Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042755 (masculinization)
 2,562 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kennedy's disease (spinal and bulbar muscular atrophy) is an X-linked form of motor neuron disease that affects adult men. The syndrome is characterized by progressive atrophy of the limb muscles, pelvic and shoulder girdles and dysphagia and dysarthria, and is caused by the degeneration of spinal and bulbar motor neurons. Kennedy's disease is caused by a trinucleotide repeat expansion of a CAG repeat in exon A of the androgen receptor gene, and is one of a group of neurological diseases caused by trinucleotide repeat expansions in different genes. The mutation in Kennedy's disease involves an increased number of glutamine residues in the amino-terminal domain of the receptor. Point mutations and deletions in the androgen receptor gene cause androgen insensitivity syndrome, however subjects with Kennedy's disease have normal virilization, although progressive gynaecomastia, testicular atrophy and infertility may occur. Androgen receptors are expressed widely in the normal brain, and in the anterior horn cells of the spinal cord; however, their role in neuronal tissue is not known, nor is it known how the androgen receptor gene mutation causes neuronal degeneration. Kennedy's disease is likely to be a 'gain of function' abnormality, so that the presence of the receptor with an increased number of glutamines is toxic to motor neurons. It is possible that the mutation alters interaction of the receptor with other neuronal transcription factors, or neuronotoxicity may occur because of a non-specific effect caused by the presence of a protein with a large homoglutamine domain. Studies of patients with Kennedy's disease have shown that expression of androgen receptor mRNA and protein in spinal cord may be decreased, as can be the affinity of the mutant receptor for androgen. In vitro studies have shown impaired transcription activation ability of the mutant androgen receptor. The age at onset of Kennedy's disease may correlate with the size of the CAG repeat, however there is a large degree of variability of age at onset between subjects with the same number of repeats. Further study of the effect of the Kennedy's disease mutation on androgen receptor function in motor neurons will allow us to increase our understanding of the pathogenesis of this disease.
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PMID:Spinal and bulbar muscular atrophy: androgen receptor dysfunction caused by a trinucleotide repeat expansion. 886 71

The X-linked androgen receptor (AR) gene contains two polymorphic trinucleotide repeat segments that code for polyglutamine and polyglycine tracts in the N-terminal trans-activation domain of the AR protein. Changes in the lengths of these polymorphic repeat segments have been associated with increased risk of prostate cancer, an androgen-dependent tumor. Expansion of the polyglutamine tract causes a rare neuromuscular disease, spinal bulbar muscular atrophy, that is associated with low virilization, reduced sperm production, testicular atrophy, and infertility. As spermatogenesis is exquisitely androgen dependent, it is plausible that changes in these two repeat segments could have a role in some cases of male infertility associated with impaired spermatogenesis. To test this hypothesis, we examined the lengths of the polyglutamine and polyglycine repeats in 153 patients with defective sperm production and compared them to 72 normal controls of proven fertility. There was no significant association between the polyglycine tract and infertility. However, patients with 28 or more glutamines (Gln) in their AR had more than 4-fold (95% confidence interval, 4.9-3.2) increased risk of impaired spermatogenesis, and the more severe the spermatogenic defect, the higher the proportion of patients with a longer Gln repeat. Concordantly, the risk of defective spermatogenesis was halved when the polyglutamine tract was short (< or = 23 Gln). Whole cell transfection experiments using AR constructs harboring 15, 20, and 31 Gln repeats and a luciferase reporter gene with an androgen response element promoter confirmed an inverse relationship between Gln number and trans-regulatory activity. Immunoblot analyses indicated that the reduced androgenicity of the AR was unlikely to be due to a change in AR protein content. The data indicate a direct relation between length of the AR polyglutamine tract and the risk of defective spermatogenesis that is attributable to the decreased functional competence of AR with longer glutamine tracts.
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PMID:Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. 936 May 40

Klinefelter syndrome is the most common sex chromosome disorder. Affected males carry an additional X chromosome, which results in male hypogonadism, androgen deficiency, and impaired spermatogenesis. Some patients may exhibit all of the classic signs of this disorder, including gynecomastia, small testes, sparse body hair, tallness, and infertility, whereas others, because of the wide variability in clinical expression, lack many of these features. Treatment consists of testosterone replacement therapy to correct the androgen deficiency and to provide patients with appropriate virilization. This therapy also has positive effects on mood and self-esteem and has been shown to protect against osteoporosis, although it will not reverse infertility. Although the diagnosis of Klinefelter syndrome is now made definitively using chromosomal karyotyping, revealing in most instances a 47,XXY genotype, the diagnosis also can be made using a careful history and results of a physical examination, with the hallmark being small, firm testes. As it affects 1 in 500 male patients and presents with a variety of clinical features, primary care physicians should be familiar with this condition.
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PMID:Klinefelter syndrome. 964 24

