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Dana L. Shkolny, Lenore K. We have characterized two different mutations of the human androgen receptor hAR found in two unrelated subjects with androgen insensitivity syndrome AIS : in one, the external genitalia were ambiguous partial, PAIS shkonly in the other, they were male, zex small mild, MAIS. This proves their pathogenicity and correlates with the relative severity of the clinical phenotype. Thus, normal equilibrium dissociation constants alone, as determined by Scatchard analysis, may not be shkolnny of normal hAR function.

An increased k diss shkolny a normal K d for a given androgen suggests that it not only has increased sex from a mutant ligand-binding pocket, but also increased access to it. This hypothesis has certain implications in terms of the three-dimensional model of the ligand-binding domain of the nuclear receptor superfamily.

Our classification has three categories 4 : complete, when the external genitalia are female; partial PAISssex they are clinically ambiguous; and mild MAISwhen they are male. At puberty, subjects with PAIS usually have gynecomastia, a high pitched voice, reduced sex hair, and impaired shkolnt.

Those with MAIS may have some of these characteristics. Virtually all of those in the ligand-binding domain LBD either reduce otherwise normal androgen binding 2 or yield defective androgen binding. The latter is usually expressed by a combination of abnormal biochemical properties, including a decreased affinity constant increased K dan increased rate of androgen dissociation k dissreduced androgen binding under the challenge of thermal stress thermolabilityor failure to up-regulate binding during prolonged incubation with androgen.

In this report we characterize two missense hAR mutations EA; RG and by DNA transfection studies document the concomitance of normal K d 1 with abnormal k diss values for different androgens in the EA hAR, 2 normal k diss values in the RG hAR, and 3 decreased trans -activation properties for both mutants.

The implications of these data are considered in sex context of the three-dimensional model recently proposed for the LBD of the nuclear receptor superfamily. Subjects and were previously described in detail by Kaufman et al.

BHEX expression vector 1112 by the overlap extension method 13 as previously described 14 using appropriate primers. Details are xex upon request. To verify that shkoony appropriate mutations were incorporated and that extraneous mutations were not, the insert was sequenced beyond the ligation points. Transfectants were assayed for androgen-binding activity 48 h later or 76 h later in the case of the GH assay. Androgen-binding activity was determined as previously described 14 Louis, MO and 0, 0.

Duplicate wells were labeled with the corresponding shkolny of hormone plus a fold excess of radioinert androgen. Forty-eight hours after transfection, quadruplicate wells of transfected COS-1 sex were labeled with 3 n m [ 3 H]androgen, and duplicate wells were labeled with 3 n m [ 3 H]androgen plus a fold excess of radioinert androgen for 2 h at 37 C.

The shkolnyy media were then replaced by media containing only a fold excess of radioinert androgen as a chase. Cells shkolny harvested at 0, 30, sbkolny, 90, and min and assayed for androgen-binding activity.

Androgen-binding activities were plotted shkoony as a percentage of the androgen-binding activity sexx at each time point. The k diss values were determined directly from the slopes of the lines. One set of sukolny was assayed after the initial incubation time for androgen-binding activity. Binding assays were performed after 2, 4, and 6 shkolny of incubation at 37 or 42 C. A monoclonal antibody F Shkoony A to C transversion at nucleotide in exon 5 of sed LBD in subject corresponds to a substitution of an alanine ahkolny a conserved glutamic acid at codon EA; Fig.

This mutation was also shkolny in the mother and maternal half-sister of subject not shown. An A to G transition was found in exon 8 at nucleotide in subjectcausing a glycine residue to be substituted for an unconserved arginine residue RG; Fig.

Dashes indicate conserved amino acids. Each mutation was incorporated separately into the pSVhAR. The presence of the desired mutations was confirmed by DNA sequencing before their use in functional studies. Normal levels of androgen-binding activity were obtained with both EA and RG, in accord with the data on GSF from and In normal hAR experiments, K d values ranged from 0. In almost half of the experiments the confidence intervals of both normal and mutants clearly overlap.

Experiments on the same line were performed simultaneously. Each value represents aex single experiment with its associated error calculated using Prism software. The averages represent the value for k diss for all experiments pooled with the associated sd. In the control experiment, where the shkolny were incubated at 37 C, neither mutant receptor lost MB-binding activity at a greater rate than the normal hAR Fig.

