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Background: Abnormal androgen receptor (AR) genes can cause androgen insensitivity syndrome (AIS), and AIS can be classified into complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS) and mild AIS. We investigated the characteristics of clinical manifestations, serum sex hormone levels and AR gene mutations of 39 AIS patients, which provided deeper insight into this disease., Methods: We prospectively evaluated 39 patients with 46, XY disorders of sex development (46, XY DSD) who were diagnosed with AIS at the Department of Endocrinology of Shanghai Children's Hospital from 2014 to 2019. We analysed clinical data from the patients including hormone levels and AR gene sequences. Furthermore, we screened the AR gene sequences of the 39 AIS patients to identify probable mutations., Results: The 39 AIS patients came from 37 different families; 19 of the patients presented CAIS, and 20 of them presented PAIS. The CAIS patients exhibited a higher cryptorchidism rate than the PAIS (100 and 55%, P = 0.001). There were no significant difference between the CAIS and PAIS groups regarding the levels of inhibin B (INHB), sex hormone-binding globulin (SHBG), basal luteinizing hormone (LH), testosterone (T), or basal dihydrotestosterone (DHT), the T:DHT ratio, DHT levels after human chorionic gonadotropin (HCG) stimulation or T levels after HCG stimulation. However, the hormone levels of AMH (P = 0.010), peak LH (P = 0.033), basal FSH (P = 0.009) and peak FSH (P = 0.033) showed significant differences between the CAIS group and the PAIS group. Twenty-one reported pathogenic and 9 novel AR mutations were identified. Spontaneous AR mutations were found in 5 AIS patients, and 21 patients inherited mutations from their mothers, who carried heterozygous mutations., Conclusions: Forty-six XY DSD patients with cryptorchidism and female phenotypes were highly suspected of having AIS. We demonstrated that CAIS patients could not be distinguished by their hormone levels alone. Compared with PAIS patients, CAIS patients exhibited higher basal FSH, peak FSH, and peak LH hormone levels but lower AMH expression. We identified 21 reported pathogenic AR mutations and 9 novel AR mutations that led to different types of AIS. Missense mutations were the major cause of AIS and mostly occurred in exon 7 of the AR gene. These findings provided deeper insight into the diagnosis and classification of AIS and will even contributed to its clinical assessment.

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Objective: To determine diagnostic accuracy of human chorionic gonadotropins stimulation test in differentiating androgen insensitivity syndrome and 5-alpha reductase deficiency, keeping testosterone to dihydrotestosterone ratio as the gold standard., Methods: The cross-sectional study was conducted at the Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from January to December, 2016, and comprised patients aged 01 day to 20 years having XY chromosomes on karyotyping and with a spectrum of phenotypes. Blood samples were collected from each subject for basal serum testosterone, serum luteinizing hormone and serum follicular stimulating hormone level. Human chorionic gonadotropins stimulation test was performed in every subject as per the protocol. Sandwich chemiluminescence immunoassay technique was used to analyse serum samples. Serum dihydrotestosterone level was also detected to determine testosterone and dihydrotestosterone ratio. Data was analysed using SPSS 24. ., Results: Of the 104 subjects with a mean age of 1.78}0.95 years,96(92.3%) were diagnosed as cases of androgen insensitivity syndrome on the basis of human chorionic gonadotropins stimulation response level, which was 2-9 times of basal serum testosterone level. Also, 8(7.7%) subjects were diagnosed to have 5-alpha reductase deficiency syndrome. In such subjects, post-human chorionic gonadotropins response level of serum testosterone was more than 10 times of the basal level., Conclusions: The human chorionic gonadotropins stimulation test was found to be comparable to testosterone-to dihydrotestosterone ratio in differentiating between case of androgen insensitivity syndrome and 5-alpha reductase deficiency.

Background: Inhibin B is a hormone produced by the Sertoli cells that can provide important information for the investigation of disorders of sex development (DSD) with 46,XY karyotype. The aim of this study is to compare two enzyme-linked immunosorbent assay (ELISA) assays for dosage of serum inhibin B in patients with 46,XY DSD with normal testosterone secretion., Methods: Twenty-nine patients with 46,XY DSD and normal testosterone secretion (partial androgen insensitivity syndrome [PAIS] [n=8]; 5α-reductase deficiency [n=7] and idiopathic 46,XY DSD [n=14]) were included. Molecular analysis of the AR and SRD5A2 genes were performed in all patients and the NR5A1 gene analysis in the idiopathic group. Measurements of inhibin B were performed by two second-generation ELISA assays (Beckman-Coulter and AnshLabs). Assays were compared using the interclass correlation coefficient (ICC) and the Bland-Altman method., Results: ICC was 0.915 [95% confidence interval (CI): 0.828-0.959], however, a discrepancy was observed between trials, which is more evident among higher values when analyzed by the Bland-Altman method., Conclusions: It is recommended to perform the inhibin B measurement always using the same ELISA kit when several evaluations are required for a specific patient.