We studied a man who sought medical attention at age 28 years because of infertility in both his first and second marriages. His sexual development appeared to have been normal, with normal puberty and virilization, and normal libido and sexual potency. At examination, his testicles were small and soft; otherwise he had a normal physical appearance. Evaluations revealed azoospermia, undetectable in serum before and after 100 microg of intravenously administered gonadotrophin releasing hormone, but moderately elevated lutropin concentration with a brisk rise after gonadotrophin releasing hormone. The alpha subunit concentration was normal before and after gonadotrophin releasing hormone; that of inhibin B was very low. Analysis of the follitropin beta gene, exon 3, revealed a Cys82 --> Arg mutation (TGT --> CGT). Judging from studies of the biosynthesis of the chorionic gonadotrophin beta subunit one may conclude that inability to form the first intramolecular disulphide bond in the follitropin beta subunit results in an abnormal tertiary structure during follitropin beta biosynthesis with extensive intracellular degradation of the products, inability to associate with the alpha subunit and defective glycosylation, as well as inability to form a biologically active hormone. This first male case of follitropin deficiency thus defines a new syndrome of male infertility.
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PMID:Follitropin (FSH) deficiency in an infertile male due to FSHbeta gene mutation. A syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations. 980 82

Background: Congenital adrenal hyperplasia (CAH) due to deficiency of steroid 21- hydroxylase (CYP21) is an autosomal recessive disease that is a major cause of ambiguous genitalia at birth in females. The milder late-onset form of the disease can cause mild virilization in women including hirsutism, infertility, and acne. Characterization of the causative mutations in a patient requires finding mutations on both chromosomes. Methods and Results: We use polymerase chain reaction (PCR) followed by restriction enzyme digestion (RED), among several other methods, to detect mutations in the CYP21 gene. The authors found two different point mutations in a patient with CAH, V281L and Q318X. Did we find two mutations in trans which would account for the disease, or two mutations in cis with a still unknown mutation(s) on the other chromosome? We devised a method to determine the cis/trans nature of the mutations using PCR amplification, digestion with a restriction enzyme (ApaL I) diagnostic for V281L, gel purification of the mutant band which lacks the cutting site, digestion with a second restriction enzyme (Pst I) which detects Q318X, and gel electrophoretic analysis of the products. Although the results initially supported a a cis orientation, consideration of the impact of heteroduplex formation during the PCR on the products of RED showed that the orientation was actually trans. Conclusions: When DNA that is heterozygous for a mutation is amplified using the PCR, four double-stranded DNA products can be formed: the two homoduplexes and two heteroduplexes. The heteroduplex DNA must be considered to ensure correct interpretation of the results of PCR-RED analysis.
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PMID:The Importance of Heteroduplexes in Interpreting the Results of PCR-RED Diagnostic Assays: Application to the Analysis of Mutations in the Steroid 21-Hydroxylase Gene in a Case of Congenital Adrenal Hyperplasia. 1002 63

Family and personal history as well as clinical examination are the basic data to be known before laboratory examinations should be started. To obtain results that can be correctly interpreted, the blood sampling has to be done in the early morning hours between day 1 and 5 of the cycle, and for some hormones on an empty stomach. Depending on the clinical data, the hormonal screening can be selective and well directed, or it has to be broader. The presence or absence of galactorrhea, of hot flushes and of androgenization or virilization play an important role for the decision about the hormones to be determined. Furthermore, an eventual desire infertility will influence the selection of the hormonal tests to be done. The present review intends to propose some simple recommendations to the non-specialist how a gynaecological-endocrinological screening for the most important clinical questions should be organized.
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PMID:[Screening for gynecologic-endocrinologic problems before menopause]. 1066 81

