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Treatment for androgen receptor mutation and thus androgen insensitivity involves supraphysiological doses of androgen (T or DHT) -- but may not work in all cases.


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Note: NOT WORK SAFE photo of reduced penile size


Response to androgen treatment in a patient with partial androgen insensitivity and a mutation in the deoxyribonucleic acid-binding domain of the androgen receptor.

http://jcem.endojournals.org/cgi/content/full/83/4/1173


Supplemental androgen therapy has enhanced virilization in only a few patients with partial androgen insensitivity (PAIS). We herein report on virilization in a patient with PAIS and a point mutation in the DNA-binding domain of the androgen receptor. At the age of 19 yr, the patient sought medical attention because of undervirilization. Endocrine findings were typical for androgen insensitivity, but 5-reductase activity and androgen binding characteristics in fibroblasts cultured from genital skin were normal. In an attempt to improve virilization, high dose testosterone enanthate treatment (250 mg by im injection once a week) was begun. After 3.5 yr of this treatment, marked promotion of virilization was achieved, i.e. lowering of voice, male pattern secondary hair distribution, marked growth of beard and coarse body hair, increase in phallic size, increase in bone mineral density, and decrease in mammary gland size. In addition, serum lipid levels were not affected. To our knowledge this is the first documentation of successful treatment in a patient with PAIS and a point mutation in the DNA-binding domain of the androgen receptor.


"... Furthermore, cotransfection assays with an androgen-responsive reporter gene revealed a diminished trans-activation property of these mutated AR at an androgen concentration of 3 x 10-11 mol/L, which could be overcome by higher androgen levels "

"... Our patient responded well to androgen therapy. This response was marked not only with respect to muscle bulk and sexual hair development, but external genital growth was also favorably affected. Stretched penile length increased by 40% from 5.5 to 7.5 cm, a value somewhat below (17), respectively within the lower limit of normal (18). Libido, which had been nonexistent before therapy, developed normally, and the patient now reports regular intercourse. In addition, lipid levels remained unaffected. "

"Thus, androgen therapy not only may be useful in PAIS individuals with androgen receptor gene mutations in the ligand-binding domain associated with defective androgen binding, but in some instances may also be successful in patients with mutations in the DNA-binding domain of the androgen receptor, presumably not affecting androgen binding to the receptor"

"... At this point it is of interest that recently the effect of long term (5-yr) high dose androgen treatment in another patient with a mutation in the DNA-binding domain of the androgen receptor at position 608 (Arg to Lys) directly beside the mutation found in our patient has been reported (15). However, in contrast to our patient, long term treatment with testosterone and its analogs over many years had no effect. He was reported to have a limited clinical response to extremely high doses of testosterone (500 mg, three times a week), which resulted in an increase in libido, more frequent erections, and the production of penile discharge during sexual arousal. The reason for the discrepancy between these two patients remains unclear. "

"The same mutation (Arg607Gln) found in our patient has also been detected in the androgen receptor of two brothers with AIS, who displayed clinical symptoms of Reifenstein’s syndrome, i.e. penoscrotal hypospadias and microphallus at birth (19). At the age of 55 and 75 yr, respectively, both patients developed breast cancer, a rare disease in men (20). In addition, a third patient with PAIS (hypospadias, microphallus, and gynecomastia) due to a mutation in the neighboring codon (Arg608Lys) developed breast cancer (21, 22). Two main hypotheses have been proposed to explain breast cancer development associated with the androgen receptor mutations found in these men. First, prolonged abnormal sex steroid exposure of the epithelium of the mammary gland, i.e. loss of the protective effect of androgens due to a defective androgen receptor in favor of estrogens, could eventually trigger malignancy. Second, the mutated androgen receptor itself could activate estrogen-regulated genes through binding to estrogen-responsive elements and in this way cause cancer.

