Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Congenital adrenal hyperplasia (CAH) is an inherited metabolic disease caused by the deficiency of one of the enzymes necessary for cortisol synthesis. Deficiency of 21-hydroxylase (21-OH) accounts for 95% of affected patients There are two forms of the disease. The first is classic, which may be incomplete (simple virilizing) or complete (salt wasting). The second is nonclassic, which may be symptomatic or asymptomatic. In classic 21-OH deficiency which occurs in 1:10000-15000 live births, prenatal exposure to excess androgens results in virilisation of female fetus. Newborn males have normal genitalia. Postnatally, untreated females as well as males present with signs of androgen excess. Three fourths of classic 21-OH deficiency cases do not effectively synthesize aldosterone and are salt wasting, a condition that is potentially fatal. Nonclassic 21-OH deficiency, allelic variant of classic 21-OH deficiency is associated with a milder enzymatic defect and no genital ambiguity at birth, but postnatal virilization may be seen. A subset of individuals with nonclassic 21-OH deficiency are asymptomatic, despite high levels of androgens (cryptic form of disease). The 21-OH enzyme, a cytochrome P450 hemoprotein (cytochrome P450 c21) is encoded by the gene CYP21, which has a closely neighboring homologous pseudogene, CYP21P. Mutations in the CYP21 gene, causing 21-OH deficiency, are common and occur owing to two mechanisms: gene deletion and apparent gene conversion. Prenatal diagnosis is important to identify a fetus affected with 21-OH deficiency. Genital ambiguity in affected females can be prevented by proper administration of dexamethasone to pregnant mother. Postnatally, the treatment of 21-OH deficiency is lifelong hormonal replacement. With carefully supervised medical treatment. CAH patients have the capacity for normal puberty and fertility.
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PMID:[Congenital adrenal hyperplasia due to 21-hydroxylase enzyme deficiency]. 875 1

Twenty-one hydroxylase (21-OH)-deficient classic adrenal hyperplasia (CAH) and nonclassic adrenal hyperplasia (NCAH) are two of the most common genetic disorders known to man, yet the mechanism(s) resulting in steroid excess remains unclear. Overactivation of the hypothalamic-pituitary-adrenal (HPA) axis and increased ACTH secretion appear to be important mechanisms resulting in steroid excess in untreated patients, at least in the classic forms of the disorder. Nonetheless, most NCAH patients do not demonstrate overactivity of the HPA axis. A few of these patients may demonstrate a mild degree of ACTH hyper-responsiveness to corticotropin-releasing hormone stimulation, and up to 40% have radiologic evidence of adrenocortical hyperplasia and/or isolated adenomas, suggesting that some degree of chronic ACTH excess is present. Another mechanism resulting in adrenocortical excess in adrenal hyperplasia, and primarily in NCAH, follows the alteration in enzyme kinetics resulting from the mutation of 21-OH. The mutated enzyme product is less efficient than the wild type, resulting in an increased precursor to product ratio, independent of ACTH levels. Hence, progesterone (P4) and 17-hydroxyprogesterone (17-HP) levels in these patients may remain above normal even in the presence of excess glucocorticoid administration. Overactivity of the renin-angiotensin system may also be important in stimulating adrenocortical steroidogenesis in patients with salt-wasting and in some with simple virilizing CAH. Alterations in ovarian and gonadotropic function, with the appearance of a polycystic ovary-like picture, also contribute to the androgen excess of these patients. Functional ovarian abnormalities in patients with CAH or NCAH may relate to a number of causes, including prenatal masculinization of the hypothalamic-pituitary-ovarian (HPO) axis by adrenal androgens, continued disruption of the HPO axis by persistently elevated P4 or androgen levels, and/or a direct glucocorticoid effect. Finally, these data suggest that the measurement of P4 or 17-HP may not be the most accurate marker of therapeutic efficacy, and suppression of both the ovaries and adrenals may be necessary for optimum steroidogenic control.
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PMID:The 21-hydroxylase-deficient adrenal hyperplasias: more than ACTH oversecretion. 892 12

The psychoendocrinology of the development of normal gender identity and its variations is poorly understood. Studies of gender development in individuals born with endocrinologically well-characterized intersex conditions are heuristically valuable for the disaggregation of factors that are acting in concert during normal development. Four 46,XX individuals with classical congenital adrenal hyperplasia (CAH) and atypical gender identity entered a comprehensive research protocol including systematic interviews and self-report inventories on gender role behavior and identity, sexual history, and psychiatric history. Some of the data on gender variables were compared to data from 12 CAH women with the salt-wasting variant (CAH-SW) with female gender identity. The four patients (ages 28, 35, 38, and 30 years) represented three different subtypes of classical early-onset CAH: 21-OH deficiency, simple virilizing (CAH-SV); 21-OH deficiency, salt-wasting (CAH-SW); and 11-beta-OH deficiency. Their medical histories were characterized by delay beyond infancy or lack of surgical feminization of the external genitalia and progressive virilization with inconsistent or absent glucocorticoid replacement therapy. Although three patients had undergone one or more genital surgeries, all had retained at least some orgasmic capacity. In regard to childhood gender-role behavior, the four gender-change patients tended to be more masculine or less feminine than (behaviorally masculinized) CAH-SW controls. All patients were sexually attracted to females only. The process of gender change was gradual and extended well into adulthood. The most plausible factors contributing to cross-gender identity development in these patients appeared to be neither a particular genotype or endocrinotype nor a sex-typing bias on the part of the parents but a combination of a gender-atypical behavioral self-image, a gender-atypical body image, and the development of erotic attraction to women. Implications for psychosocial management are also discussed.
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PMID:Gender change from female to male in classical congenital adrenal hyperplasia. 904 60

The polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) profile analysis could be applied to the prenatal diagnosis of steroid 21-hydroxylase deficiency. We designed PCR primers to amplify most of the 21-hydroxylase gene, including all the mutations previously reported. PCR-SSCP analysis in eight patients showed at least one polymorphic site in each case. We confirmed that the mobility shifts in SSCP in an affected kindred were transmitted as a Mendelian trait. As these results indicated that PCR-SSCP profiles could be used for DNA-based diagnosis, we attempted to use this technique for prenatal diagnosis. DNA was obtained by chorionic villus sampling of a fetus and PCR-SSCP profiles were analysed in the PCR-amplified fragments in which the mobility shifts had been observed in the SSCP of the proband. We concluded that the fetus was a carrier. Direct nucleotide sequencing and allele-specific oligonucleotide hybridization confirmed that the fetus was heterozygous. At birth, the infant showed no signs of virilization or of abnormal endocrine findings on laboratory study. The results suggest that this new application of PCR-SSCP has advantages over conventional RFLP analysis and is useful in making a prenatal diagnosis of steroid 21-hydroxylase deficiency both rapidly and accurately.
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PMID:Prenatal diagnosis of steroid 21-hydroxylase deficiency by analysis of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) profiles. 917 18

21-hydroxylase (21-OH) deficiency accounts for the vast majority of nonclassic (NC) forms of congenital adrenal hyperplasia (CAH), and is associated with symptoms detectable either in childhood (precocious puberty) or sometimes only later in adulthood (hirsutism, acne, amenorrhea). While the severe forms of the disease responsible for salt wasting or simple virilization have been extensively studied, the NC 21-OH deficiency is less well characterized, especially in adults. We studied the 21-OH gene (CYP21) in a population of 69 unrelated hyperandrogenic subjects suspected to be homozygous or heterozygous for NC 21-OH deficiency, based on basal and adrenocorticotrophin (ACTH)-stimulated plasma 17-hydroxyprogesterone (17-OHP, 17-OHPSI) and 21-desoxycortisol (21-DOF, 21-DOFSI) levels. To identify all mutations involved, determination of the whole gene sequence, including exons, exon-intron junctions, and promoter region, was performed, followed by a study of large rearrangements and identification of compound heterozygotes. Alterations were identified in at least one allele of 55 hyperandrogenic subjects. Two NC alterations, Val282Leu and Pro454Ser, were detected in 68% and 7% of the affected alleles, respectively, whereas mutations involved in severe forms were identified in 21% of them. These results document the utility of a molecular diagnosis in hyperandrogenic women suspected of being either heterozygous or homozygous for NC 21-OH deficiency and clearly indicate the importance of genetic counseling in such a population.
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PMID:Exhaustive screening of the 21-hydroxylase gene in a population of hyperandrogenic women. 938 70

Patients with female pseudohermaphroditism have female internal genitalia and karyotype (XX) and various degree of external genitalia virilization. External genitalia is musculinized congenitally when female fetus is exposed to excess androgenic environment. Congenital adrenal hyperplasia (CAH), mostly 21-hydroxylase deficiency, is the most common cause. Maternal androgen excess due to maternal ovarian tumor or drug intake also causes female pseudohermaphroditism. Combination of hormonal therapy and surgical correction is required for CAH. When appropriate treatments were given, normal puberty, fertility and child bearing are possible. HLA typing in patient's family is useful for identifying heterozygote and homozygote, because of close linkage of 21-hydroxylase gene and HLA gene. Prenatal diagnosis and genetic diagnosis for female pseudohermaphroditism due to 21-hydroxylase deficiency can be performed, however prenatal treatment is not completely established.
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PMID:[Female pseudohermaphroditism]. 939 89

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH), in its severe forms, produces virilization of the external genitalia of the affected female fetus. Early treatment with dexamethasone of the pregnant mother at risk of a fetus with 21-OH deficiency avoids the masculinization of the affected female fetus. We present a pregnant mother, where the prenatal diagnosis was established by DNA analysis of a chorionic villous sample obtained in the 9th week of gestation. Molecular analysis showed the female fetus to be affected of 21-OH deficiency. Maternal treatment with dexamethasone started on the 6th week of gestation has prevented the virilization of the affected baby. No significant side effects have been encountered. Prenatal diagnosis and treatment for 21-OH deficiency is effective and safe, as is described in the literature. This is the first case in Spain where both prenatal molecular diagnosis and treatment for 21-OH deficiency have been reported.
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PMID:[Prenatal molecular genetic diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency]. 948 57

The molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency are reviewed. In Sweden, mutation detection based on allele-specific PCR has been used for genetic diagnosis of this disease since 1993. Around 400 affected 21-hydroxylase genes have been analysed so far. An update of the spectrum of mutations among the Swedish patients shows that nine common pseudogene-derived mutations are responsible for the disease in around 95% of alleles. A total of 13 rare, mostly population-specific mutations have been characterized among the remaining 5%. The mutations can be divided into different groups according to severity. This makes it possible to predict clinical outcome in affected subjects based on genotyping. The risk of salt-wasting and prenatal virilization can be estimated, and over-treatment can be avoided in mildly affected cases.
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PMID:Molecular genetics of congenital adrenal hyperplasia (21-hydroxylase deficiency): implications for diagnosis, prognosis and treatment. 951 1

The physiological importance of adrenal 21-hydroxylase cytochrome P450 (CYP21) expression is clearly demonstrated by 21-hydroxylase deficiency, which results in adrenal hyperplasia and over-production of C19 steroids, leading to virilization. The mechanisms regulating normal expression of this key enzyme in human adrenocortical cells are ill defined. Herein we examine the role of the calcium, protein kinase C, and protein kinase A signaling pathways in the expression of CYP21 messenger ribonucleic acid (mRNA) using the H295R human adrenocortical cell model. Forskolin (10 mumol/L) treatment caused a progressive increase in CYP21 mRNA levels (maximum, 4-fold; P < 0.05) over 36 h of treatment, whereas angiotensin II (AII; 10 nmol/L) produced a smaller, biphasic rise (maximum, 1.8-fold at 12 h; P < 0.05). K+ (14 mmol/L) also induced a time-dependent (maximal, 1.5-fold at 12 h; P < 0.05) and dose-dependent (P < 0.05 12 mmol/L or above at 20 h) rise in CYP21 mRNA levels. The action of forskolin was reproduced by dibutyryl cAMP, confirming the involvement of cAMP in this response. The action of AII was greater than that of K+ or the calcium channel agonist BAYK8644, suggesting that AII action was not solely through the Ca2+ signaling pathway. The action of AII was reproduced and indeed exceeded by the protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA; 10 nmol/L; 5.5-fold increase; P < 0.05). The actions of forskolin alone were not significantly increased by combined treatment with AII, suggesting neither synergy nor attenuation of the effects of protein kinase A activation. This was further demonstrated at the level of mRNA and 21-hydroxylase activity by the observation that the effect of forskolin and TPA in combination did not exceed that of TPA alone. Inhibition of protein synthesis with cycloheximide blocked induction of CYP21 as well as type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSDII) mRNA expression in response to AII, forskolin, and dibutyryl cAMP, but had no effect on 17 alpha-hydroxylase cytochrome P450 (CYP17) or cholesterol side-chain cleavage cytochrome P450 (CYP11A) mRNA. Together, these findings were remarkably similar to those of our previous studies regarding mechanisms regulating 3 beta HSDII expression and underline the existence of a subset of steroidogenic enzymes regulated positively (CYP21 and 3 beta HSDII) as opposed to negatively (CYP17 and CYP11A) by the protein kinase C signaling pathway. The additional finding of a small induction of CYP21 expression in response to increased Ca2+, as previously reported for CYP17, but not 3 beta HSDII, expression, also demonstrates that the mechanisms of control of CYP21 and 3 beta HSDII are not identical. This latter finding may also relate to how CYP21 as well as CYP17 expression continues in the zona reticularis after adrenarche, whereas 3 beta HSD expression declines.
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PMID:Protein kinase A, protein kinase C, and Ca(2+)-regulated expression of 21-hydroxylase cytochrome P450 in H295R human adrenocortical cells. 958 61

An update on the molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is given. In Sweden, direct mutation detection has been used for genetic diagnosis of this disease since 1990. Around 400 affected 21-hydroxylase genes have been analyzed so far. Mutations that have arisen by interaction with the adjacent pseudogene, including gene deletion and nine smaller sequence aberrations, are responsible for the disease in around 95% of alleles. A total of 13 rare, mostly population-specific mutations have been characterized among the remaining 5%. Some of these rare mutations are present in the pseudogene at a low frequency, indicating that they have started to spread at a low rate in the population. The mutations can be divided into different groups according to severity. This makes it possible to predict clinical outcome in affected subjects based on genotyping. The risk of salt-wasting and prenatal virilization can be estimated, and overtreatment can be avoided in mildly affected cases.
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PMID:An update on the molecular genetics of congenital adrenal hyperplasia: diagnostic and therapeutic aspects. 982 8


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