Androgen insensitivity syndrome (AIS) is the most common cause of 46,XY disorders of sex development (46,XY DSD). This syndrome is an X-linked inheritance disease and it is caused by mutations in the human androgen receptor (AR) gene. Non-synonymous point AR mutations are frequently described in this disease, including in the complete phenotype. We present a novel synonymous mutation in the human AR gene (c.1530C > T) in four 46,XY patients from two unrelated families associated with complete androgen insensitivity syndrome (CAIS). The analysis of mRNA from testis showed that synonymous AR mutation changed the natural exon 1 donor splice site, with deletion of the last 92 nucleotides of the AR exon 1 leading to a premature stop codon 12 positions ahead resulting in a truncate AR protein. Linkage analyses suggested a probable founder effect for this mutation. In conclusion, we described the first synonymous AR mutation associated with CAIS phenotype, reinforcing the disease-causing role of synonymous mutations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Themutations of androgen receptor (AR) gene are the most common cause for complete androgen insensitivity syndrome (CAIS). We aimed to characterize the six cases enrolled in our hospital (the First People's Hospital of Yunnan, China) and explore the molecular mechanism of CAIS. Between 2010 and 2013, six female cases were enrolled in our hospital for the agenesis of secondary sexual characteristics. The clinical examinations such as sex hormone test and B ultrasound were performed and the genetic characterization of patients were evaluated by karyotype analysis, polymerase chain reaction and DNA sequencing. The six cases with 46, XY karyotype were diagnosed with CAIS and four novel AR mutations were discovered, which were responsible for Chinese CAIS. The molecular study of the AR gene facilitated the understanding of themechanism of CAIS and provided the genetic counselling clinically.

Background: Androgen insensitivity syndrome is an X-linked disorder, and is characterised by a female phenotype in a chromosomally male individual. It usually occurs in puberty with primary amenorrhoea or as an inguinal tumour in a female infant. In recent years, it is often also diagnosed in fertility clinics in adulthood., Objective: The case is presented of a pure seminoma in a woman with the reference diagnosis of inguinal hernia., Clinical Case: A 53 year old woman, who was operated on in 2014 due to a nodule in left groin. Androgen insensitivity syndrome was corroborated, and histopathology reported it as a right testicular seminoma., Discussion: The importance of early diagnosis is discussed, highlighting the consequences of misdiagnosis, and question whether these patients have been adequately treated in the past. The risk of malignant transformation of an undescended testicle increases with age, thus gonadectomy should be performed after puberty, and in some cases hormone replacement therapy., (Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.)

Background: The hormonal management of patients with androgen insensitivity can be challenging., Case: An illustrative case is presented of a newborn with ambiguous genitalia who was raised female. She was diagnosed as 46,XY Disorder of Sexual Development with partial androgen insensitivity. To induce puberty, conjugated equine estrogens were administered beginning at age 12. At age 13, she instead began taking combined oral contraceptives for maternal concerns about height and continued taking them for social reasons. Invasive ductal carcinoma was diagnosed at age 27, and the patient was treated with chemotherapy, radiation therapy, bilateral mastectomies, and endocrine therapy., Summary and Conclusion: The current literature is reviewed, and hormonal management and other risks for breast cancer are discussed., (Copyright © 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Summary Introduction: Androgen insensitivity syndrome (AIS) belongs to disorders of sex development, resulting from complete or partial resistance to the biological actions of androgens in persons who are genetically males (XY) with normally developed testes and age-appropriate for males of serum testosterone concentration., Case Outline: A 21-year-old female patient was admitted at our Clinic further evaluation and treatment of testicular feminization syndrome, which was diagnosed at the age of 16 years.The patient had never menstruated. On physical examination, her external genitalia and breast development appeared as completely normal feminine structures but pubic and axillary hair was absent. Cytogenetic analysis showed a 46 XY karyotype. The values of sex hormones were as in adult males. The multi-sliced computed tomography (MSCT) showed structures on both sides of the pelvic region, suggestive of testes. Bilateral orchiectomy was performed. Hormone replacement therapy was prescribed after gonadectomy. Vaginal dilatation was advised to avoid dyspareunia., Conclusion: The diagnosis of complete androgen insensitivity is based on clinical findigs, hormonal analysis karyotype, visualization methods and genetic analysis. Bilateral gonadectomy is generally recommended in early adulthood to avoid the risk of testicular malignancy. Vaginal length may be short requiring dilatation in an effort to avoid dyspareunia. Vaginal surgery is rarely indicated for the creation of a functional vagina.

The aim of this study was to evaluate the effect of hormone therapy (HT) in the endothelial function of 46,XY disorders of sexual development (DSD) patients with female phenotype. Biochemical and ultrasound measurements were performed in 20 patients at initiation of oral 2 mg 17β-estradiol/1 mg norethisterone acetate, and after 6 months of therapy. Lipid profile, including total cholesterol (TC), LDL, HDL, triglycerides (TG) and Atherogenic Index of Plasma (AIP), as well as levels of VE-Cadherin, E-Selectin, Thrombomodulin and vWf were determined. Ultrasonographic examinations included evaluation of flow-mediated dilatation (FMD) and measurement of Carotid and Femoral Intima Media Thickness (IMT). HT raised HDL (35.4 mg/dl versus 40.1 mg/dl, p = 0.019) while lowering TG (166 mg/dl versus 109 mg/dl, p = 0.026) and AIP (0.24 versus 0.04, p = 0.007). No changes were noted in TC and LDL (215.7 mg/dl versus 192.25 mg/dl and 87.46 mg/dl versus 76.35 mg/dl, respectively). There was significant reduction of VE-Cadherin (4.05 ng/ml versus 2.20 ng/ml, p = 0.002) and E-selectin (73.98 ng/ml versus 56.73 ng/ml, p = 0.004). No change was observed in Thrombomodulin and vWf (11.76 ng/ml versus 13.90 ng/ml and 80.75% versus 79.55%, respectively). FMD improved significantly (5.4% versus 8.15%, p = 0.003), while only carotid bulb IMT decreased significantly (0.65 mm versus 0.60 mm, p = 0.018). Overall, HT was found to improve biochemical and ultrasound markers of endothelial function in 46,XY DSD patients with female phenotype.

