Complete Androgen Resistance Research Articles

Evaluation of pubertal and pathological gynaecomastia in children: A single-center experience.

Gynaecomastia in adolescents is a benign glandular proliferation of the male breast. Secondary causes of gynaecomastia in adolescents are relatively rare and may result from a wide variety of rare pathological conditions. Among these, klinefelter syndrome, complete androgen resistance, adrenal tumours and oestrogen-secreting testicular tumours, hypogonadism, hyperthyroidism, kidney disease and medications play a role in aetiology. The aim of our study is to review the demographic characteristics, hormone profile, aetiological characteristics of paediatric gynaecomastia patients admitted to a single center and to determine the frequency of pathological gynaecomastia. Forty-three male patients with gynaecomastia who applied to the paediatric endocrinology outpatient clinic were included in our study. Demographic characteristics, physical examination findings, hormone profile, breast ultrasonography and karyotype results of the patients were recorded. There were 43 male patients in our study. Thirty-six (83.7%) of the patients were pubertal gynaecomastia, 7 (16.2%) were pathological gynaecomastia. Three of the patients with pathological gynaecomastia were prepubertal gynaecomastia, 2 had klinefelter syndrome, 1 had hypergonadotropic hypogonadism after acute lymphoblastic leukaemia treatment and 1 had gynaecomastia after spirololactone use. Careful evaluation of patients with gynaecomastia is especially important in detecting pathological types. We reported the rare prepubertal gynaecomastia and klinefelter frequency in our study.

The Sexual Differentiation of the Human Brain: Role of Sex Hormones Versus Sex Chromosomes.

Men and women differ, not only in their anatomy but also in their behavior. Research using animal models has convincingly shown that sex differences in the brain and behavior are induced by sex hormones during a specific, hormone-sensitive period during early development. Thus, male-typical psychosexual characteristics seem to develop under the influence of testosterone, mostly acting during early development. By contrast, female-typical psychosexual characteristics may actually be organized under the influence of estradiol during a specific prepubertal period. The sexual differentiation of the human brain also seems to proceed predominantly under the influence of sex hormones. Recent studies using magnetic resonance imaging have shown that several sexually differentiated aspects of brain structure and function are female-typical in women with complete androgen insensitivity syndrome (CAIS), who have a 46 XY karyotype but a female phenotype due to complete androgen resistance, suggesting that these sex differences most likely reflect androgen action, although feminizing effects of estrogens or female-typical socialization cannot be ruled out. By contrast, some male-typical neural characteristics were also observed in women with CAIS suggesting direct effects of sex chromosome genes in the sexual differentiation of the human brain. In conclusion, the sexual differentiation of the human brain is most likely a multifactorial process including both sex hormone and sex chromosome effects, acting in parallel or in combination.

Neural Activation During Mental Rotation in Complete Androgen Insensitivity Syndrome: The Influence of Sex Hormones and Sex Chromosomes.

Sex hormones, androgens in particular, are hypothesized to play a key role in the sexual differentiation of the human brain. However, possible direct effects of the sex chromosomes, that is, XX or XY, have not been well studied in humans. Individuals with complete androgen insensitivity syndrome (CAIS), who have a 46,XY karyotype but a female phenotype due to a complete androgen resistance, enable us to study the separate effects of gonadal hormones versus sex chromosomes on neural sex differences. Therefore, in the present study, we compared 46,XY men (n = 30) and 46,XX women (n = 29) to 46,XY individuals with CAIS (n = 21) on a mental rotation task using functional magnetic resonance imaging. Previously reported sex differences in neural activation during mental rotation were replicated in the control groups, with control men showing more activation in the inferior parietal lobe than control women. Individuals with CAIS showed a female-like neural activation pattern in the parietal lobe, indicating feminization of the brain in CAIS. Furthermore, this first neuroimaging study in individuals with CAIS provides evidence that sex differences in regional brain function during mental rotation are most likely not directly driven by genetic sex, but rather reflect gonadal hormone exposure.