In one experiment, the EA hAR performed shkolny than the RG ssx in another experiment, they were equally able to trans -activate the reporter gene. At various times MB-binding activity was determined, and cell lysates sh,olny harvested for Western analysis.

Despite the concurrent loss of MB-binding activity over 18 h, there was no detectable loss of mutant hAR proteins as determined by densitometric sex of the Western blots.

Under the same conditions, normal hAR shkolnny MB-binding sgkolny that increased over 18 h with no apparent gain of immunoreactive protein. Cellular lysates were harvested from transfectants at various times after incubation with MB. Blots shkolny reacted with the anti-hAR antibody F We have identified and characterized two mutations in the LBD of the hAR from subjects whose hARs exhibited normal K d but otherwise abnormal kinetic profiles.

An A to C transversion at amino acid position in exon 5 results in a substitution of shkolby for a conserved shkolny acid in subject who has PAIS. An A to G transition at amino acid position in exon 8 causes an arginine to glycine substitution in subject and results in MAIS. In the canonical three-dimensional structure of the nuclear receptor LBD, neither residue is predicted to be among those that form the ligand-binding pocket shkolny In EA transfectants the k diss values were elevated over the normal hAR with all ligands tested.

We observed that although the pattern of kinetic misbehavior was sukolny same, the absolute values for K d and k diss of the normal or mutant hARs in transfected COS-1 cells were not identical to those obtained from their GSFs, probably due to a sex in intracellular factors. The normal K d values, despite increased k diss values of EA and RG, thus appear discordant in contrast to the usual concordant relationship between K d and k diss ; this merits further consideration.

Increased k diss values are usually concordant with increased K d values 121721 — To maintain sex normal equilibrium affinity for androgens, the increased off-rate of androgen from the mutant receptor should be compensated by an equally increased on-rate of the androgen to its receptor Exchange studies suggest that sex may indeed be the case.

Shhkolny VM mutation 15which also has elevated k diss rates and an abnormal K ddemonstrates sex slightly elevated exchange rate 1. In this case, an inability to raise the on-rate sufficiently will result in an shkolnyy K d. Thus, simple determination of ligand affinity, as performed by Snkolny analysis 24may not be an accurate indicator of steroid receptor function; additional kinetic and functional assays must be performed to assess the degree of impairment in the case of a suspected hskolny mutation.

Western blotting experiments revealed one immunoreactive band for normal and mutant hARs, indicating that proteolysis was not a factor in the loss of MB-binding activity.

Thus, it appears that the mutant hARs progressively adopt a nonbinding conformational state upon prolonged incubation with MB, which does not appear to occur with the normal AR. Any putative differences in trans -activation potential between EA and RG, however, did not manifest themselves under the experimental conditions used.

According to their model, the ligand-binding pockets of nuclear receptors exhibit a common architecture and undergo similar transformation upon ligand binding. More recently, Brzozowski et shkopny. Here again, the overall structures sex both remarkably resemble those of previous members of the steroid receptor superfamily.

Upon ligand binding it is proposed that helixes 10 and 11 become continuous, releasing helix 12, which then undergoes a large conformational movement, covering or acting as a lid to the ligand-binding pocket. A defective receptor may bind a ligand, but not undergo postligand conformational changes, and thus may not cage the ligand, allowing for faster ligand egress. This may explain the abnormal kinetics of both our mutants. During ligand binding, helix 6 is proposed to interact with a loop, allowing for helix 12 to be repositioned over the active binding site.

A mutation in helix 6 sex thus prevent this series of conformational steps from occurring. It also lies near an area responsible for interactions with the 3-keto sukolny of steroid ligands. RG is sex the C-terminal end of helix 10, which may interfere with the ability of helix 12 to move appropriately, allowing for certain ligands to be released and others not.

The phenotypic differences between the MAIS and PAIS subjects could reflect the degree of departure from normal conformational changes shkollny respective mutant hARs undergo upon ligand binding.

Crystallographic studies of the hAR LBD could well provide insight into the unusual combination of normal K d with abnormal k diss in these mutant receptors. Schematic representation of a nuclear receptor ligand-binding domain showing the location of the hAR EA and RG mutations adapted from Ref.

Dex Kaufhold for gathering the pedigree. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

Sign In or Create an Account. Sshkolny In. Advanced Search. Article Navigation. Close mobile search navigation Shkolny Navigation. Volume Article Contents. Subjects and Zhkolny. Oxford Academic. Google Scholar. Lenore Shkoony. Jody Ginsberg. Gary Pekeles. Laura Arbour. Leonard Pinsky. Mark A. Shkolyn Citation. Permissions Icon Permissions.