Objective: To describe the natural history of phenotype, growth and gonadal function in patients with partial androgen insensitivity syndrome., Setting: Tertiary paediatric endocrine centre., Methods: Retrospective evaluation of 14 male patients with partial androgen insensitivity syndrome (PAIS) with verified androgen receptor (AR) mutations. The authors recorded phenotypic characteristics at birth and external masculinisation score (EMS), registered longitudinal growth, circulating levels of testosterone, estradiol, luteinising hormone (LH), follicle-stimulating hormone (FSH), inhibin-B and sex hormone binding globulin (SHBG), in addition to phenotype at postpubertal follow up., Results: The EMS ranged from 5 to 12 in PAIS at birth. Six patients were born with hypospadias and all patients developed gynaecomastia in puberty. Eight of the patients received testosterone treatment. At follow-up penile size was impaired irrespective of EMS at birth, but responded to pubertal androgen therapy in some of the patients. Serum levels of testosterone, estradiol, SHBG and LH, but not FSH and inhibin B, were markedly elevated in puberty. Final height was 181.3 cm (165.7-190.5 cm) corresponding to an SD score of 0.7 (-2.1 to +2.1 SD, n=10)., Conclusion: Gynaecomastia and impaired phallic growth are frequently observed in adults with PAIS, but may be ameliorated by androgen therapy. The authors suggest that male patients presenting with gynaecomastia in puberty, and elevated circulating levels of testosterone, estradiol and LH in puberty, but normal FSH, should be suspected of having PAIS and undergo genetic testing for AR mutations.

Objective: To report a case of an azoospermic subject with mild androgen insensitivity syndrome (MAIS) and review the relevant literature., Design: Case report., Setting: Academic research hospital., Patient(s): A 49-year-old man with undermasculinized features and a history of cryptorchidism and azoospermia., Intervention(s): Hormonal evaluation and genetic testing of the androgen receptor gene (AR)., Main Outcome Measure(s): Hormonal levels and sequence chromatogram of the proband and his mother., Result(s): We found total T in the normal range and high levels of gonadotropins. Karyotype was 46,XY. Genetic testing identified a novel mutation of exon 1 of AR, which resulted in an alanine to serine substitution in the transactivation domain at codon 240 (A240S). Fourteen other mutations of exon 1 of AR have been associated with MAIS to date., Conclusion(s): The novel mutation A240S of AR is involved in MAIS, a syndrome associated with azoospermia., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Late-onset hypogonadism describes the co-occurrence of a range of physical, psychological and sexual symptoms in aging men, with the implication that these symptoms are caused by androgen deficiency. Previous investigations examined mostly population samples and did not take into account the testosterone modulating effects of the genetically determined CAG repeat polymorphism (CAGn) of the androgen receptor (AR) gene. This is the first study which investigates aging male symptoms (AMS) in relation to the genetically determined androgen receptor CAG polymorphism, estradiol and testosterone levels in men > or =50 years of age in a healthy population sample (n=100), outpatients of an andrological department (n=76) who presented with sexual and "aging male" symptoms and a psychosomatic/psychiatric sample (n=120) who presented with various psychological and medically unexplained somatic complaints. Although the population sample was significantly older than the two patient groups, they reported significantly fewer AMS and had higher testosterone levels and shorter CAG repeats of the AR. Regression analysis revealed influences of CAGn on the AMS global score and the psychological and somatic subscale only in the two patient samples, while testosterone had some impact on the sexual subscale. Our results suggest that the so-called aging male symptoms show a certain association to androgenicity, but that they are rather unspecific and of multifactorial origin. Other factors contributing to AMS need further clarification., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Clinical and experimental data suggest that androgen receptor (AR) signaling plays a role on body composition, glucose homeostasis and lipid metabolism. The effect of AR disruption on such parameters was not extensively investigated in human people. A group of young to middle-age adult women with complete androgen insensitivity syndrome (CAIS, n = 18, age 32.2 +/- 9.3 years; women with testes removed n = 14) was investigated for body mass index (BMI), body composition (dual energy X-ray absorptiometry), serum glucose levels, insulin sensitivity (HOMA-IR) and lipid profile. Mean BMI (24.2 +/- 7.4 kg/m(2)) was not significantly increased (T-score 1.0 +/- 2.5, p = NS vs Italian female reference values), but prevalence of obesity was higher in women with CAIS than that reported in age-related Italian females (16.7% vs 3.6%, respectively). The majority of obese individuals with CAIS was in the subgroup with intact testes (3/4). DXA assessment (n = 15) demonstrated values of total free fat mass similar to that of 46,XX female controls. Increased body fat was found in CAIS women in comparison with both female and male controls. Abnormal values of cholesterol (total and LDL) and HOMA-IR were present in a large subset of patients. Our data suggest that in women with CAIS disruption of AR signaling may increase body fat and affect some metabolic parameters. Assessment of body composition, metabolic profile and, likely, cardiovascular risk seems to be advisable with ageing in these individuals., ((c) 2009 S. Karger AG, Basel.)

Context: Choosing the sex of rearing of an XY neonate with a major sexual ambiguity and a mutated androgen receptor remains one of the more difficult questions of neonatal endocrinology. A direct consequence of this choice is the accomplishment of sexual function in adulthood. There is very limited knowledge of the sexual performance of patients with partial androgen insensitivity syndrome., Objective: The objective of this study is to describe physical acts of sexuality in partial androgen insensitivity syndrome patients reared as males., Design: We were able to obtain factual information regarding the sexual activity of 15 adult patients who had been reared as males and followed at our institution since birth. We evaluated their sexual performance using two validated questionnaires (Golombok-Rust Inventory of Sexual Satisfaction and International Index of Erectile Dysfunction)., Results: We documented a major impairment of all parameters of sexual activity., Conclusion: This long-term insight into the consequences of male sex assignment will have to be balanced by a study of the consequences of female sex assignment.