Polycystic ovary syndrome(PCOS) is characterized by clinical symptoms such as menstrual dysfunction, unovulatory infertility, masculinization, obesity, polycystic ovary by ultrasound, and endocrine abnormalities such as hyperandrogenism, and elevated LH to FSH ratio. Recent reports suggest that insulin resistance plays an important role in the pathogenesis of PCOS, and several insulin sensitizing agents have been used for the treatment of PCOS. Troglitazone, one of the thiazolidinediones, improves not only insulin sensitivity but also hyperandrogenism and ovulatory function. Troglitazone appears to be useful in treating women with PCOS. Further investigations are needed to assess the effectiveness and safety.
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PMID:[Troglitazone for treatment of polycystic ovary syndrome]. 1070 78

The androgen receptor (AR) protein regulates transcription of certain genes. Usually, this activity depends upon a central DNA-binding domain that permits the binding of androgen-AR complexes to regulatory DNA sequences near or in a target gene. The AR also has a C-terminal androgen-binding domain (ABD) and an N-terminal modulatory domain. These domains interact among themselves and with coregulatory, nonreceptor proteins to determine vector control over a gene's transcription rate. The precise roles of these proteins are active research areas. Severe X-linked androgen receptor gene (AR) mutations cause complete androgen insensitivity, mild ones impair virilization with or without infertility, and moderate ones sometimes yield a wide phenotypic spectrum among sibs. Different expressivity may reflect variability of AR-interactive proteins. The family history must identify heterozygous XX females with sparse, delayed, or asymmetric pubic/axillary hair or delayed menarche and infertile XY maternal aunts or uncles. Mutation type and density vary along the length of the AR. N-terminal polyglutamine tract expansion limits AR transactivation, causing a form of mild androgen insensitivity. Analysis of ABD mutations that do not impair androgen binding or impair it selectively will illuminate its intradomain properties. For partial androgen insensitivity and mild androgen insensitivity, pharmacotherapy with certain androgens or other steroids may overcome some dysfunction of certain mutant ARs. Experience with this approach is limited; outcomes have been generally disappointing.
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PMID:Androgen insensitivity. 1072 96

Abnormal human spermatogenesis is caused by a variety of genetic and acquired conditions. Because spermatogenesis is dependent on androgens, some males may have a minimal form of androgen insensitivity that does not inhibit virilization but impairs fertility. This has lead us to investigate the possibility of abnormalities in the androgen receptor (AR) gene in a large cohort of males suffering from infertility of unknown cause. We studied 180 males with variable impairment of spermatogenesis. In all patients, serum levels of testosterone and gonadotropins were analyzed to define an androgen sensitivity index (ASI). Single-strand conformation analysis and direct DNA sequencing of PCR-amplified blood leukocyte DNA were used to identify mutations within the whole coding region of the AR-gene. Endocrine and molecular investigations were compared with 53 normal males with proven fertility. In three infertile males, mutations in the AR were identified. Two unrelated males had the same variation within the first exon encoding for the transactivation domain of the receptor (Pro390Ser), whereas, in the third, a mutation in the hormone-binding region was characterized (Gln798Glu). All identified mutation carriers had a significantly elevated ASI. A proportion of males with idiopathic infertility carry relevant variations within the AR-gene. These males may be distinguished on the basis of hormone levels, calculating the ASI, although this index lacks specificity.
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PMID:Significance of mutations in the androgen receptor gene in males with idiopathic infertility. 1094 87

The multi-factorial etiology of hypospadias is becoming more defined with ongoing investigation. Implicated factors include testosterone biosynthesis defects, 5 alpha-reductase type 2 mutations, androgen receptor mutations (rare), IVF (progesterone administration or endocrine abnormalities associated with infertility), and environmental agents that can disrupt the male sex hormone axis. It also seems that the incidence of hypospadias is on the rise, both in the United States and in Europe. Hypospadias is a physical manifestation that may be a consequence of numerous physiological aberrations, and our ability to understand and to potentially prevent this problem will require a significant amount of additional work. Our challenge for the future remains to identify the various etiologies, provide prenatal counseling for affected families with a history of hypospadias, and minimize or eliminate exposure to environmental agents that may contribute to this problem. It is even possible that some day we may be able to offer prenatal therapy to prevent hypospadias when the risk for this birth defect seems high. Does this sound far-fetched? Consider the modern management of a family with a child born with the adrenogenital syndrome, another endocrine derangement that can cause abnormal genital development. In this situation, dexamethasone can be administered to the mother in subsequent pregnancies to prevent fetal virilization until the sex of the fetus can be determined or adrenal enzyme mutations can be excluded. Perhaps in the future a similar approach will be taken for those families with strong risk factors for hypospadias.
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PMID:What is the etiology of hypospadias? A review of recent research. 1098 77


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