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Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders with defects in the synthesis of cortisol. The synthesis of other steroids such as mineralocorticoids and adrenal/gonadal sex steroids may also be affected. The clinical presentation of the various forms of CAH depend on the following: (1) the affected enzyme, (2) the resid...
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... La forma más frecuente, es la ocasionada por la deficiencia de 21 hidroxilasa (gene CYP 21) que se localiza en el citocromo P450 del retículo endoplásmico y es la causa en 90% de los casos. [1][2][3][4][5][6][7][8] Esta hidroxilasa es la que cataliza la conversión de progesterona a deoxicorticosterona y de 17 hidroxiprogesterona a 11 deoxicortisol, cuyos productos finales son: la aldosterona y el cortisol, respectivamente. 2,5,6 Es por eso que la deficiencia de esta enzima aumenta la concentración de las hormonas adrenocorticotrófica (ACTH), progesterona y de 17 hidroxiprogesterona, activando vías alternas para la biosíntesis de hormonas sexuales y da lugar a un exceso de andrógenos, y la viri-RESUMEN Se informa de una niña recién nacida, con genitales ambiguos, cromatina sexual positiva y cariotipo 46XX, que al final de su segunda semana de vida, presentó hiponatremia, hiperkalemia y alteración ácido-base, con compromiso cardiopulmonar. ...
... [1][2][3][4][5][6][7][8] Esta hidroxilasa es la que cataliza la conversión de progesterona a deoxicorticosterona y de 17 hidroxiprogesterona a 11 deoxicortisol, cuyos productos finales son: la aldosterona y el cortisol, respectivamente. 2,5,6 Es por eso que la deficiencia de esta enzima aumenta la concentración de las hormonas adrenocorticotrófica (ACTH), progesterona y de 17 hidroxiprogesterona, activando vías alternas para la biosíntesis de hormonas sexuales y da lugar a un exceso de andrógenos, y la viri-RESUMEN Se informa de una niña recién nacida, con genitales ambiguos, cromatina sexual positiva y cariotipo 46XX, que al final de su segunda semana de vida, presentó hiponatremia, hiperkalemia y alteración ácido-base, con compromiso cardiopulmonar. Se corrigen sus trastornos metabólicos y se le trata con hidrocortisona con la cual gradualmente se normaliza su desequilibrio iónico. ...
... lización de los genitales femeninos externos o genitales ambiguos. [1][2][3][4][5][6][7][8] PRESENTACIÓN DEL CASO Se trata de una niña recién nacida cuya madre (de 21 años) es intervenida por cesárea, debido a la falta de progresión de su trabajo de parto. Se obtiene producto único vivo, con Apgar de 7/9, Silverman Andersen de 2, Capurro de 41 semanas de gestación. ...
... However, the low level of cortisol causes a compensatory increase in ACTH that drives the synthesis of 11-deoxycorticosterone (has mineralocorticoid activity) and corticosterone (a weak glucocorticoid) leading to mineralocorticoid excess [61]. In addition, cortisol production remains intact with defects in C17,20-lyase activity [62]. Thus, patients treated with AA were predicted to have mineralocorticoid excess versus the adrenal insufficiency seen with ketoconazole treatment. ...
The majority of prostate cancer (PCa) cases are diagnosed as a localized disease. Definitive treatment, active surveillance or watchful waiting are employed as therapeutic paradigms. The current standard of care for the treatment of metastatic PCa is either medical or surgical castration. Once PCa progresses in spite of castrate androgen levels it is termed ‘castration-resistant prostate cancer’ (CRPC). Patients may even exhibit rising PSA levels with possible bone, lymph node or solid organ metastases. In 2010, the only agent approved for the treatment of CRPC was docetaxel, a chemotherapeutic agent. It is now known that cells from patients with CRPC express androgen receptors (AR) and remain continuously influenced by androgens. As such, treatments with novel hormonal agents that specifically target the biochemical conversion of cholesterol to testosterone have come to the forefront. The use of cytochrome P450c17 (CYP17A1) inhibitor underlies one of the most recent advances in the treatment of CRPC. Abiraterone acetate (AA) was the first CYP17A1 inhibitor approved in the United States. This review will discuss CRPC in general with a specific focus on AA and novel CYP17A1 inhibitors. AA clinical trials will be reviewed along with other novel adjunct treatments that may enhance the effectiveness of abiraterone therapy. Furthermore, the most recently identified CYP17A1 inhibitors Orteronel, Galeterone, VT-464, and CFG920 will also be explored.
... La hidrocortisona es el glucocorticoide de elección, ya que su potencia biológica es superponible a la del cortisol endógeno, y además, por su corta vida media tiene menor repercusión sobre el crecimiento y otros sistemas, como el tejido óseo y el metabolismo hidrocarbonado. Las dosis diarias de hidrocortisona recomendadas han ido variando en los últimos años, y hoy se prefiere la administración de dosis ligeramente superiores a la producción endógena de cortisol, que se estima de 6-8 mg/m 2 /día (267), aunque la dosis óptima para un paciente es aquella dosis mínima eficaz que garantice el equilibrio entre un crecimiento y desarrollo puberal normal con una supresión adecuada de andrógenos suprarrenales (378,379). El empleo de preparados de glucocorticoides de vida media más prolongada, como prednisona y dexametasona deben ser evitados durante la infancia y la adolescencia por su mayor efecto supresor sobre el crecimiento. ...