As mentioned, our patient developed gynecomastia at puberty. Thus, we have monitored the patient’s mammary gland size, performing a mammography before and after 2 and 3 yr of treatment. Interestingly, a marked decrease in mammary gland size was achieved with therapy. A possible explanation for this outcome is that the deficient action of androgen (in the presence of a normal response to estrogen) on the epithelium of the mammary gland was partially reversed by high dose androgen treatment and thus might be protective against prolonged abnormal estrogen exposure. However, at the moment we do not know the long term effect of this therapy with respect to the development of mammary cancer in men with mutations of the androgen receptor. Consequently, regular examinations of the breasts during high dose androgen therapy for AIS are necessary.

In conclusion, to our knowledge no clear and general applicable parameter or functional test is available to predict the outcome of androgen treatment in PAIS patients. Our results indicate that even in the case of a mutation in the DNA-binding domain of the androgen receptor, high dose testosterone therapy might be successfully instituted and thus appears to be warranted for a limited period of months to decide whether long term treatment should be continued. It is clear that thorough clinical monitoring is mandatory. "



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Analysis of a Mutant Androgen Receptor Offers a Treatment Modality in a Patient with Partial Androgen Insensitivity Syndrome

http://content.karger.com/ProdukteDB/pr ... ?Doi=19540

Objectives: In male pseudohermaphroditism patients, we have detected androgen receptor (AR) gene mutations as the underlying molecular defect. The properties of these mutant receptors regarding hormone binding and transactivation were characterized. In a newborn patient with partial androgen insensitivity syndrome caused by an AR gene point mutation, the functional analysis of the mutated AR offers a possible treatment modality.

Methods: Specific binding of dihydrotestosterone in the patient's genital skin fibroblasts, thermostability, and 5-reductase activity were evaluated. Furthermore, an AR gene mutation was detected by direct sequencing. The ability of the mutant receptor to activate androgen-responsive elements in the DNA was determined by recreating an AR expression vector and cotransfection experiments.

Results: The newborn patient with partial androgen insensitivity showed a qualitative and quantitative binding defect. A point mutation in the ligand binding domain was identified as the underlying cause. Transactivation assays demonstrated that increasing androgen concentrations can restore the function of the mutated receptor completely. Therefore, the patient received androgen stimulation which resulted in good growth of his external genitalia and underwent surgical correction in the male direction.

Conclusions: Diagnosis and therapy in affected patients will be improved identifying the molecular mechanisms that cause the various forms of sex ambiguity. Exact characterization of AR activation and function may offer a possible treatment modality in patients with the androgen insensitivity syndrome. Our results led to a surgical correction of our newborn patient in the male direction.



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Studies of androgen receptor gene mutations in patients phenotypically ranging from complete androgen insensitivity to men with preserved fertility

http://diss.kib.ki.se/2000/91-628-4365-6/

"... Partial forms of AIS present as varying degrees of undermasculinization, ranging from a predominantly female phenotype to boys with genital malformations, such as hypospadias or cryptorchidism. It has also been speculated, that subtle androgen receptor defects could cause impaired spermatogenesis without genital malformations. In the present work 13 missense mutations are described, identified in the AR gene of patients phenotypically ranging from complete androgen insensitivity to men with preserved fertility at the other end of the spectrum. The functional properties of 10 mutations have been characterized, using the approaches of site-directed mutagenesis, transient expression in COS-1 cells, and transactivation assays using an androgen sensitive reporter gene. Hormone binding assays in transfected COS-1 cells and genital skin fibroblasts from some patients were also performed."

"...With a few exceptions, the degrees of impairment of mutant ARs in vitro were roughly in agreement with the severity of symptoms seen in the patients. Mutation A596T was an exception. A596T was functionally normal at high concentrations of androgens in vitro, although it was found in two newborns with PAIS. In accordance with this finding, treatment of the two boys with high doses of androgens resulted in a positive response.

"... In both men, in vitro studies showed reduced transactivational capacity as compared to wild type AR. The patient carrying the N233K mutation displayed additional symptoms not generally seen in patients with AIS; he suffered from musculoskeletal and urogenital pain. He reported a remarkable relief upon high-dose androgen treatment. We speculate, that these symptoms result from abnormal protein- protein interactions arising as a consequence of the mutation, which is located in the transactivating domain of the AR where very few mutations previously have been found."


