we examined whether androgen levels show a similar seasonal variation to 25(OH)D.

RESULTS: Men with sufficient 25(OH)D levels (> or =30 microg/l) had significantly higher levels of testosterone and FAI and significantly lower levels of SHBG when compared to 25(OH)D insufficient (20-29.9 microg/l) and 25(OH)D-deficient (<20 microg/l) men (P < 0.05 for all). In linear regression analyses adjusted for possible confounders, we found significant associations of 25(OH)D levels with testosterone, FAI and SHBG levels (P < 0.05 for all). 25(OH)D, testosterone and FAI levels followed a similar seasonal pattern with a nadir in March (12.2 microg/l, 15.9 nmol/l and 40.8, respectively) and peak levels in August (23.4 microg/l, 18.7 nmol/l and 49.7, respectively) (P < 0.05 for all).

CONCLUSION: Androgen levels and 25(OH)D levels are associated in men and reveal a concordant seasonal variation. Randomized controlled trials are warranted to evaluate the effect of vitamin D supplementation on androgen levels.

#254

ncbi.nlm.nih.gov/pubmed/19820295

The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome.

Insulin resistance (IR) is one of the common features of the polycystic ovary syndrome (PCOS), and recent studies indicate the possible role of vitamin D in the pathogenesis of IR and glucose metabolism. Aim of this study was aimed to determine the effect of vitamin D replacement therapy on glucose metabolism, insulin, and androgen levels in obese, insulin-resistant women with PCOS. Eleven women with PCOS were included in the study. Mean age of the patients was 23.6+/-5.7 yr, body mass index 33.9+/-5.1 kg/m(2). Six patients (54.5%) had acantosis nigricans and 10 (90.9%) oligoamenorrhea. The mean Ferriman Gallwey score was 14.1+/-4.6. Only 2 women were within the normal limits of vitamin D levels as >20 ng/ml. Three weeks after the administration of the single dose of 300,000 units of vitamin D3 orally, 25-hydroxyvitamin D3 significantly increased from 16.9+/-16 ng/ml to 37.1+/-14.6 ng/ml (p: 0.027) and only 2 women were detected to have vitamin D3 levels <20 ng/ml. Although glucose and insulin levels were decreased non-significantly, homeostasis model assessment (HOMA)-IR significantly decreased from 4.41+/-1.38 to 3.67+/-1.48 (p: 0.043). No significant alterations were witnessed at the levels of DHEAS, total and free testosterone, androstenedione. No correlation was found between vitamin D with HOMA and other hormonal parameters. In conclusion, women with PCOS have mostly insufficient vitamin D levels, and vitamin D replacement therapy may have a beneficial effect on IR in obese women with PCOS.

#255

asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=73&abstractID=30745

Effect of dietary vitamin D on androgen responsiveness and prostate carcinogenesis murine models.

Our studies support the hypothesis that low dietary vitamin D has a stimulatory effect on the early stages of prostate carcinogenesis in vivo by modulating the procarcinogenic effects of testosterone.

encognitive.com/files/Interactions%20Between%20Vitamin%20D%20and%20Androgen%20Receptor%20Signaling%20in%20Prostate%20Cancer%20Cells.pdf

Interactions Between Vitamin D and Androgen Receptor Signaling in Prostate Cancer Cells

In an analysis of 1,25(OH)2D ac- tion in LNCaP cells, we found that an androgen-induced gene that inhibits cell growth (AS3/APRIN) was also induced by 1,25(OH)2D.

My thoughts on vitamin D is that it seems high vitamin D levels are an indicator of high androgen levels. Supplementing with it may help

ncbi.nlm.nih.gov/pubmed/21154195 - Our results suggest that vitamin D supplementation might increase testosterone levels.

onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2009.05227.x/abstract

The nuclear receptor superfamily of steroid hormones and vitamin D gene regulation

Nuclear receptors bind to chromatin and seed formation of complexes comprising coregulators at the hormone response element. Nuclear receptors and coregulators can mediate chromatin remodeling, epigenetic modification, and ultimately gene expression. Chromatin immunoprecipitation has shown that nuclear receptors bind to chromatin throughout the genome, often at locations distant from the transcription start site. New findings related to the regulation of key vitamin D target genes in intestine and bone as well as nonclassical actions of 1,25-dihydroxyvitamin D3[1,25(OH)2D3], including effects on breast cancer cells and on the immune system, are discussed. These studies will form the basis for future studies examining global networks regulated by the vitamin D receptor. It is becoming increasingly recognized that the actions of 1,25(OH)2D3, similar to those of other steroids, is complex, involving regulation of gene activity at a range of locations.