Complete androgen insensitivity syndrome: diagnosis and management

Complete androgen insensitivity syndrome (CAIS) is an X-linked genetic disorder affecting 46,XY individuals, characterized by the loss of function of the androgen receptor gene resulting in complete peripheral androgen resistance. Patients have a nonambiguous female phenotype with normal female external genitalia. Gonads are undescended testes (either intra-abdominal or inguinal), there is no uterus and the length of the vagina is usually very short. Gender identity is always female. This review focuses on the importance of accurate diagnosis of CAIS versus partial androgen insensitivity syndrome and other disorders of sex development by genotyping the androgen receptor, and raises issues of the optimal management of these patients. In the era of the Consensus Statement on Management of Intersex Disorders, we provide new insights into CAIS screening, surgical management of the gonads (balancing between hormonal production and malignancy risk) and of vaginal adequacy, and the ethics concerned with the disclosure to patients and their families.

Male Pseudohermaphroditism Caused by Mutations of the Human Androgen Receptor1

A exert their effects in mediating the development of the normal male phenotype via a single receptor protein, the androgen receptor (AR), which is encoded on the X chromosome. Abnormalities that alter the function of this receptor result in a range of abnormalities of male phenotypic development. These phenotypes range from that of normal females (complete testicular feminization, complete androgen insensitivity) to those that are characterized by only minor degrees of undervirilization and/or infertility. The defects of receptor function that have been characterized fall into two major categories. The first are those that disrupt the primary sequence of the AR. These mutations can be due to the introduction of premature termination codons, frameshift mutations, deletions or insertions, or alterations of RNA splicing. The ARs that are produced as a result of these genetic alterations are uniformly associated with complete androgen resistance. The second, and most common type of AR mutation, is that which is caused by single amino acid substitutions within the AR protein. In contrast to the preceding category, mutations of this type may result in the full spectrum of androgen resistant phenotypes. These mutations cluster in two important domains of the receptor protein: the DNAand the hormonebinding domains. Substitutions in the DNA-bindingdomain act to impair the ability of the AR to recognize target sequences within or adjacent to androgen-responsive genes. The degree of impairment of DNA binding is directly related to the degree of impairment of receptor function. Amino acid replacements within the hormone-binding domain can have a range of effects on the binding of ligand by the AR. In some instances, the capacity to bind hormone is completely abolished, while in other instances, only subtle qualitative abnormalities of ligand binding can be detected. In all mutants containing amino acid substitutions within the hormone-binding domain, the ability to form stable ARhormone complexes determines the amount of receptor function that remains. The phenotype that is observed does not appear to correlate with the identity of the residue that is mutated or its replacement. Instead, the phenotype appears to be a reflection of the degree to which androgen action is impaired. As the level of mutant AR protein expressed is similar to that observed in normal subjects, this usually reflects the degree to which AR function is altered. The male hormones, androgens, control wide range of processes in the male during embryonic development and in postnatal life. During embryogenesis, the concerted actions of testosterone (T) and 5a-dihydrotestosterone (DHT) are critical to the virilization of the Wolffian duct structures and the external genitalia. Genetic defects that impair androgen synthesis or action will result in abnormalities of male phenotypic development in 46, XY individuals with testes (male pseudohermaphroditism). Among the potential etiologies, defects of the AR are among the most common.

Molecular Pathophysiology and Clinical Manifestations of Gonadotropin Receptor Defects

The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) bind specific receptors, members of the G protein-coupled receptor superfamily. Mutations of gonadotropin receptors are classified into activating (constitutively active or gain-of-function mutations) and inactivating (loss-of-function mutations). Activating mutations of the LH receptor have been described in familial and sporadic forms of male-limited pseudoprecocious puberty, whereas they do not appear to have any particular phenotype in females. The only activating mutation of the FSH receptor described to date was found in a hypophysectomized man who was fertile despite undetectable serum gonadotropin levels; the effects of constitutive FSH receptor activity in the context of normal pituitary function are not known. Homozygous inactivating mutations of the LH and FSH receptor invariably lead to amenorrhea in genotypical female subjects. In males, inactivation of the LH receptor in its more severe form results in a clinical picture similar to the syndrome of complete androgen resistance, but milder forms of hypoandrogenization have been described as well. In males, homozygous inactivation of the FSH receptor can also be associated with infertility. Finally, polymorphic variants of the FSH receptor are present in the normal population.

Molecular pathophysiology of the pituitary-gonadal axis.