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Response to local dihydrotestosterone treatment in a patient with partial androgen-insensitivity syndrome due to a novel mutation in the androgen receptor gene

http://www3.interscience.wiley.com/jour ... 8/abstract

-- Anyone have access to PDF?

I believe I have stated this. I have always believed that some responsible TRT combined with PCT at the same time could be very beneficial to all of us. "Get things moving back in the right direction, and functioning properly again for a sustained period of time."

Mew, what does it say about sustained functionality upon cessation of this longterm TRT?

Not sure Boston, don't recall them following up, also not sure if this treatment is for life or for a certain period of time, wether that would "correct" the issue... I would guess it's a lifetime thing.

I have understood that it is just for a period of time, to restore function, not for life.

Could be... if I come across more studies that say either way, I'll post them.

Guys, please look at this study above...This maybe of value here....

but long term TRT will shutdown your own HPTA? so do TRT and clomid or Nolva at the same time?
I could not understand whole idea, it is to heavy for me to digest.

Mew did you find more study yet about Androgen Receptor mutation, androgen insensitivity syndrome --

This matches up rather well with Dr. Crisler's experiences treating men with Post-Propecia Syndrome. He has said that it is often necessary to raise testosterone to supraphysiological levels in order to obtain any tangible benefits (this is second-hand info: I forget at this point where I read this).

This reinforces my decision to go on TRT. I believe that this is likely the only effective treatment for men like myself who have been dealing with PPS for many years.

http://www.endocrine-abstracts.org/ea/0 ... 003p36.htm

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Efficacy and Safety of High Dose Testosterone Therapy in Partial Androgen Insensitivity

S. Bandyopadhyay, W.A.Watson, C. M.Park, P. Abraham, S. Philip, S. Acharya , J.S. Bevan. Department of Endocrinology, Aberdeen Royal Infirmary, Aberdeen, AB25 2ZN.


INTRODUCTION: There have been few reports of the efficacy and safety of high dose androgen therapy in men with partial androgen insensitivity (PAI). We report on the responses of a patient carrying an androgen receptor (AR) mutation predicted (in vitro) to be overcome by high testosterone (T) concentrations.


CASE REPORT: This 29 year old patient had ambiguous genitalia at birth but was found to be 46 XY. He had a small, hypospadiac penis with underdeveloped bifid scrotum. There was no significant family history. After puberty he developed female secondary sexual characteristics. He responded poorly to low dose exogenous androgen and underwent multiple genital reconstructive operations. He was then lost to follow up.

On representation in Aberdeen at the age of 27 years his T was 38nmol/l, FSH 3.7u/l, LH 12u/l and oestradiol 240pmol/l. He commenced Sustanon IM weekly injections, initially 250mg for 2 months and then 500mg for 2 years. He has shown significant increase in libido, development of facial and body hair and deepening of voice. His current T is 120nmol/l, FSH 1u/l, LH 3.6u/l and oestradiol 170pmol/l. Lipid profile and haematocrit have remained normal throughout.


DISCUSSION: He was previously shown to have a Serine to Glycine substitution at position 703 in exon D of the androgen receptor ( Prof. I.A.Hughes, Cambridge).

We have demonstrated the in-vivo efficacy of pharmacological doses of testosterone in overcoming this AR defect. Significant falls in LH/FSH confirmed negative feedback at pituitary level. High dose Sustanon was well-tolerated with no adverse changes in cardiovascular risk factors.

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Has this study been posted anywhere?

http://www.jci.org/articles/view/111563/files/pdf

The below is very exciting and promising, as it points to the fact that individualized treatment and reversal of certain variations of androgen insensitivity in patients is possible, based on newly developed diagnostic techniques ("high content analysis (HCA)") and resultant tailored treatments.