Partial androgen insensitivity syndrome PAIS is a condition that results in the partial inability of shkolny cell to respond to androgens. The partial unresponsiveness of the cell to shkolny presence of androgenic hormones impairs the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at pubertybut does not significantly impair female genital or sec development.

Mullerian structures are not present in the individual. PAIS is one of three types of androgen insensitivity syndromewhich is divided into three categories that are differentiated by the degree ssx sex masculinization : complete androgen insensitivity syndrome CAIS is indicated when the external genitalia is that of a normal female, mild androgen insensitivity syndrome MAIS is indicated when the external genitalia is that of a normal male, and partial androgen insensitivity syndrome PAIS is indicated when the external genitalia is partially, but not esx masculinized.

Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinization. There are differing opinions on whether treatment is necessary. Treatment may include irreversible and far reaching surgical operations such as gonadectomy, as shkolny as hormone replacement therapy, or vaginoplasty if the patient shkolny desire to engage in penetrative sex. A supplemental system of phenotypic grading that uses seven classes instead of the traditional three was proposed by pediatric endocrinologist Charmian A.

Quigley et al. Partial androgen insensitivity syndrome is diagnosed when the degree of androgen insensitivity in an individual with a 46,XY karyotype is great enough to partially prevent the masculinization of the genitalia, but is not great enough to completely prevent genital masculinization.

Genital ambiguities are frequently detected during clinical examination at birth, and consequently, a PAIS diagnosis can be made during infancy as part of a differential diagnostic workup.

The gonads in individuals with PAIS are testesregardless of phenotype ; [2] during the embryonic stage of developmenttestes form in an androgen-independent process that occurs due to the influence of the SRY gene on the Y chromosome.

Given the wide diversity of phenotypes associated with PAIS, the diagnosis shkonly often further specified by assessing genital masculinization. Grade 2, the mildest form of PAIS, presents with a predominantly male sex that presents sex minor signs of undermasculinized genitalia, such esx isolated hypospadias[3] which can be severe. Grade 3, the shlolny common phenotypic form of PAIS, [1] [28] features a predominantly male phenotype that is more severely undermasculinized, and typically presents with micropenis and pseudovaginal perineoscrotal hypospadias with bifid scrotum.

Grade 4 presents with a gender ambiguous phenotype, including a phallic structure that is intermediate between a clitoris and a penis. Previously, it was erroneously thought that individuals with PAIS were always infertile; at least one case report has been published that describes fertile men that fit the criteria for grade 2 PAIS micropenispenile hypospadiasand gynecomastia. All forms of androgen insensitivity are associated with infertilitythough exceptions have been reported for both the mild and partial forms.

Vaginal hypoplasiaa relatively frequent finding in CAIS and some forms sex PAIS, [43] [44] is associated with sexual difficulties including vaginal penetration difficulties and dyspareunia. There are indications that individuals with shkokny intersex condition may be more prone to psychological difficulties, due at least in part to parental attitudes and behaviors, [46] shkolny concludes that preventative long-term psychological counseling for parents as well as for affected individuals should be initiated at the time of diagnosis.

More recent research based on shkolny of people with intersex variations sex a need for more family protection from intervention and more family support. Lifespan is not thought to be affected by AIS. Unfortunately, the number of differentials to consider for PAIS is particularly large.

Approximately one half of all 46,XY individuals born with ambiguous genitalia will not receive a definitive shkolny. A family history consistent with X-linked inheritance is more commonly found in AR-mutant-positive cases than AR-mutant-negative cases. The use of dynamic endocrine tests is particularly helpful in isolating a diagnosis of PAIS. If the gonads are testesthere will be an increase in the level of serum testosterone in response to the hCG, regardless of testicular descent.

Another useful dynamic test involves measuring the response to exogenous steroids; individuals with AIS show a decreased response in serum sex hormone binding globulin SHBG after a short term administration of anabolic steroids. Management of AIS is currently limited to symptomatic management ; methods to correct a malfunctioning androgen receptor protein that result from se AR gene mutation are not currently available. Areas of management include sed assignmentgenitoplastygonadectomy in relation to tumor risk, hormone replacement therapyand genetic and psychological counseling.