... Circulating levels of DHEA are reduced in the elderly (Carlstrom, et al., 1988;Ukkola, et al., 2001) and in patients with adrenal insufficiency (Cutler, et al., 1979). Adrenal hyperplasia can be associated with increased DHEA levels (Collett-Solberg, 2001). In humans, low DHEA levels have been associated with cognitive decline (Davis, et al., 2008;Ferrari and Magri, 2008). ...
... Clearly, these levels are well below those which would be expected, on the basis of the present data, to modulate GABA A receptors. However, circulating levels of DHEA and metabolites may rise dramatically after systemic administration (Labrie, et al., 2007a,b) or as a consequence of adrenal hyperplasia (Bongiovanni, 1981;Brunelli, et al., 1995;Collett-Solberg, 2001) or other disease states (Sciarra, et al., 1995). Moreover, local synthesis in the brain may result in much higher levels of neurosteroids in specific regions. ...
Dehydroepiandrosterone (DHEA) and its metabolites, DHEA-sulphate (DHEA-S) and androsterone, have neurosteroid activity. In this study, we examined whether DHEA, DHEA-S and androsterone, can influence serotonin (5-HT) neuronal firing activity via modulation of γ-aminobutryic acid (GABA(A)) receptors. The firing of presumed 5-HT neurones in a slice preparation containing rat dorsal raphe nucleus was inhibited by the GABA(A) receptor agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridinyl-3-ol (THIP) (25 μM) and GABA (100 μM). DHEA (100 and 300 μM) and DHEA-S (1, 10 and 100 μM) caused a rapid and reversible attenuation of the response to THIP. DHEA (100 μM) and DHEA-S (100 μM) also attenuated the effect of GABA. Androsterone (10 and 30 μM) markedly enhanced the inhibitory response to THIP (25 μM). The effect was apparent during androsterone administration but persisted and even increased in magnitude after drug wash-out. The data indicate that GABA(A) receptor-mediated regulation of 5-HT neuronal firing is sensitive to negative modulation by DHEA and its metabolite DHEA-S is sensitive to positive modulation by the metabolite androsterone. The effects of these neurosteroids on GABA(A) receptor-mediated regulation of 5-HT firing may underlie some of the reported behavioural and psychological effects of endogenous and exogenous DHEA.
... 17a a a a a-hydroksylazy/17,20-liazy Zlokalizowany w mikrosomach enzym P450c17 katalizuje dwie ważne reakcje w procesie steroidogenezy: hydroksylację progesteronu i pregnenolonu w pozycji 17a oraz rozłożenie wiązania C17–C20 z wytworzeniem dehydroepiandrosteronu (DHEA, dehydroepiandrosterone ) oraz androstendionu [12] . Reakcje te zachodzą zarówno w nadnerczach, jak i gonadach [13, 14]. O ile do wytworzenia glukokortykosteroidów wymagana jest wyłącznie aktywność 17a-hydroksylowa, to synteza androgenów nadnerczowych i gonadalnych wymaga zachowania obu tych aktywności enzymatycznych [12]. ...
... rylacji enzymu P450c17 i zależy od obecności pewnych czynników regulacyjnych wpływających na transport elektronów z NADPH na ten enzym, takich jak cytochrom b 5 [12, 14]. Niedobór 17a-hydroksylazy/17,20-liazy, uwarunkowany mutacją genu CYP17, stanowi rzadką (ocenianą zaledwie na ok. ...
... Upośledzona synteza glukokortykoidów i androgenów nadnerczowych powoduje przesunięcie steroidogenezy nadnerczowej w kierunku związków wykazujących właściwości mineralokortykoidowe, takich jak: 11-dezoksykortykosteron, a zwłaszcza kortykosteron [10, 16] . Efektem tego jest typowa dla stanów nadmiaru mineralokortykoidów prezentacja kliniczna tego zespołu, obejmująca wystąpienie nadciśnienia tętniczego , zasadowicy metabolicznej, hipokaliemii oraz wtórnej hiporeninemii [14, 16] . Obniżone u większości chorych stężenie aldosteronu, mimo braku blokady enzymatycznej w procesie jego biosyntezy, jest konsekwencją występującej w tym zespole hiporeninemii oraz hipokaliemii, wynikających z nadmiaru dezoksykortykosteronu i kortykosteronu [17]. ...