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2009 - Androgen Receptor Mutations Associated with Androgen Insensitivity Syndrome: A High Content Analysis Approach Leading to Personalized Medicine

Online: http://www.plosone.org/article/info:doi ... ne.0008179

PDF: http://www.plosone.org/article/fetchObj ... tation=PDF

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"Androgen insensitivity syndrome (AIS) is a rare disease associated with inactivating mutations of AR that disrupt male sexual differentiation, and cause a spectrum of phenotypic abnormalities having as a common denominator loss of reproductive viability. No established treatment exists for these conditions, however there are sporadic reports of patients (or recapitulated mutations in cell lines) that respond to administration of supraphysiologic doses (or pulses) of testosterone or synthetic ligands. Here, we utilize a novel high content analysis (HCA) approach to study AR function at the single cell level in genital skin fibroblasts (GSF). We discuss in detail findings in GSF from three historical patients with AIS, which include identification of novel mechanisms of AR malfunction, and the potential ability to utilize HCA for personalized treatment of patients affected by this condition"


"...varyingly degrees of impaired AR action from mutation is causative in individuals affected by androgen insensitivity syndrome (AIS) [1],1 [2]. Three main clinical phenotypes in humans define AIS: Complete, Partial and Minimal Androgen Insensitivity (CAIS, PAIS and MAIS), and they range from complete lack of virilization of the internal and external genitalia (CAIS), to intermediate virilization (PAIS), to apparently normal virilization in infertile males (MAIS)."


"... A data-base of AR mutations in AIS patients is published on-line (http://androgendb.mcgill.ca/), and a large body of previous work has defined three broad varieties of AR 3H-DHT binding abnormalities in monolayer binding analyses:

1) absent binding (i.e. 3H-DHT binding is undetectable) [3];

2) qualitatively abnormal binding [e.g., binding is normal but with qualitative abnormalities such as increased ligand dissociation rate (the dissociation rate is considered abnormal if <60% of the specific androgen binding remains after 3 hours) [4]; or thermolability (defined as a reduction in specific androgen binding at 41°C compared to 37°C of greater than 40%) [5]]; or,

3) decreased binding (e.g., binding is detectable but below normal) [1]. The degree of abnormality caused by each individual mutation is usually related to the patient phenotype, the 3H-DHT binding characteristics, and the amount of residual reporter gene activity present in cells transfected with an AR carrying that particular mutation; in general, in the more feminized phenotypes, lack of 3H-DHT binding and abnormal transcriptional activity parallel increasing AR malfunction."


"... Despite the clinical dogma that “AIS is not treatable,” some sporadic PAIS and MAIS patients respond to endocrine management consisting of pharmacologic doses of androgens [6]–[9]. Further, in vitro analysis of some AR mutations with the binding phenotype of normal 3H-DHT dissociation constant (Kd) and maximal binding (Bmax), but increased ligand-receptor dissociation rate can be normalized under certain culture conditions.

For instance, such an AR containing a single amino acid substitution (Y763C) and a reduced polyglutamine tract (Q12) normalized its transcriptional activity when exposed to pharmacologic concentrations of androgens both in vitro [10] and in vivo [6]. In other such CAIS or PAIS mutations, transcriptional activity normalized either after administration of supraphysiologic concentrations of endogenous androgens (e.g., testosterone or dihydrotestosterone, DHT), synthetic androgens (Mibolerone or R1881), or after treatment with frequent pulses (up to every four hours) of physiologic doses of DHT."


"Our group has recently developed a high throughput microscopy-based technology to simultaneously analyze multiple AR activities at the single cell level, an approach often referred to as high content analysis (HCA). Our AR-oriented HCA involves multi-parametric interrogation of cultured cells using automated high magnification, high resolution imaging and immunofluorescence or green fluorescent protein-fused AR (GFP-AR) in combination with use of a red fluorescent protein-based transcriptional reporter protein [14]–[17]. Utilizing custom-developed image analysis routines, the datasets can be quantitatively explored to yield a “multiplex” view of interrelated AR functions. The image data mining yields information including (but not limited to) AR expression, subcellular trafficking, reporter gene activity, cell cycle position, mitotic index, and literally hundreds of other measurements per cell [15].