Must be noted that androgen receptor is a nuclear receptor. Another thing i have noted is most of these papers are very recent. Within last year. Now increasing levels of testosterone whilst it may provide some symptom relief has not given prolonged relief in many. Again this points to receptors and not hormones.

#256

ncbi.nlm.nih.gov/pubmed/20977699

Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats.

Abstract
BACKGROUND: The steroid hormone testosterone has been found to be greatly reduced by opioids in different experimental and clinical conditions. The purpose of this study on male rats was to determine the effects of a single injection of morphine (5 mg/Kg) on persistent pain (formalin test) and the single or combined effects on p450-aromatase and 5-alpha reductase type 1 mRNA expression in the brain, liver and testis. Testosterone was determined in the plasma and in the brain, morphine was assayed in the plasma.

RESULTS: In the morphine-treated rats, there were increases of 5-alpha reductase mRNA expression in the liver and aromatase mRNA expression in the brain and gonads. Morphine was detected in the blood of all morphine-treated rats even though there were no clear analgesic affects in the formalin-treated animals three hours after treatment. Testosterone was greatly reduced in the plasma and brain in morphine-treated subjects.

CONCLUSIONS: It appears that morphine administration can induce long-lasting genomic effects in different body areas which contribute to the strong central and peripheral testosterone levels. These changes were not always accompanied by behavioral modifications.

#257

ncbi.nlm.nih.gov/pmc/articles/PMC424493/

Circulating dihydrotestosterone may not reflect peripheral formation.

We compared the blood (PBDHT) and urine (PUDHT) production rate of dihydrotestosterone (DHT) in normal men and women to determine whether peripheral formation was totally reflected in blood. PBDHT was similar when measured at both sites in men (674 +/- 79 vs. 788 +/- 207 SE micrograms/d); however, PUDHT was greater than PBDHT in women (174 +/- 55 vs. 55 +/- 8 micrograms/d, P less than 0.02). Excretion rates of DHT and 3 alpha-androstanediol (3 alpha diol) were similar in both sexes despite major differences in blood levels. However, between sexes large differences were present in 3 alpha diol glucuronide (3 alpha diolG) in both plasma and urine. These observations indicate that peripheral (renal) formation of DHT and probably 3 alpha diol were not accurately determined by measurement of these steroids in blood. The large difference between blood and urine production rates in women suggests an important role of non-testosterone precursors of 5 alpha-reduced steroids. Measurements of 3 alpha diolG may provide more insight into these peripheral events.

#258

ncbi.nlm.nih.gov/pubmed/15094514

Anticonvulsant activity of the testosterone-derived neurosteroid 3alpha-androstanediol.

3alpha-Androstanediol is synthesized from testosterone in peripheral tissues and in the brain, but the clinical importance of this neurosteroid remains unclear. This study evaluated the effects of 3alpha-androstanediol on seizure susceptibility in mouse models of epilepsy. 3alpha-Androstanediol protected mice against seizures induced by GABAA receptor antagonists pentylenetetrazol, picrotoxin, and beta-carboline ester in a dose-dependent fashion. However, 3alpha-androstanediol was inactive against seizures induced by glutamate receptor agonists kainic acid, NMDA and 4-aminopyridine. Pretreatment with the androgen receptor antagonist flutamide had no effect on seizure protection by 3alpha-androstanediol. These results suggest that 3alpha-androstanediol has powerful anticonvulsant activity that occurs largely through non-genomic mechanisms. Testosterone-derived 3alpha-androstanediol might be an endogenous protective neurosteroid in the brain.

nature.com/jid/journal/v119/n5/pdf/5601659a.pdf

Cutaneous androgen metabolism: basic research and clinical perspectives.