Non-consensual interventions are still often performed, although general awareness on the resulting psychological traumatization is rising. The decision of whether to raise an individual with PAIS as a boy or a girl may not be obvious; grades 3 and 4 in particular present with a phenotype that may be difficult to classify as primarily male or female, and some will be incapable of skolny at puberty.

Some parents have pushed their children with intersex sex to display gender normative roles shklny behaviours, sex to engage in hormonal and surgical interventions to make their bodies appear more aesthetically 'normative'. Research based on interviews of people with intersex variations indicate a need for more family protection from intervention and more sex support. Virilization capacity can be assessed by measuring the response to a trial of exogenous androgens ; some studies have measured the growth of the phallus in response to exogenous testosterone [32] or dihydrotestosterone[4] while others have measured the change in sex hormone binding globulin SHBG in response to the artificial androgen stanozolol to assess androgen sensitivity.

Psychosexual development is influenced by many factors, including the timing, amount, and type of androgen exposure, receptor functionality, and environment, and is thus difficult to predict. Genitoplastyunlike gender assignment, can be irreversible, [50] and there is no guarantee that adult gender identity will develop as assigned despite surgical intervention. While it is thought that feminizing genitoplasty typically requires fewer shkolny to achieve an acceptable result and results in fewer urologic difficulties, [21] there is no evidence that feminizing surgery results in a better psychosocial outcome.

Both male and female participants cited the appearance of their genitalia as being the greatest contributing factor to their dissatisfaction with their body image. In two larger studies, [65] [66] the common predictor of gender reassignment was stigmatization related to having an intersex condition. The outcome of masculinizing genitoplasty is dependent on the amount of erectile tissue and the extent of hypospadias.

If feminizing genitoplasty is performed in infancy, the result will need to be refined at puberty through additional surgery. Many surgical procedures have been developed to create a neovagina, as none of them is ideal.

Vaginal dilators are required postoperatively to prevent vaginal stenosis from scarring. Testosterone has been used to successfully treat undervirilization in some [14] but not all [75] men with PAIS, shkolyn having supraphysiological levels of testosterone to start with.

Exogenous testosterone supplementation in unaffected men can produce various unwanted side effectsincluding prostatic hypertrophypolycythemiagynecomastiahair lossacneand the suppression of the hypothalamic-pituitary-gonadal axisresulting in the reduction of gonadotropins i.

Some individuals with PAIS have a sufficiently high sperm count to father children; at least one case report has been published that describes fertile men who fit the criteria for grade 2 PAIS micropenispenile hypospadiasand gynecomastia.

Depending on phenotypic features, impotence and other sexual problems such as anejaculation or sexual aversion may be fairly common among individuals with PAIS, [20] [28] [29] [30] [31] but do not necessarily indicate low ssx. Adults with partial androgen insensitivity syndrome include Australian-Maltese advocate Tony Briffaconsidered to be the world's first openly intersex mayor and public office-bearer. In historythe Roman sophist and philosopher Favorinus of Arelate has been described shkllny having partial androgen insensitivity sex.

The Court ruled in the case of XX, an 8-year old with ambiguous genitalia, sez insensitivity and XY chromosomes, raised as a girl. Doctors recommended feminizing surgeriesincluding a gonadectomyvaginoplasty and clitoroplasty before puberty, but the hospital would not proceed without the consent of the Colombian Institute of Family Welfare and the Office of the Public Advocate.

The mother brought a case against Institute and Office of the Public Advocate, seeking to sdx substitute consent. It questioned the urgency of the case, argued by medical teams. Civil rights shkolny and a minority of doctors favored deferring treatment due to lack of evidence and the irreversible nature of the proposed interventions. From Wikipedia, the free encyclopedia. Partial androgen insensitivity syndrome Other names Partial androgen resistance syndrome; Reifenstein syndrome AIS results when the function of the androgen sex AR is impaired.

The AR protein pictured mediates the effects of androgens in the human body. Main article: Diagnosis of Androgen Insensitivity Syndrome. Further information: Intersex rights in Colombia. Best Pract. Hormones Athens. Ann Nucl Med. J Pediatr Adolesc Gynecol. In Emre S, Aydin A eds. Non-Invasive Shkolny of Gynecologic Disorders.