We theorized that HCA of AR would be an ideal technology to directly analyze patient-derived genital skin fibroblasts to identify not only mechanisms associated with abnormal AR activities, but also therapeutic options normalizing mutant AR functions. While there are many AIS mutations described, those localized in the LBD and associated with 1) normal Kd, 2) normal Bmax, and 3) qualitative abnormalities of ligand-receptor interaction would be the most amenable to normalization. We present here unique cytological profiles generated by HCA from three historical patients affected by CAIS or PAIS, which were complemented by NH2-COOH-terminal domain interaction (NC-TDI) experiments, and previously published ligand-binding studies [11]. All patients carried AR mutations with the specifications listed above. HCA revealed the type of functional defects associated with these mutations, and ligand-dependent restoration of AR functions using experimental conditions that increase the stability of the ligand receptor complex in two of the three patients. Normalization of AR function was associated in each case with improvement of NC-TDI. These studies provide a proof-of-concept demonstration that specific clinical mutations of AR can be examined by HCA for use in personalized medicine."


"...We hypothesized that AR point mutations localized in the ligand binding domain and associated with normal 3H-DHT Bmax and Kd may be reversible, and proved this by using the new AR HCA technology and conventional assays, such as NC-TDI. HCA not only proved to be a powerful tool to understand the functional abnormalities of AR mutations directly in patient-derived specimens, but was also utilized to predict clinical responses to a variety of experimental treatments."


"... More studies are needed with additional cell lines before direct translation into clinical practice. Safety will be an important issue, particularly for the synthetic agonists, which are not FDA-approved. The CAIS phenotype of patients AR-P766S and AR-F764L argues against treating these patients, because 100% of them reared as females maintained throughout life a female gender identity [41]. Nevertheless, the prediction is that significant virilization may have occurred after observing the in vitro response of AR-P766S and AR-F764L. PAIS patients would clearly be the first beneficiaries of this technology... "

"...In conclusion, this work represents a step forward toward the utilization of modern high-speed microscopic techniques for the diagnosis and treatment of diseases related to AR. It will be interesting to expand these studies to include evaluation of more global effects of AR rescue using different concentrations of ligand, or with ligands other than the endogenous AR agonists. Future investigation will continue to analyze AR malfunction in AIS and other clinical conditions, such as prostate cancer, hypospadias, cryptorchidism and sarcopenia."

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This is defiantly exciting... but it would be even better if just one of our members could actually be tested and be shown to be androgen insensitive. So far, none have. (please tell me if i am incorrect). I know goldstein proposes this, but so far, there is no data confirming this.

I also think that we should and would all have high or normal levels of adiol-g (because we were going bald, because of our age) if androgen insensitivity / receptor defects were truly the issue - but so far the testing shows that the majority of members, with the exception of mercatu, all have low values. Perhaps his issues lies somewhere else.

Anyway, good news none the less.

To reiterate what Golf has said, there seem to be too many supporters of the AIS theory. (In my opinion). If AIS proves to be the main cause of our suffering, then yes, the above literature shows some promise.

JN

OMG this is SO PROMISING...Guys, we need to act on this quick and see who can do the tests on us.... THIS SHOULD BE A PRIORITY!

anon -
http://www.geneclinics.org/servlet/acce ... M&qry=2575

Mew, can you post this on dr. crisler board...this could explain why supraphyiological testosterone works well with his patients...

They state this new test "high content analysis (HCA)" is not available yet:

"More studies are needed with additional cell lines before direct translation into clinical practice. Safety will be an important issue, particularly for the synthetic agonists, which are not FDA-approved"

However, it is still possible to check for certain issues with androgen receptor binding, mutation etc per the link golf17331 provided.

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What possibilities does this potentially offer? I can't understand or am too fogged to pick up the nuances of the study?

Could it potentially help with muscle growth, erections via tailored TRT?