The skin, especially the pilosebaceous unit composed of sebaceous glands and hair follicles, can synthesize androgens de novo from cholesterol or by locally converting circulating weaker androgens to more potent ones. As in other classical steroidogenic organs, the same six major enzyme systems are involved in cutaneous androgen metabolism, namely steroid sulfatase, 3beta-hydroxy-steroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, steroid 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase, and aromatase. Steroid sulfatase, together with P450 side chain cleavage enzyme and P450 17-hydroxylase, was found to reside in the cytoplasm of sebocytes and keratinocytes. Strong steroid sulfatase immunoreactivity was observed in the lesional skin but not in unaffected skin of acne patients. 3beta-hydroxysteroid dehydrogenase has been mainly immunolocalized to sebaceous glands, with the type 1 being the key cutaneous isoenzyme. The type 2 17beta-hydroxysteroid dehydrogenase isoenzyme predominates in sebaceous glands and exhibits greater reductive activity in glands from facial areas compared with acne nonprone areas. In hair follicles, 17beta-hydroxysteroid dehydrogenase was identified mainly in outer root sheath cells. The type 1 5alpha-reductase mainly occurs in the sebaceous glands, whereby the type II isoenzyme seems to be localized in the hair follicles. 3alpha-hydroxysteroid dehydrogenase converts dihydrotestosterone to 3alpha-androstanediol, and the use of 3alpha-androstanediol glucuronide serum level to reflect the hyperandrogenic state in hirsute women may be a reliable parameter, especially for idiopathic hirsutism. In acne patients it is still controversial if 3alpha-androstanediol glucuronide or androsterone glucuronide could serve as suitable serum markers for measuring androgenicity. Aromatase, localized to sebaceous glands and to both outer as well as inner root sheath cells of anagen terminal hair follicles, may play a “detoxifying” role by removing excess androgens. Pharmacologic development of more potent specific isoenzyme antagonists may lead to better clinical treatment or even prevention of androgen-dependent dermatoses.

#259

I found these posted elsewhere on the forum

endotext.org/male/male2/male2.htm

[b]Acquired androgen insensitivity may occur without AR mutations by mechanisms such as drugs including non-steroidal (flutamide, bicalutamide, nilutamide) and steroidal (cyproterone acetate), drugs that block part of testosterone activation such as 5α reductase inhibitors (finasteride, dutasteride) or estrogen antagonists or aromatase inhibitors.

In addition, drugs may have physiological effects or pharmacological actions that oppose various steps in androgen action such as LH and FSH suppression by estrogens or progestins or that cause an increase in circulating SHBG which may influence testosterone transfer from blood into tissues to produce a functional phenocopy of androgen insensitivity.[/b]

An acquired insensitivity without a genetic reason must be founded upon epigenetic grounds.

Also look at:

viewtopic.php?f=8&t=512

The authors also showed, in another experiment, that finasteride markedly inhibited PSA secretion and expression while the level of AR was dramatically decreased (28)."

#260

Andersen ML, Guindalini C, Santos-Silva R, Bittencourt LRA, Tufik S. Androgen Receptor CAG Repeat Polymorphism Is Not Associated with Erectile Dysfunction Complaints, Gonadal Steroids and Sleep Parameters: Data from a Population-Based Survey. J Androl:jandrol.110.012013. Androgen Receptor CAG Repeat Polymorphism Is Not Associated with Erectile Dysfunction Complaints, Gonadal Steroids and Sleep Parameters: Data from a Population-Based Survey – Andersen et al., 10.2164/jandrol.110.012013 – Journal of Andrology

Erectile dysfunction (ED) can be affected by androgen levels, which exert their action through the androgen receptor (AR). Androgenic action has been demonstrated to inversely correlate with a polymorphic trinucleotide CAG repeat region in the AR gene.

Objectives: We conducted an epidemiologic study to determine the potential association between the CAG repeat polymorphism of the AR gene and ED complaints, gonadal steroids and sleep parameters in a large population-based sample in Sao Paulo, Brazil.

Findings: AR CAG repeat was genotyped in 79 cases in which men had ED complaints and in 340 controls. Sleep and hormonal profiles were measured in all men. There was no association between the AR CAG repeat polymorphism and ED complaints. Moreover, there was no significant correlation among free and total testosterone, estradiol, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels as well as sleep parameters with the CAG repeat length, when evaluating the population as a whole, as well as subdivided into ED and control groups independently. The results were not affected when the data was analyzed in quartiles, divided by the median of the sample, or after correction for population stratification.

Conclusions: AR CAG repeat polymorphism is not associated with ED complaints, gonadal steroids and sleep parameters in men from a population-based sample in Brazil.

Read more from the MESO-Rx Steroid Forum at: forum.mesomorphosis.com/steroid-forum/androgen-receptor-134293581.html#ixzz1AINO0oY7