Mutations of gonadotropin beta subunits or gonadotropin receptors are involved in some reproductive diseases leading to alterations of pubertal maturation or infertility. Homozygous inactivation of LH results in absence of pubertal maturation and hypogonadism in the male, whereas inactivation of FSH causes primary amenorrhea in females. Mutations of the gonadotropin receptors are classified into activating (the receptor is also active in the absence of the hormone: gain-of-function mutations) and inactivating types (the receptor is not properly processed and/or the hormone cannot bind: loss-of-function mutations). Activating mutations of the LH receptor have been described in familiar and sporadic forms of male-limited pseudoprecocious puberty, whereas they do not express any phenotype in females. The only activating mutation of the FSH receptor described to date was found in a hypophysectomized man who was fertile despite undetectable serum gonadotropin levels; the effects of constitutive FSH receptor activity occurring with normal pituitary function are not known. Homozygous inactivations of the LH and FSH receptor invariably lead to amenorrhea in genotypically female subjects. In males, inactivation of the LH receptor in its more severe form results in a clinical picture similar to the syndrome of complete androgen resistance, but milder forms of hypoandrogenization have been described as well. The clinical consequences of homozygous inactivation of the FSH receptor in males are associated with subfertility. Finally, polymorphic variants of both the gonadotropin LH and the FSH receptor are present in the normal population.

A novel substitution (Leu707Arg) in exon 4 of the androgen receptor gene causes complete androgen resistance.

A wide spectrum of androgen receptor (AR) gene mutations has been reported in complete androgen insensitivity syndromes. The molecular basis of androgen resistance was investigated in a female newborn with complete testicular feminization. Sequencing identified a point mutation in exon 4 responsible for a leucine (CTG) to arginine (CGG) replacement at codon 707. This novel mutation is located in the amino-terminal part of the ligand-binding domain of the AR. To determine the functional properties of the mutated AR and to establish the correlation with the clinical phenotype of androgen resistance, the mutation was reproduced in AR wild-type complementary DNA, and the plasmid was transfected into AR-free mammalian cells. In vitro studies showed that the mutant AR was functionally defective as an androgen-binding molecule. Electrophoretic mobility shift assay revealed that the binding of mutated AR to DNA was reduced. Finally, the mutant was unable to induce the transcriptional activation of androgen-responsive reporter gene. This amino acid defect in the primary sequence probably involves the rupture of hydropathicity in a region that is conserved among members of the steroid receptor subfamily. Our data substantiate the major contribution of leucine 707 to normal AR function and demonstrate that its substitution by an arginine caused the complete androgen insensitivity in this patient. Our findings also contribute to the elaboration of the structure-function map of the AR based on naturally occurring mutations.

A novel substitution (Leu707Arg) in exon 4 of the androgen receptor gene causes complete androgen resistance

A novel substitution (Leu707Arg) in exon 4 of the androgen receptor gene causes complete androgen resistance

ETIOLOGIC DIAGNOSIS IN 126 CASES OF SEX AMBIGUITY

The complexity of human sex differentiation becomes manifest in the variety of diseases associated with sex ambiguity (SA). There are a few clinical centers especially dedicated to the managament of such patients, and hence, few large series have been published. We had the oportunity to evaluate 126 cases of SA. Among them, 57 (45.2%) were male pseudohermaphrodites (MPH), 35 (27.8%) were female pseudohermaphrodites (FPH), 23 (18.3%) had anomalies of gonadal differentiation (AGD), and 11 (8.71) exhibited other genital abnormalities. Among MPH, 36 were considered idiopathic, due to our impossibility to study androgen/receptor binding in cultured fibroblasts to diagnose partial androgen resistance, 11 were syndromic, there were 5 anorchias, 3 had complete androgen resistance, 1 had mullerian persistence and 1 5-alpha-reductase deficiency. Congenital adrenal hyperplasia was the main cause of FPH (24); there were also 6 syndromic cases and 5 idiopathic cases. Among AGD, there were 10 cases of true hermaphroditism, 8 Klinefelter syndromes, 3 mixed gonadal dysgenesis and 2 testicular dysgenesis due to sex chromosome aberrations. There were also 4 cases of balano-prepucial hypospadias, 3 of cryptorchidism, 3 incarcerated ovaries and 1 idiopathic microrchidism. Such a large series could only be achieved as a result of an interdisciplinary approach to SA over approximately 5 years.