Background: Androgen receptor defects affect the regulation of the gonadotropic axis. However, little is known about the timing of pubertal maturation in complete androgen insensitivity syndrome (CAIS)., Aims: To evaluate growth, skeletal maturation and gonadotropin and sex steroid secretion in patients with CAIS and intact gonads at puberty., Methods: Clinical, auxological and hormonal evaluation of 9 patients with CAIS from birth up to 17 years of age, prior to gonadectomy, in a single institution, retrospective study., Results: Breast development occurred at a median age of 11.1 years, thumb sesamoid appeared at 11.5 years, and peak height velocity at 12.3 years, all consistent with average female values. However, median adult male height (+1.2 SDS) was closer to the patients' male target height (-0.3 SDS). Plasma testosterone levels rose early compared to normal boys. LH (basal and GnRH-stimulated) increased rapidly, above normal male values, in early puberty., Conclusions: This retrospective evaluation of a limited number of cases with a heterogeneous pattern of follow-up suggests that patients with CAIS may enter puberty at an age closer to female standards. These results imply a major role of direct androgen action, in utero or in early life, in determining the pattern of pubertal gonadotropin maturation.

Kallmann syndrome (KS) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia/hyposmia. Other congenital abnormalities may also coexist. This present report describes two sisters, aged 13 and 12 years, born from Lebanese consanguineous parents. The two sisters have complete androgen insensitivity (normal female appearance and an XY karyotype) due to a novel mutation, a C-to-G transversion in intron 2 of the androgen receptor gene, resulting in an aberrant splicing leading to an insertion of 66 nucleotides in the mRNA. In addition, the older sister has KS, together with synkinesia and multiple skeletal abnormalities, mainly kyphosis, vertebral abnormalities, and short right hand and feet. Her testosterone, FSH and LH levels were very low compared with her younger sister. No mutation in the KAL1 and FGFR1/KAL2 genes were found. This unique report raises the possibility of an autosomal recessive or X-linked form of KS with new phenotypic expression.

Androgen insensitivity syndrome (AIS) is the major cause of male pseudohermaphroditism. The severity of the disorders varies widely, ranging from the phenotypic women with female external genitalia in cases of complete AIS to the phenotype of ambiguous genitalia in partial androgen insensitivity syndrome (PAIS) and a rare group of phenotypic normal males with azoospermia. Here, we report an infant of PAIS with a missense mutation at position 2881 (G-->A) in exon 7, encoding substitution of histidine for arginine at codon 840 of the androgen receptor (AR) gene. Both the biochemical and molecular studies are presented. Establishing the diagnosis of PAIS is very important for gender assignment to an infant of ambiguous genitalia. The molecular analysis will facilitate genetic counselling to the maternal side relatives for carrier detection and prenatal diagnosis.

We present a case of a 16-year-old girl who attended Endocrinology Clinic in Kraków. Her main complains were amenorrhea and lack of pubic and axillary hair development. Breast development was normal. Based on those features, male karyotype (46, XY) as well as high levels of blood testosterone and lack of uterus on ultrasound examination allowed for establishing the diagnosis of complete androgen insensitivity syndrome. The authors emphasize the possibility of diagnosing severe disorders of sex differentiation, such as sex reversal, not earlier than in teenage patients with delayed puberty. In such cases the diagnosis can be established based on physical examination with evaluation of sexual development, basic blood hormonal tests and karyotype results. Reliable knowledge of male sex differentiation physiology is needed for their correct interpretation.

Androgen insensitivity syndrome (AIS) is caused by mutations in the androgen receptor gene and is associated with a variety of phenotypes in 46,XY individuals, ranging from phenotypic women [complete form (CAIS)] to men with minor degrees of undervirilization or infertility [partial form (PAIS)]. We studied 32 subjects with male pseudohermaphroditism from 20 families (9 CAIS, 11 PAIS) with the following criteria for AIS: 46,XY karyotype, normal male basal and human chorionic gonadotropin-stimulated levels of serum testosterone and steroid precursors, gynecomastia at puberty, and, in prepubertal patients, a family history suggestive of X-linked inheritance. The entire coding region of the androgen receptor gene was analyzed, and mutations were found in all families with CAIS and in eight of 11 families with PAIS. Fifteen different mutations were identified, including five (S119X, T602P, L768V, I898F, and P904V) that have not been described previously. Detailed clinical and hormonal features were compared with genotype in 25 subjects with AIS and confirmed by mutational analysis. LH hormone levels and the LH x testosterone product were high in all postpubertal subjects with AIS. All subjects with PAIS maintained at postpubertal age the gender identity and social sex that was assigned to them in infancy, in contrast to other forms of pseudohermaphroditism.