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Article on high content analysis:
http://www.bcm.edu/news/item.cfm?newsID=1623


Hi-tech microscopes make androgen therapy 'personal'

RSS icon HOUSTON -- (December 9, 2009) -- On rare occasions, an infant is born with outward appearance of a female but the XY chromosomes of a male. If the child has a normal Y chromosome -- the chromosome responsible for testicular development -- the condition is known as androgen insensitivity syndrome.

Experts estimate such births occur in about one in 20,000 infants. Other children are born with a partial form of the condition that can affect their genitalia and/or fertility, but how many is not known.

The cause is a wide range of androgen receptor (AR) mutations that fail to perceive the presence of the male hormones testosterone and dihydrotestosterone to differing degrees. How to overcome the problem remained a mystery until Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center experts used a high throughput, automated microscopy technique called high content analysis to solve the puzzle. A report of their findings appears in the current issue of PLoS One, an open access journal.
Reverse effect of mutation

They not only identified the functional abnormality of the AR, but also used high content analysis to "personalize" a treatment that reverses the effects of that mutation.

"With this microscopy technique, we have been able to quantify how the receptor moves and functions inside cells taken from children with normal receptors and in those with the mutation," said Dr. Marco Marcelli, professor of medicine-endocrinology at BCM and a physician at the Michael E. DeBakey Veterans Affairs Medical Center. He and Dr. Michael Mancini, associate professor of molecular and cellular biology at BCM, and director of its Integrated Microscopy Core, are senior authors of the report.
Androgen insensitivity syndrome

They used banked cells taken from patients – both those with the mutation and those without – to study the action of the receptor in cell cultures grown in the laboratory. Dr. Michael J. McPhaul, a collaborator on the study and a professor of internal medicine—endocrinology at The University of Texas Southwestern School of Medicine Dallas, provided the samples from patients with androgen insensitivity syndrome.

"We did this on a cell-by-cell basis, using high content analysis," said Mancini. "It is a proof-of-principle study carried out as though we had a patient and a library of hormones. We tried to find the perfect hormone for the mutation through high-speed collection of dozens of measurements from thousands of cells."

"In two of the three specimens we tested, we found we were able to reverse the activity of the mutated receptor to almost normal," said Marcelli.

In one patient, large doses of the male hormone dihydrotestosterone were sufficient. In another, they used a synthetic androgen that also activated the receptor.

These approaches overcame the central problem – the mutation changes the shape of the receptor and prevents it from maintaining normal contact with the hormone. It is as though a key is bent and can no longer turn the tumblers in a lock. In these cases, the hormone is designed to go into a pocket created by the receptor. When the pocket is changed by the mutation, the hormone is unable to establish good contact.

"Large amounts of testosterone may create more stable contact," said Marcelli. "The synthetic androgen may have a conformation that establishes better contact."
Superandrogen

In the future, scientists may be able to screen large banks of such compounds to find a "superandrogen" that may be even more efficient.

"We might be able to use this technique to create a personalized medicine test," said Mancini.

Similar techniques might be used to screen drugs for treatment of different cancers, particularly those in which the androgen receptor is responsible for cancer progression. This study proves that the concept is valid providing quantitative information collected quickly on numerous measurements normally requiring separate biochemical tests and huge numbers of cells.

Marcelli said they have yet to use this kind of technique in patients, and such studies will require careful preparation, and go through a variety of approvals before it can be used in clinics. He also said it would be used only in individuals with the partial form of the syndrome. Finding well-matched hormones to defective androgen receptors through screening of thousands of compounds from available libraries could be one of the future developments of this technique.

The paper's first author, Dr. Adam T. Szafran, an M.D./Ph.D. student who worked in Mancini's laboratory, championed these studies, said Mancini. Szafran is now finishing the clinical part of his studies at BCM.

Others who took part in this study include Drs. Sean Hartig and Ivan P. Uray, Maria Szwarc, Jennifer Bell, Huiying Sun, Yuqing Shen and Sanjay N. Mediwala, all of BCM. Sun, Shen and Mediwala are also of the MEDVAMC.

Funding for this work came from the National Institute of Diabetes and Digestive and Kidney Diseases, the John S. Dunn Foundation and the Veterans Administration.

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