Laparoscopic removal of gonads containing an occult seminoma in a woman with complete androgen resistance

A 20-year-old woman with complete androgen resistance (AR; 46,XY), underwent prophylactic laparoscopic gonadectomy because of the known increased risk of gonadal malignancy. The procedure was performed with electrocoagulation using a four-puncture technique. Pelvic and abdominal inspection revealed no gonadal or metastatic tumor. The testes and attached structures were retracted medially, and the peritoneum and gonadal vessels were incised after electrocoagulation, thereby removing the gonads from the sidewalls. The gonads were individually placed into a specimen retrieval bag and removed through the suprapubic cannula site. Pathologic examination revealed an occult 8-mm seminoma in the left gonad, as well as bilateral Sertoli cell hamartomas, fallopian tube remnants, and smooth muscle tissue (mullerian remnants) adjacent to the gonads. Postoperatively, tumor markers were normal, and abdominal and pelvic computerized tomographic scans and chest radiographs were negative for possible metastatic disease. This case confirms that laparoscopic removal of testes in women with AR is effective, safe, and quick. Because a normal-appearing gonad may contain an occult tumor, we recommend using a retrieval bag, which may prevent dissemination of potentially malignant cells that may occur with unprotected morcellation.

Hormonal control of testicular descent and the cause of cryptorchidism.

This paper briefly reviews the literature on testicular descent and presents new observations from the authors' laboratory which suggest new ways of looking at old problems. There is now good evidence that testicular descent occurs in two morphologically and hormonally distinct phases. Relative 'transabdominal migration' of the testis compared with the ovary occurs at 10-15 weeks of gestation in the human and 'inguinoscrotal' migration occurs at 26-35 weeks of gestation. We have proposed previously that the first phase is controlled by Müllerian inhibiting substance although this remains controversial. The second phase is androgen dependent and is possibly mediated indirectly through the release from the genitofemoral nerve (GFN) of the neuropeptide calcitonin gene-related peptide (CGRP). Recently we have used three different rodent models of undescended testis to determine the involvement of the GNF and/or CGRP. The testicular feminization mouse with complete androgen resistance and the rat exposed prenatally to the antiandrogen flutamide have a deficiency of CGRP in the GFN. In contrast, the mutant trans-scrotal rat which has normal androgen levels has an excess of CGRP in the GFN. All cryptorchidism models, despite their different primary cause, have in common an abnormality of the GNF and/or CGRP which is consistent with the hypothesis that normal testicular descent in the rodent may be mediated by the GFN.

The Gubernaculum in adult female, adult male and TFM male mice

There is still controversy over whether androgens are involved in gubernacular migration during descent of the testis, prompting a review of anatomical events controlled by androgens. The gubernacular position in adult female, male, and testicular feminized male (TFM) mice (with complete androgen resistance) was observed macroscopically to determine its caudal limit and whether the adult TFM male still contained guvernacular bulk. The length of the processus vaginalis was measured, and the presence of a differentiated cremaster muscle was determined histologically. In 10 adult female mice there was neither a processus vaginalis nor a cremaster muscle, and the gubernaculum (round ligament of the ovary) attached to the external inguinal ring. In 10 adult TFM mice the gubernaculum ended at or just beyond the external ring, and was present in an amount corresponding to its size at the end of the outgrowth phase of development, with secondary infiltration by fat. The processus vaginalis was poorly developed, the cremaster muscle was undifferentiated, and there was no eversion of the cremaster sac. In 10 normal adult male mice the gubernaculum and testis had migrated to the scrotum, and the gubernaculum had regressed fully. Because gubernacular development in the androgen-resistant mouse cases after termination of transabdominal testicular migration, the anatomy of the adult confirms that, in the mouse, normal androgenic function is essential for eversion of the cremaster sac and gubernacular migration beyond the groin to the genital folds.

Exogenous calcitonin gene-related peptide causes gubernacular development in neonatal (Tfm) mice with complete androgen resistance

It has been proposed that testicular descent is controlled indirectly by androgens acting on the central nervous system to mediate migration of the gubernaculum to the scrotum. Accumulating evidence suggests that the genitofemoral verve may release a newly described neurotransmitter, calcitonin gene-related peptide (CGRP) to stimulate gubernacular motility during migration. This study aimed to determine whether exogenous CGRP could stimulate gubernacular migration in mice with complete androgen resistance (testicular feminization mouse [Tfm]). CGRP was injected into the right groin of neonatal Tfm mice at 2-day intervals untill 2 weeks of age, when the length of the processus vaginalis was measured under a dissecting microscope. The processus vaginalis length in normal male littermates was 5.9 ± 1.8 mm (mean ± SD) while in the female it was 1.2 ± 0.9 mm. Exogenous CGRP had no effect on either of these. In Tfm males CGRP caused a significant increase in the length of the processus vaginalis on the injected side (2.3 ± 0.8 mm) compared with the uninjected side (1.4 ± 1.0 mm). These results are consistent with the hypothesis that CGRP can replace, at least partially, the effect of androgens on gubernacular migration.