Objective: Testicular feminised (Tfm) mice express a non-functional androgen receptor, and also have reduced levels of circulating testosterone. Recent studies support a cardio-protective role for testosterone since it elicits systemic and pulmonary vasodilatation. The aim of the present study was to determine whether androgen insensitivity and hypotestosteronaemia in the Tfm mouse are associated with abnormal vascular reactivity or hormone status., Methods: Adult male Tfm and littermate control mice were killed and the blood collected. Femoral (diameter range = 183-508 microm) and pulmonary (diameter range = 320-816 microm) arteries were dissected and loaded in either a wire or pressure myograph, at 100 mmHg or 17.5 mmHg respectively. Pharmacological assessment of the vasoreactivity to potassium chloride (KCl, 80 mmol/l) and either noradrenaline (NA, 1 nmol/l-100 micromol/l) and acetylcholine (ACh, 0.1-100 micromol/l) or testosterone (1 nmol/l-100 micromol/l) was then made., Results: Tfm mice had reduced levels of testosterone (1.8+/-0.3 nmol/l) compared with controls (9.3+/-2.0 nmol/l, P<0.001) and elevated levels of cholesterol (3.6+0.1 mmol/l) compared with controls (3.2+0.1 mmol/l, P<0.05). Femoral arteries from Tfm mice exhibited reduced vasoconstriction to 80 mmol/l KCl (3.27+/-0.23 mN/mm) compared with vessels from controls (4.44+/-0.41 mN/mm, P<0.05), and reduced endothelial-dependent vasodilatation to 0.1-100 micromol/l ACh (23.3+/-3.6% relaxation) compared with vessels from controls (41.6+/-5.4% relaxation, P<0.05). Vasoconstriction to NA (1 nmol/l-100 micromol/l) and vasodilatation to testosterone were unaffected., Conclusions: Androgen receptor deficiency and hypotestosteronaemia in the Tfm mouse reduced endothelial function and impaired voltage-operated calcium channel activity, which may pre-dispose to cardiovascular disease. Testosterone-induced vasodilatation was unaffected, demonstrating no involvement of the androgen receptor in this response.

Androgen insensitivity syndromes (AIS) result from the incapacity for T and dihydrotestosterone to virilize male embryos and is mainly attributable to molecular defects of the AR gene. In normal males, T and LH rise during the first few months of life, and this physiological surge is commonly used to evaluate the gonadotropic axis at this age. This neonatal surge has not been evaluated in detail in newborns with AIS. We sequentially measured plasma T, LH, and FSH during the first 3 months of life in 15 neonates with AIS and AR mutation. A GnRH and an human CG stimulation test were also performed. Patients were divided in 2 groups with complete (n = 10) or partial (n = 5) AIS (CAIS or PAIS), based on the clinical phenotype. In patients with PAIS, T levels were in the high-normal range at d 30 (18.4 +/- 6.9 nM) and d 60 (12.8 +/- 3.8 nM). In contrast, plasma T values were below the normal range in 9 of 10 patients with CAIS at d 30 (1 +/- 0.3 nM) and d 60 (1.4 +/- 0.7 nM, both P < 0.004 vs. PAIS). Plasma LH values were low in CAIS at d 30 (0.7 +/- 0.1U/liter) and increased normally in PAIS (8.7 +/- 2.5 U/liter, P = 0.004). We conclude that the postnatal T and LH surge occurs expectedly in neonates with PAIS but is absent in those with CAIS and that the postnatal T rise requires the receptivity of the hypothalamo-pituitary axis to T.

Objective: Recent reports suggest that low testosterone:androstenedione (T:A) ratio following hCG stimulation may be a useful method of diagnosing 17beta-hydroxysteroid dehydrogenase-3 (17 betaHSD3) deficiency. The aim of this study was to establish the range of T:A ratios in cases of undermasculinization with proven aetiologies other than 17 betaHSD3., Design: Register-based study of cases of male undermasculinization reported to a central database by clinicians., Subjects: Amongst the 421 cases of under-masculinization, 114 cases had testosterone and androstenedione levels before and after hCG stimulation. Of the 114, there were 18 cases of abnormal testes, 17 cases of complete androgen insensitivity syndrome (CAIS), 68 cases of partial AIS (PAIS). Of the 17 cases of CAIS, 13 had evidence of androgen receptor (AR) dysfunction; in the PAIS cohort, 26 cases had evidence of AR dysfunction. Analysis of T:A ratios in the above cohorts and comparison of these ratios to those in a group of previously described cases of 17 betaHSD3 deficiency with a mean ratio of 0.4 (SD: 0.2)., Results: The median age (range) for the CAIS, PAIS and abnormal testes cohort was 1.25 years (0.06-16.5), 0.7 years (0.02-40.3) and 0.5 years (0.04-6.5), respectively. In CAIS, the median T:A rose from 0.4 (0.1 to 8.0) to 4.5 (0.5-16.7); in PAIS, median T:A rose from 0.7 (0.1 to 15) to 3.9 (0.3-20.5); in cases with abnormal testes, median T:A rose from 0.4 (0.1 to 5.6) to 0.6 (0.1-3.6). The median post-hCG T:A ratio was significantly lower in the abnormal testes cohort (P < 0.01). None of the cases of AIS with AR mutation had a low T:A ratio. Only four out of 84 cases diagnosed as AIS had a T:A ratio less than 0.8 (mean + 2SD in 17betaHSD3 deficiency). In one of the four cases, the T:A ratio rose to 3.5 following a prolonged hCG stimulation test., Conclusion: Deficiency of 17betaHSD3 should be considered in 46XY undermasculinization if the post-hCG stimulation T:A ratio is less than 0.8. However, low T:A ratios may be encountered in conditions such as abnormal testes. Before embarking on mutational analysis, we would also recommend careful evaluation for testicular dysgenesis including a prolonged hCG stimulation test in cases with a low T:A ratio.

Aims: To study the value of assessing serum concentrations of luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in patients with male undermasculinisation not caused by androgen insensitivity., Methods: A retrospective study of a register of cases of male undermasculinisation (20 with abnormal testes, eight with 5alpha-reductase deficiency, three with testosterone biosynthetic defects, seven with Drash syndrome, and 210 undiagnosed)., Results: A human chorionic gonadotropin (hCG) stimulation test was performed in 66 of 185 children with male undermasculinisation. In 41 of 66 patients the dose of hCG was either 1000 U or 1500 U on three consecutive days. The rise in testosterone was related to basal serum testosterone and was not significantly different between the two groups. Testosterone:DHT ratio in patients with 5alpha-reductase deficiency was 12.5-72.8. During early infancy, baseline concentrations of LH and FSH were often within normal reference ranges. In patients with abnormal testes, median pre-LHRH (luteinising hormone releasing hormone) concentrations of LH and FSH were 2 and 6.4 U/l, respectively, and post-LHRH concentrations were 21 and 28 U/l. An exaggerated response to LHRH stimulation was observed during mid-childhood in children where the diagnosis was not clear and in all children with abnormal testes., Conclusions: The testosterone:DHT ratio following hCG stimulation is more reliable than the basal testosterone:DHT ratio in identifying 5alpha-reductase deficiency. During infancy, the LHRH stimulation test may be more reliable in identifying cases of male undermasculinisation due to abnormal testes than basal gonadotrophin concentrations.