Congenital defects of adrenal steroidogenesis comprises a group of autosomally recessive disorders, which are usually caused by inactivating mutations in single enzymes involved in adrenal steroid biosynthesis. Each of the defects causes different biochemical consequences and clinical features. A different degree of enzyme dysfunction is responsible for a wide range of phenotypic expression even in the same disorder. The basis for the diagnosis of inborn errors of steroidogenesis are often refined methods for steroid determination. Because these defects may result in life-threatening conditions and, if not treated, lead to serious complications, its is essential to consider their presence in a differential diagnosis of various symptoms. Deficiency of 21-hydroxylase, the most common of these disorders, has been recently extensively reviewed. Therefore, this paper discusses the etiopathogenesis, clinical manifestation, biochemical abnormalities and management of other less frequent defects of adrenal steroidogenesis.
... Excess production of hormones proximal to the enzymatic defect results in various clinical phenotypes. The most frequent forms of CAH are 21-hydroxylase (CYP21A2) and 11-hydroxylase (CYP11B1) deficiency (1). Defective mineralocorticoid synthesis may lead to life-threatening salt-wasting crisis. ...
... In the Caucasian population, 21-hydroxylase deficiency, the classical form of CAH, accounts for more than 90% of all cases, whereas 5% are caused by 11-hydroxylase deficiency. Other enzyme deficiencies and clinical phenotypes are less frequent (1). ...
Neonatal screening programs for congenital adrenal hyperplasia (21-CAH) using an immunoassay for 17alpha-hydroxyprogesterone (17-OHP) generate a high rate of positive results attributable to physiological reasons and to cross-reactions with steroids other than 17alpha-OHP, especially in preterm neonates and in critically ill newborns.
To increase the specificity of the screening process, we applied a liquid chromatography-tandem mass spectrometry method quantifying 17alpha-OHP, 11-deoxycortisol, 21-deoxycortisol, cortisol, and androstenedione. The steroids were eluted in aqueous solution containing d8-17alpha-OHP and d2-cortisol and quantified in multiple reaction mode.
Detection limit was below 1 nmol/liter, and recovery ranged from 64% (androstenedione) to 83% (cortisol). Linearity was proven within a range of 5-100 nmol/liter (cortisol, 12.5-200 nmol/liter), and total run time was 6 min. Retrospective analysis of 6151 blood samples and 50 blood samples from newborns with clinically confirmed 21-CAH, as well as prospective analysis of 1609 samples of a total of 242,500 testing positive in our routine 17-OHP immunoassay, allowed clear distinction of affected and nonaffected newborns. High levels of 21-deoxycortisol were only found in children with 21-hydroxylase deficiency. Calculating the ratio of 17alpha-OHP to 21-deoxycortisol divided by cortisol further increased the sensitivity of the method.
Our liquid chromatography-tandem mass spectrometry procedure as a second-tier test can be used to reduce false-positive results of standard 21-CAH screening. The short total run time of 6 min allows for immediate reanalysis of all immunoassay results above the cutoff.
Changes in pituitary-ovarian hormones across the menopausal transition have multiple physiological consequences. However, little is known about how the major types of post-menopausal hormone therapy (HT) affect pituitary-ovarian hormonal relationships. This study evaluated these relationships in recently menopausal women (52.45± 2.49 years of age) in the Kronos Early Estrogen Prevention Study (KEEPS) who were compliant to randomized, double-blinded treatment with oral conjugated equine estrogen (o-CEE, n=109), transdermal 17β-estradiol (t-E2, n=107), or placebo (n=146). Androstenedione, testosterone, 17β-estradiol, estrone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum prior to (baseline) and 48 months after randomization to treatment. Descriptive summaries of hormone levels were performed, and multiple regression analyses were used to examine the effects of o-CEE , t-E2, and placebo on these hormone levels at 48 months adjusting for baseline levels. A network analysis examined the covariance of changes in hormone levels over the 48 months within treatment groups. As expected, at 48 months of treatment, hormone levels differed between women in the two active treatment groups compared to placebo, and network analysis indicated stronger relationships among hormone levels in the t-E2 and o-CEE groups as compared to placebo. Associations among testosterone, 17β-estradiol, FSH and LH differed between the o-CEE group compared to t-E2 and placebo groups. Thus, two common HT regimens differentially alter pituitary-ovarian hormone levels, altering feedback cycles and inter-hormonal associations in recently menopausal women. These interactions provide the basis for future studies investing the impact of hormonal modulation of aging including cognitive decline in women.
Fluid and electrolyte disturbances of endocrine emergencies may be life-threatening but can be highly rewarding if management is carried out promptly and appropriately. A newborn with congenital adrenal hyperplasia presenting as a case of ambiguous genitalia and salt loss needs life-saving treatment promptly. In the absence of ambiguity of genitalia, a high index of suspicion is required to identify this condition. Diabetic ketoacidosis is often the presenting feature of insulin dependent diabetes mellitus at the initial diagnosis. Unless recognized, it may be mistaken for a host of other conditions. Treatment requires careful monitoring. Careful choice of intravenous fluids will be necessary when a child with central diabetes insipidus presents with dehydration.
The author presents a historical review of the knowledge of adrenal cortex function. Present diagnostic and therapeutic possibilities are described according to the consensus of American and European Children Endocrinology Society.