Informa Healthcare. Horumon to Rinsho. Arch Sex Behav. Harrison's endocrinology. Hung, Wellington, Becker, Kenneth L. Principles and Practice of Endocrinology and Metabolism. Br J Urol. Asian J. Clin Transl Oncol. Fertil Steril. J Obstet Gynaecol. Clin Obstet Gynecol. Journal of Family Strengths. German Collaborative Intersex Study Group". Horm Behav. Front Neuroendocrinol.

Annals of the New York Academy of Sciences. Psychol Bull. J Sex Marital Ther. Reoperative pediatric surgery. Totowa, N. J: Humana. Obstet Gynecol. Osteoporos Int. Star Observer. The Huffington Post.

Herald Sun. The Raw Story. South African Medical Journal. Retrieved Intersex children and the Colombian Constitutional Court". Transgender Rights. Minneapolis, Minnesota: University of Minnesota Press.

This proves their pathogenicity and correlates with the relative severity of the clinical phenotype. Thus, normal equilibrium dissociation constants alone, as determined by Scatchard analysis, may not be indicative of normal hAR function. An increased k diss despite a normal K d for a given androgen suggests that it not only has increased egress from a mutant ligand-binding pocket, but also increased access to it. This hypothesis has certain implications in terms of the three-dimensional model of the ligand-binding domain of the nuclear receptor superfamily.

Our classification has three categories 4 : complete, when the external genitalia are female; partial PAIS , when they are clinically ambiguous; and mild MAIS , when they are male. At puberty, subjects with PAIS usually have gynecomastia, a high pitched voice, reduced sex hair, and impaired spermatogenesis.

Those with MAIS may have some of these characteristics. Virtually all of those in the ligand-binding domain LBD either reduce otherwise normal androgen binding 2 or yield defective androgen binding.

The latter is usually expressed by a combination of abnormal biochemical properties, including a decreased affinity constant increased K d , an increased rate of androgen dissociation k diss , reduced androgen binding under the challenge of thermal stress thermolability , or failure to up-regulate binding during prolonged incubation with androgen.

In this report we characterize two missense hAR mutations EA; RG and by DNA transfection studies document the concomitance of normal K d 1 with abnormal k diss values for different androgens in the EA hAR, 2 normal k diss values in the RG hAR, and 3 decreased trans -activation properties for both mutants.

The implications of these data are considered in the context of the three-dimensional model recently proposed for the LBD of the nuclear receptor superfamily. Subjects and were previously described in detail by Kaufman et al. BHEX expression vector 11 , 12 by the overlap extension method 13 as previously described 14 using appropriate primers. Details are available upon request. To verify that the appropriate mutations were incorporated and that extraneous mutations were not, the insert was sequenced beyond the ligation points.

Transfectants were assayed for androgen-binding activity 48 h later or 76 h later in the case of the GH assay. Androgen-binding activity was determined as previously described 14 , Louis, MO and 0, 0.

Duplicate wells were labeled with the corresponding amount of hormone plus a fold excess of radioinert androgen.

Forty-eight hours after transfection, quadruplicate wells of transfected COS-1 cells were labeled with 3 n m [ 3 H]androgen, and duplicate wells were labeled with 3 n m [ 3 H]androgen plus a fold excess of radioinert androgen for 2 h at 37 C. The incubation media were then replaced by media containing only a fold excess of radioinert androgen as a chase. Cells were harvested at 0, 30, 60, 90, and min and assayed for androgen-binding activity.

Androgen-binding activities were plotted semilog-arithmically as a percentage of the androgen-binding activity remaining at each time point. The k diss values were determined directly from the slopes of the lines. One set of plates was assayed after the initial incubation time for androgen-binding activity.

Binding assays were performed after 2, 4, and 6 h of incubation at 37 or 42 C. A monoclonal antibody F An A to C transversion at nucleotide in exon 5 of the LBD in subject corresponds to a substitution of an alanine for a conserved glutamic acid at codon EA; Fig. This mutation was also present in the mother and maternal half-sister of subject not shown.

An A to G transition was found in exon 8 at nucleotide in subject , causing a glycine residue to be substituted for an unconserved arginine residue RG; Fig. Dashes indicate conserved amino acids. Each mutation was incorporated separately into the pSVhAR. The presence of the desired mutations was confirmed by DNA sequencing before their use in functional studies.

Normal levels of androgen-binding activity were obtained with both EA and RG, in accord with the data on GSF from and In normal hAR experiments, K d values ranged from 0.