Steroidogenic tumors are derived from cells of male and female reproductive tracts, adrenal glands, central nervous system, and, to a lesser degree, from the liver and pituitary gland. The symptoms caused by these tumors are related to their secretory products. Because enzymatic pathways are shared by both adrenal- and gonadal-derived tissues, and the conversion of some of these steroids occurs in the adipose tissue, positive identification of many lesions cannot be based on peripheral blood hormone levels alone, but require complex protocols to improve diagnostic accuracy. Furthermore, these tumors often are smaller than the size limit of conventional imaging modalities and thus demand more precise imaging techniques. Although diagnosis and localization may be challenging, the rewards of a positive prognosis, with complete reversal of symptoms, are more likely to occur with early detection and treatment. This article is a review of the clinical syndromes associated with pediatric steroidogenic tumors; suggested strategies to facilitate their diagnosis, localization, and treatment are provided.

A female infant with partial androgen insensitivity (PAIS) was first seen at 4 months of age with slight virilization of the genitalia and externally palpable testes. Sex chromosome was 46,XY. She received left orchidectomy and exploratory laparotomy at 2 yr of age. At exploratory laparotomy, neither a uterus nor fallopian tubes were found. The right testis was preserved by fixing it at the external inguinal ring expecting spontaneous pubertal maturation. After discharge, serum levels of LH, FSH, testosterone (T) and estradiol (E2) were measured annually, and the steroid responses to hCG stimulation were examined every two yr. At the age of 10 yr, she developed breasts and a very feminine body habitus. At 12 yr, she received a clitoroplasty and right orchidectomy. The fibroblast cultures were made from the genital skin whereby androgen receptor (AR) binding was assessed by radioreceptor assay using 3H-DHT as the ligand, and thermoinstability of AR was noted despite normal maximum binding (Bmax) and dissociation constant (Kd) at 22 degrees C. But another binding experiment with 3H-Mibolerone resulted in the lack of receptor binding. AR gene analysis with direct sequencing of coding exons of the gene revealed no abnormality of the AR gene. 5 alpha-reductase activity was normal. Aromatase activity appeared to be enhanced in the genital skin fibroblast (GSF) cells as well as in the testicular tissue. The results of these studies indicated that the patient had PAIS with impaired AR functions and increased aromatase activity. After the discharge, the patient has maintained feminine phenotype, receiving estrogen therapy with mestranol 0.02 mg/day po.

This study investigated the relationship between alcoholics' personality characteristics [as indexed by the Eysenck Personality Questionnaire (EPQ)] and sex steroid levels. Three serum samples were drawn over a 90-min period in 58 inpatient male alcoholics (mean 33 days sober) and 33 non-alcoholic controls. The EPQ was administered at approximately the same point in the treatment process. Replicating previous work, we found alcoholics scored significantly higher on the Neuroticism and Psychoticism scales of the EPQ than controls. Alcoholics also had higher levels of estradiol and total testosterone than controls, which may be reflective of a biological rebound or characteristic premorbid levels. A significant positive correlation was found between testosterone and extroversion in controls, but not in alcoholics. Alcoholics showed a positive correlation between estradiol and neuroticism and a negative relationship between estradiol and extroversion. The results suggest that (a) 'normal' hormone-personality relationships are disrupted in male alcoholics, and b) personality and psychological changes consistent with the physical feminization syndrome may occur in male alcoholics.

A patient with a complete form of testicular feminization with normal gonadotropin and high testosterone levels is described here. These findings are in contrast to previous reports that have shown high circulating luteinizing hormone (LH) levels in adults affected by this syndrome. Testicular histology revealed tubular atrophy and hyperplastic Leydig cells which are in accordance with the high testosterone levels and the difficulty in visualization of the testes. Because of the increased risk of gonadal malignancy, a laparoscopic gonadectomy was performed.

Testicular feminization is a syndrome due to androgen insensitivity. It occurs in a complete and incomplete form. The case of a 17 years old girl with complete androgen insensitivity syndrome is reported. Patient came to medical attention because of primary amenorrhea as the only pathology, with normal external, female genitalia. Diagnosis, findings, management and a five months follow up, are described, as well as a review of this subject.

On the basis of investigation and observation of 41 individuals with androgen insensitivity syndrome (AIS) author confirms that at the phenotypic female and genotypic male patients the value of testosterone in plasma is 6.4 +/- 1.6 mg/ml, corresponding to that characteristic to healthy males. In the classical form there is absent or very scarce pubic hair in 100%, normal development of breasts in 97% of cases, blind vagina of mean length 5.0 +/- 2.3 cm in 97% of cases and inguinal hernia in 30% of cases. In the incomplete form of AIS normal breasts occurs in 62.5%, public hair in 50%, complete absence of vagina in 62.5%, blind vagina of mean length 2.5 cm in 37.5%, inguinal hernia in 75% and hypertrophy of clitoris of mean length 2.0 +/- 1.0 cm in 62.5%, what distinguishes this form of the syndrome from classical form. In incomplete form surgery for inguinal hernia in 87.5% is necessary. In 37.5% artificial vagina has to be created. Classical form occurs in 80.5% and incomplete form in 19.5%. The malignity of the gonads in the discussed syndrome is rare. Castration should be avoided before the patient attains full sexual maturity. Normal value at testosterone level characteristic for men suggests that the lack of sensitivity to androgens of the target cells is the main cause of the disease and is definitively caused by mutations in the androgen receptor gene.

