Treatment for androgen receptor mutation and thus androgen insensitivity involves supraphysiological doses of androgen (T or DHT) – but may not work in all cases.
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.
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. "
Analysis of a Mutant Androgen Receptor Offers a Treatment Modality in a Patient with Partial Androgen Insensitivity Syndrome
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.
Studies of androgen receptor gene mutations in patients phenotypically ranging from complete androgen insensitivity to men with preserved fertility
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.”
Response to local dihydrotestosterone treatment in a patient with partial androgen-insensitivity syndrome due to a novel mutation in the androgen receptor gene
www3.interscience.wiley.com/jour … 8/abstract
– Anyone have access to PDF?