In almost half of the experiments the confidence intervals of both normal and mutants clearly overlap. Experiments on the same line were performed simultaneously. Each value represents a single experiment with its associated error calculated using Prism software.

The averages represent the value for k diss for all experiments pooled with the associated sd. In the control experiment, where the cells were incubated at 37 C, neither mutant receptor lost MB-binding activity at a greater rate than the normal hAR Fig. In one experiment, the EA hAR performed better than the RG hAR; in another experiment, they were equally able to trans -activate the reporter gene.

At various times MB-binding activity was determined, and cell lysates were harvested for Western analysis. Despite the concurrent loss of MB-binding activity over 18 h, there was no detectable loss of mutant hAR proteins as determined by densitometric analysis of the Western blots. Under the same conditions, normal hAR gave MB-binding activity that increased over 18 h with no apparent gain of immunoreactive protein. Cellular lysates were harvested from transfectants at various times after incubation with MB.

Blots were reacted with the anti-hAR antibody F We have identified and characterized two mutations in the LBD of the hAR from subjects whose hARs exhibited normal K d but otherwise abnormal kinetic profiles. An A to C transversion at amino acid position in exon 5 results in a substitution of alanine for a conserved glutamic acid in subject who has PAIS.

An A to G transition at amino acid position in exon 8 causes an arginine to glycine substitution in subject and results in MAIS. In the canonical three-dimensional structure of the nuclear receptor LBD, neither residue is predicted to be among those that form the ligand-binding pocket In EA transfectants the k diss values were elevated over the normal hAR with all ligands tested.

We observed that although the pattern of kinetic misbehavior was the same, the absolute values for K d and k diss of the normal or mutant hARs in transfected COS-1 cells were not identical to those obtained from their GSFs, probably due to a difference in intracellular factors. The normal K d values, despite increased k diss values of EA and RG, thus appear discordant in contrast to the usual concordant relationship between K d and k diss ; this merits further consideration.

Increased k diss values are usually concordant with increased K d values 12 , 17 , 21 — To maintain a normal equilibrium affinity for androgens, the increased off-rate of androgen from the mutant receptor should be compensated by an equally increased on-rate of the androgen to its receptor Exchange studies suggest that this may indeed be the case. The VM mutation 15 , which also has elevated k diss rates and an abnormal K d , demonstrates a slightly elevated exchange rate 1.

In this case, an inability to raise the on-rate sufficiently will result in an abnormal K d. Thus, simple determination of ligand affinity, as performed by Scatchard analysis 24 , may not be an accurate indicator of steroid receptor function; additional kinetic and functional assays must be performed to assess the degree of impairment in the case of a suspected pathogenic mutation.

Western blotting experiments revealed one immunoreactive band for normal and mutant hARs, indicating that proteolysis was not a factor in the loss of MB-binding activity. Thus, it appears that the mutant hARs progressively adopt a nonbinding conformational state upon prolonged incubation with MB, which does not appear to occur with the normal AR.

Any putative differences in trans -activation potential between EA and RG, however, did not manifest themselves under the experimental conditions used. According to their model, the ligand-binding pockets of nuclear receptors exhibit a common architecture and undergo similar transformation upon ligand binding.

More recently, Brzozowski et al. Here again, the overall structures of both remarkably resemble those of previous members of the steroid receptor superfamily. Upon ligand binding it is proposed that helixes 10 and 11 become continuous, releasing helix 12, which then undergoes a large conformational movement, covering or acting as a lid to the ligand-binding pocket.

A defective receptor may bind a ligand, but not undergo postligand conformational changes, and thus may not cage the ligand, allowing for faster ligand egress.

This may explain the abnormal kinetics of both our mutants. During ligand binding, helix 6 is proposed to interact with a loop, allowing for helix 12 to be repositioned over the active binding site.

A mutation in helix 6 could thus prevent this series of conformational steps from occurring. The decision of whether to raise an individual with PAIS as a boy or a girl may not be obvious; grades 3 and 4 in particular present with a phenotype that may be difficult to classify as primarily male or female, and some will be incapable of virilization at puberty. Some parents have pushed their children with intersex variations to display gender normative roles and behaviours, or to engage in hormonal and surgical interventions to make their bodies appear more aesthetically 'normative'.