This paper describes the time course of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in two patients with the complete androgen insensitivity syndrome (AIS) during puberty and adolescence prior to gonadectomy. In early puberty, LH values were comparable to normal male as well as female standards. At the age of 17 and 18.7 years, respectively, a sudden rise in LH occurred just after the start of estradiol supplementation. These high LH concentrations in the late puberty of our patients are comparable to the values found during early puberty in castrated individuals and children with gonadal dysgenesis. In contrast, FSH concentrations continuously showed levels in the normal male or female range with no rise during adolescence. The sudden increase of LH in late puberty is most probably due to defective testosterone receptors in the pituitary/hypothalamus which apparently can no longer be suppressed by rising testosterone levels and an escape from the negative estradiol feedback. The role of estradiol supplementation might be incidental and further investigation into its role is needed. In contrast to the elevated levels of FSH in patients with defective spermatogenesis, FSH is normal in our patients with AIS and testes in situ. This indicates that FSH secretion is regulated by a combined action of estradiol and gonadal hormones like inhibin.

A case is presented of a 23-year-old female hospitalized for infertility in whom full Morris syndrome was diagnosed. In the patient apart from testosterone level typical of a sexually mature man, high "castration" LH and FSH values and extreme hyper-estrogen secretion were found in hormonal investigation. In the histopathological pattern of the testicles removed from both inguinal canals numerous adenomas were demonstrated, originating from Sertoli cells and also, to a lesser degree, from Leydig cells. The unusual character of the case results also from complete insensitivity of the hypothalamo-hypophyseal system to circulating oestrogens and androgens (LH and FSH levels were not significantly changed after castration, and the GnRH stimulation test gave similar results before and after the operation). The authors discuss the possible mechanisms of the observed phenomena.

A case of complete testicular feminization (Morris syndrome) in a male pseudohermaphrodite is described. The results of the hormone analyses and the histological features of the resected gonad are presented. The literature is reviewed with special reference to whether gonadectomy should be performed in the pre or post-pubertal period. We advocate early castration because of the high incidence of germ cell neoplasia and the possibility of virilization in case of incomplete androgenic resistance. Our approach is based on the satisfactory feminization achieved by exogenous estrogen therapy.

Androgen insensitivity syndrome (testicular feminization) is classically diagnosed by history, physical examination, karyotype and ultimately exploratory laparotomy. In this case, the diagnosis was verified by amenorrhea, female phenotype, Barr body negative buccal smear, and finally, exploratory laparotomy which revealed bilateral abdominal testes. Testicular vein blood samples obtained at the time of surgery were analyzed for testosterone, follicle stimulating hormone, luteinizing hormone, and prolactin and compared to peripheral vein blood samples. The testosterone concentration in the testicular vein was twice the concentration in the peripheral sample, reflecting gonadal function. The other testicular vein hormone concentrations mirrored the peripheral vein concentrations.

We report on a patient with synchrony of mastopathic alterations and incomplete testicular feminization. In the 54-year old patient, typical climacteric complaints as well as mastopathy-associated symptoms occurred. After orchiectomy and subsequent oestrogen substitution, clinical symptoms disappeared.

Testicular feminized (Tfm) mice are totally insensitive to androgen and may be used to study the role of the androgen receptor in normal development and function. We have examined testicular and Leydig cell steroidogenesis in Tfm mice. Serum bioactive LH was high in Tfm mice but serum testosterone was low and this was associated with a severe reduction in testicular testosterone production in vitro. Examination of [3H]pregnenolone metabolism by testes of Tfm mice indicated that progesterone, rather than testosterone, was the major steroid produced. Leydig cells were isolated from normal and Tfm mice and from normal mice in which testicular descent was surgically prevented before puberty. As in whole testes, androgen production in response to human chorionic gonadotrophin was severely reduced in Leydig cells from testes of Tfm mice compared with normal or cryptorchid groups. In contrast, progesterone production by Leydig cells from testes of Tfm mice was markedly increased in comparison with other groups. Total steroid production (progesterone plus androstenedione plus testosterone), however, was only 24% of normal in Leydig cells from Tfm mice. The pattern of steroid production by Leydig cells from cryptorchid testes was similar to control, although total steroid production was reduced to about 50% (this was significantly higher than the Tfm group, P less than 0.05). The high progesterone/androgen ratio in testes from Tfm mice suggested that 17 alpha-hydroxylase was depleted in these animals. To confirm this, activity of the four major steroidogenic enzymes associated with the smooth endoplasmic reticulum was measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Transsexualism and homosexuality have been theorized to originate in the male from insufficient androgenization of the brain. For verification of this hypothesis clinical science must rely on subjects with an abnormal prenatal/perinatal endocrine history. A case of a 33-year-old 46,XY subject with an incomplete form of androgen insensitivity syndrome (AIS) is presented. In adulthood the only genital sign of masculinization is a clitoris of 4 cm; the vagina is normal size. The diagnosis AIS was verified by androgen receptor studies. At birth there was confusion as to the sex of the newborn. Originally, the subject was assigned to the male sex, but this decision was reversed 5 days after birth and the subject was reared as a girl. At age 30 the subject applied for gender reassignment treatment to the male sex. Upon psychological evaluation the gender identity was unambiguously male and the sexual orientation was exclusively towards women. The estrogen feedback effect on LH, regarded by some as a marker of the sexual differentiation of the neuroendocrinium was negative before orchiectomy but positive after orchiectomy. Our observation demonstrates that in 46,XY subjects a male gender identity and a sexual orientation towards women can develop with a strikingly lower-than-normal level of biological action of androgens.