Single base mutations in the human androgen receptor gene causing complete androgen insensitivity: rapid detection by a modified denaturing gradient gel electrophoresis technique.

Mutations of the human androgen receptor (AR) gene impair normal sexual differentiation and development in karyotypic males, resulting in a spectrum of external genital phenotypes ranging from complete female to nearly complete male. Identification and characterization of these mutations can provide valuable information regarding the functional importance of specific amino acids of the AR. To screen for point mutations in the AR gene underlying the phenotypic abnormalities in the androgen insensitivity syndrome (AIS), the eight exons of the AR gene were amplified from genomic DNA using the polymerase chain reaction (PCR) and analyzed by denaturing gradient gel electrophoresis. A computer program, MELTMAP, was used to identify optimum sequences for denaturing gradient gel electrophoresis, and mutation detection sensitivity was enhanced by forming heteroduplexes between control and subject PCR products to create base mismatches. In seven families with complete AIS, single base mutations were found in the region of the AR gene encoding the steroid-binding domain of the receptor. The mutations that converted amino acid 774 from Arg to His and amino acid 864 from Asp to Gly were recreated using site-directed mutagenesis and the mutant ARs expressed in COS 7 and CV1 cells. In both cases, abnormalities of androgen binding and transcriptional activation were consistent with the observed sex phenotype. These results together with others reported previously demonstrate that single amino acid changes within the region encoded by exons D to H of the AR gene can alter androgen binding and are a common cause of complete androgen resistance. The strategy used herein, employing denaturing gradient gel analysis of heteroduplex PCR products, provides a valuable aid to rapid detection of single base mutations in AIS.

Definition of the Human Androgen Receptor Gene Structure Permits the Identification of Mutations that Cause Androgen Resistance: Premature Termination of the Receptor Protein at Amino Acid Residue 588 Causes Complete Androgen Resistance

We have isolated and characterized the gene encoding the human androgen receptor. The coding sequence is divided into eight coding exons and spans a minimum of 54 kilobases. The positions of the exon boundaries are highly conserved when compared to the location of the exon boundaries of the chicken progesterone and human estrogen receptor genes. Definition of the intron/exon boundaries has permitted the synthesis of specific oligonucleotides for use in the amplification of segments of the androgen receptor gene from samples of total genomic DNA. This technique allows the analysis of all segments of the androgen receptor gene except a small region of exon 1 that encodes the glycine homopolymeric segment. Using these methods we have analyzed samples of DNA prepared from a patient with complete androgen resistance and have detected a single nucleotide substitution at nucleotide 1924 in exon 3 of the androgen receptor gene that results in the conversion of a lysine codon into a premature termination codon at amino acid position 588. The introduction of a termination codon into the sequence of the normal androgen receptor cDNA at this position leads to a decrease in the amount of mRNA encoding the human androgen receptor and the synthesis of a truncated receptor protein that is unable to bind ligand and is unable to activate the long terminal repeat of the mouse mammary tumor virus in cotransfection assays.

147 FRG IMPAIRED SEXUAL DEVELOPMENT DUE TO TESTICULAR DYSFUNCTION AND TRAGET ORGAN INSENSITIVITY. DIFFERENTIATION BY A NEW ANDROGEN SENSITIVITY TEST

Regular testicular function and responsiveness of target organs to testicular androgens are prerequisites of normal male sexual development. Impairment of either function can cause varying degrees of incomplete mascullnization. A pilot study had revealed a different SHBG-reaction to anabolic steroids in patients with the testicular feminization syndrome (ESPE'87, Abstr.No.160). We now investigated the effect of Stanozolol and Oxandrolone (3 days 0.2 mg/kg per os) on SHBG, CBG, TBG, albumin, total protein, testosterone, estradiol, thyroxin, Cortisol, LH and FSH in 4 patients with Impaired testicular function (gonadal dysgenesis, 17β-hydroxysteroid-dehydrogenase defect), 4 patients with target organ insensitivity (partial and complete androgen resistance), and in 20 controls. In testicular dysfunction and in the controls SHBG-levels decreased significantly (p<0.001) down to a minimum of 61.6 % ± 6.0 (SD) (Stanozolol) and 66.2 ± 10.3 (SD) (Oxandrolone) of the initial values at days 5, 6, 7, or 8 after initiation of the test, while in partial androgen resistance the decrease was moderate (81% and 89%), and absent in complete testicular feminization. Differences In all other parameters were not statistically significant. Conclusion: 1.) The SHBG-decrease induced by short term anabolic steroid application is a specific reaction. 2.) This reaction requires regular target tissue sensitivity. 3.) It can be used for the differentiation of testicular dysfunction syndromes from androgen insensitivity syndromes.