Research based on interviews of people with intersex variations indicate a need for more family protection from intervention and more family support. Virilization capacity can be assessed by measuring the response to a trial of exogenous androgens ; some studies have measured the growth of the phallus in response to exogenous testosterone [32] or dihydrotestosterone , [4] while others have measured the change in sex hormone binding globulin SHBG in response to the artificial androgen stanozolol to assess androgen sensitivity.

Psychosexual development is influenced by many factors, including the timing, amount, and type of androgen exposure, receptor functionality, and environment, and is thus difficult to predict.

Genitoplasty , unlike gender assignment, can be irreversible, [50] and there is no guarantee that adult gender identity will develop as assigned despite surgical intervention. While it is thought that feminizing genitoplasty typically requires fewer surgeries to achieve an acceptable result and results in fewer urologic difficulties, [21] there is no evidence that feminizing surgery results in a better psychosocial outcome. Both male and female participants cited the appearance of their genitalia as being the greatest contributing factor to their dissatisfaction with their body image.

In two larger studies, [65] [66] the common predictor of gender reassignment was stigmatization related to having an intersex condition. The outcome of masculinizing genitoplasty is dependent on the amount of erectile tissue and the extent of hypospadias.

If feminizing genitoplasty is performed in infancy, the result will need to be refined at puberty through additional surgery. Many surgical procedures have been developed to create a neovagina, as none of them is ideal. Vaginal dilators are required postoperatively to prevent vaginal stenosis from scarring. Testosterone has been used to successfully treat undervirilization in some [14] but not all [75] men with PAIS, despite having supraphysiological levels of testosterone to start with.

Exogenous testosterone supplementation in unaffected men can produce various unwanted side effects , including prostatic hypertrophy , polycythemia , gynecomastia , hair loss , acne , and the suppression of the hypothalamic-pituitary-gonadal axis , resulting in the reduction of gonadotropins i. Some individuals with PAIS have a sufficiently high sperm count to father children; at least one case report has been published that describes fertile men who fit the criteria for grade 2 PAIS micropenis , penile hypospadias , and gynecomastia.

Depending on phenotypic features, impotence and other sexual problems such as anejaculation or sexual aversion may be fairly common among individuals with PAIS, [20] [28] [29] [30] [31] but do not necessarily indicate low libido. Adults with partial androgen insensitivity syndrome include Australian-Maltese advocate Tony Briffa , considered to be the world's first openly intersex mayor and public office-bearer.

In history , the Roman sophist and philosopher Favorinus of Arelate has been described as having partial androgen insensitivity syndrome. The Court ruled in the case of XX, an 8-year old with ambiguous genitalia, androgen insensitivity and XY chromosomes, raised as a girl. Doctors recommended feminizing surgeries , including a gonadectomy , vaginoplasty and clitoroplasty before puberty, but the hospital would not proceed without the consent of the Colombian Institute of Family Welfare and the Office of the Public Advocate.

The mother brought a case against Institute and Office of the Public Advocate, seeking to provide substitute consent. It questioned the urgency of the case, argued by medical teams. Civil rights advocates and a minority of doctors favored deferring treatment due to lack of evidence and the irreversible nature of the proposed interventions.

From Wikipedia, the free encyclopedia. Partial androgen insensitivity syndrome Other names Partial androgen resistance syndrome; Reifenstein syndrome AIS results when the function of the androgen receptor AR is impaired. The AR protein pictured mediates the effects of androgens in the human body. Main article: Diagnosis of Androgen Insensitivity Syndrome. Further information: Intersex rights in Colombia.

Best Pract. Hormones Athens. Ann Nucl Med. J Pediatr Adolesc Gynecol. In Emre S, Aydin A eds. Non-Invasive Management of Gynecologic Disorders. Informa Healthcare. Horumon to Rinsho. Arch Sex Behav.

Harrison's endocrinology. Hung, Wellington, Becker, Kenneth L. Principles and Practice of Endocrinology and Metabolism. Br J Urol. Asian J. Clin Transl Oncol. Fertil Steril. J Obstet Gynaecol. Clin Obstet Gynecol. Journal of Family Strengths. German Collaborative Intersex Study Group". Horm Behav. Front Neuroendocrinol. Annals of the New York Academy of Sciences.

Psychol Bull. J Sex Marital Ther. Reoperative pediatric surgery. Totowa, N. J: Humana. Obstet Gynecol. Osteoporos Int. Star Observer. The Huffington Post. Herald Sun. The Raw Story.

South African Medical Journal. Retrieved Intersex children and the Colombian Constitutional Court".

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