A familial variant of male pseudohermaphroditism different from the classical form of the complete testicular feminization syndrome was studied. The three affected 46, XY sibling (16,18 and 20 years old) exhibited female phenotype identical to that of a 17 years old patient with the classical form, included as a control. The major endocrine and biochemical differences observed in this family, as compared with the classical form, includes: a. Markedly elevated serum levels of LH and FSH; b. Non-elevated serum testosterone levels; c. Poor testicular hCG responsiveness; d. Abnormally elevated baseline and hCG-stimulated androstenedione: testosterone ratio; e. Slight pituitary responsiveness to androgens; f. presence of residual androgen uptake by cultured fibroblasts derived from genital skin. These differences were more evident in the two older patients. All subjects presented a lack of nitrogen retention following testosterone administration. These results were interpreted as demonstrating a testicular impairment of testosterone biosynthesis in the older subjects of this family, which resulted in an unusual gonadotropin profile. The altered androstenedione: testosterone ratio suggests a secondary partially decreased activity of testicular 17-hidroxysteroid dehydrogenase, as demonstrated in TFM mice and rats. The overall data indicate an age-dependent variability in the expression of androgen insensitivity in this family, thus demonstrating the wide biochemical heterogeneity of the androgen resistant syndromes.

We reported a case with Kennedy-Alter-Sung syndrome (KAS) associated with bilateral external ophthalmoplegia. The patient had movement disturbance of bilateral infra-oblique muscles. The doll's eye phenomenon was not noted. It was suggested that the external ophthalmoplegia was due to the involvement of the oculomotor nucleus that innervated infra-oblique muscle. The serum levels of testosterone and gonadotropin were high, suggesting that the feminization of KAS patients was caused by androgen insensitivity. The feminization of KAS patients is similar to the incomplete form of testicular feminization syndrome except that they do not have feminization of genitals. Therefore, we proposed that abnormalities of androgen receptors might play a role in the pathogenesis of KAS. Fluoxymesterone therapy significantly improved the muscle weakness of the extremities of the patient, even though the therapeutic efficacy was shown temporarily. The therapeutic efficacy of fluoxymesterone for muscle weakness supports our hypothesis.

Information about the reaction of the hypothalamic pituitary axis by Gn-Rh-stimulation dependent from gonadectomy and steroid substitution in 3 patients with androgen insensitivity syndrome. The test was done before and after gonadectomy, under receipt of within the intake of a sequential hormonal contraceptive (Sequenz-Ovosiston) in the 16th cycle and after a pill free interval of 3 months, LH and FSH were estimated with a RIA-method. The LH-base-concentration is independent from the moment of the gonadectomy normogonadotrop and indicate after Gn-Rh-stimulation a regular LH-answer. The FSH-reaction is clearly dependent from the moment of gonadectomy. Not the gonadectomy but the steroid substitution over a long time is decisive about the reaction of the adenohypophysis.

Ten cases with testicular feminization syndrome (TFS) diagnosed at the National Institute of Endocrinology and Metabolism, were studied. The patients were interviewed and subjected to the following psychological tests: Raven's Progressive Matrices, the MMPI, the 16PF, and the TAT. Laboratory determinations included: nuclear chromatin, karyotype, FHS, LH, estradiol, testosterone and nitrogen retention test. Intellectual achievement was found normal, and as far as psychological stability is concerned (MMPI) there was no common profile typical of the group. Psychosexual attitudes showed alterations related to acceptance of body image, fears to be unable to maintain the stability of the couple, and lack of a strong maternal drive. Personality profile manifested two outstanding traits in the group: Dominance (E+) and Shrewdness (N+), the former being remarkably high for a female population. A hypothesis is advanced in regard to the psychological alterations of the possible role of partial androgenization of the central nervous system in these patients.

FSH and LH were functionally examined in 5 women with feminizing testis and compared with the peripheral sex steroid hormones. The oestradiol levels were found decreased, while those of testosteron were elevated. FSH disclosed no significant differences while the basal levels of LH and its stimulatory response to LH-RH were increased in the patients.

The patient, diagnosed as a case of testicular feminisation in infancy, was examined at the age of 15 years because of severe symptoms of virilising puberty with poor breast development. Plasma steroid analyses revealed a 10-fold elevated androstenedione concentration (A: 1562 ng/100 ml). Testosterone (T: 266 ng/100 ml) was in the male pubertal range. Thus the A/T-ratio was far above normal. The oestrone/oestradiol ratio was also elevated (Oe1/Oe2: 10.2/2.2 ng/100 ml). A, T, Oe1 and Oe2 could not be suppressed by dexamethasone, but reacted promptly to fluoxymesterone (A: 781 ng/100 ml). hCG caused a further increase of the A/T-radio (2220/246 ng/100 ml); ACTH did not alter the A-concentration. These findings together with simular investigations after gonadectomy suggest that the failure to convert A to T and Oe1 to Oe2 is essentially located in the testes. In vitro incubations of testicular tissue showed reduced 17-ketosteroid reductase activity in tissue slices and in the subcellular fractions microsomes and cytosole. This form of male pseudohermaphroditism can easily be detected already in infancy, if steroid analyses and stimulation tests are performed. In case of female sex assignment patients should be submitted to early orchidectomy in order to avoid virilisation in puberty.