Extracellular correction of the androgen-receptor transformation defect in two families with complete androgen resistance

We have characterized the cellular and extracellur phenotype of the mutant androgen receptor (AR) from two families who have complete androgen resistance despite a normal androgen-binding capacity ( B m ) in their genital skin fibroblasts (GSF). The cellular receptors fail to up-regulate their basal AR activity in response to prolonged incubation with 5α-dihydrotestosterone (DHT), or with two synthetic androgens, methyltrienolone (MT) and mibolerone (MB), and form A-R complexes with increased equilibrium ( K d ) and non-equilibrium (k) dissociation constants. In addition, they are thermolabile when recently dissociated, but not in their native state. A-R complexes made in normal or mutant cytosol at 4°C elute from DEAE-Sephacel at ~0.25 M KCl (untransformed), with or without prior passage through Sephadex G-25; when made in cells at 37°C, extracted with 0.4 M KCl in a buffer containing 10 mM Na 2MoO 4, and desalted by G-25, they elute at ⩽0.1 M KCl. Normal KCl-extracted DHT- and MB-R complexes dissociate (37°C) at the same slow, linear rate as their in-cell counterparts (transformed); the mutant ones dissociate more slowly than their rapidly-dissociating in-cell counterparts and, to a variable extent, nonlinearly—an early faster phase, a later slower (transformed). Thus, as judged by two conventional criteria of steroid-R complex transformation, the mutant A-R complexes can transform, possibly in two steps, under certain cell-free conditions. This behavior differentiates a class of structural AR mutations whose molecular definition awaits application of recombinant DNA techniques to the X-linked AR locus.

Exogenous oestrogens prevent transabdominal testicular descent in mice with complete androgen resistance (testicular feminisation)

Testicular descent is believed to be hormonally mediated, but the precise mechanism remains unknown. Androgens have been proposed as the main stimulus for descent, based in part on the inhibition of descent by exogenous oestrogens, which supress fetal testosterone secretion by negative feedback on the hypothalamus. To test whether testosterone secretion was causally linked to descent, fetal male mice with complete androgen resistance (testicular feminisation (TFM)) were exposed to exogenous oestrogens and examined as neonates. The testes descended to the internal inguinal region in control TFMs at birth, but were significantly undescended after exposure to diethylstilboestrol or oestradiol benzoate (P<0.005). These results are consistent with the hypothesis that the first, or transabdominal, phase of descent occurred normally despite complete androgen resistance. Moreover, they suggest that exogenous oestrogens produce cryptorchidism completely independently of the action of testosterone. It is suggested that testicular descent, which appears biphasic, may be controlled by Mullerian Inhibiting Substance during the first phase, and that oestrogens have inhibited this directly. The suppression of testosterone secretion may not be the causedof cryptorchidism, but an unrelated effect of exogenous oestrogen.

Action of androgen on fibroblast collagen synthesis: a receptor-dependent response.

Several groups are still investigating an vitro biological response of androgen action. The purpose of this study was to determine whether dihydrotestosterone (DHT) influences the secretion of collagen by cultured foreskin fibroblasts raised from patients with normal or undetectable DHT-binding activity (complete androgen resistance). Collagen synthesis and secretion were evaluated by 3H-proline incorporation in newly synthetized collagen by confluent fibroblasts alone, or in the presence of DHT (10−5 to -10−10M). Production of collagen is expressed as a ratio between tritiated OH-proline and OH-proline plus proline,within the cells or in the culture medium. These data show that : -in control cells,DHT significantly increases production of collagen released in the culture medium (p < 0.001), -In complete androgen resistance with no detectable androgen binding activity, DHT does not modify basal collagen synthesis. These results strongly suggest that this hormonal response is mediated via a DHT-receptor or is receptor-dependent. This could be used as a biological response of androgen action in patients with androgen resistance associated with a post-receptor defect.