[Aldosterone- and cortisol-co-secreting adrenal tumors: an uneasy sum of well-known parts (review)].

Primary aldosteronism (PA) is the most common form of secondary arterial hypertension. In patients with PA, more so than in the general population, there is a prevalence of insulin resistance, diabetes mellitus, metabolic syndrome, osteoporosis, and symptoms of depression; these conditions are more likely to manifest a gluco- rather than mineralocorticoid excess. This fact is of particular importance in light of recent studies that have shown that PA is often associated with glucocorticoid excess. Since the first reports of cases of combined secretion of aldosterone and cortisol in 1979, the number of cases of so-called Connshing syndrome has increased. An analysis of data from recent studies suggests that hypercortisolism in PA is closely associated with an increased risk of cardiovascular complications, metabolic disorders and post-surgical adrenal insufficiency. The most important diagnostic problem in adenomas with combined secretion is the risk of false interpretation of the results of adrenal venous sampling (AVS). The indications that suggest aldosterone-and-cortisol-co-producing adenoma are the lack of suppression of cortisol levels following a night test with 1mg of dexamethasone, and an adrenal tumo of over 2.5cm. As an alternative test capable of differentiating this type of tumor, a number of researchers have proposed measuring the level of so-called hybrid steroids in the peripheral plasma and urine. Taking into account the high prevalence and potential risks, ruling out of excess corisol secretion is obligatory in all cases of PA before AVS and when planning surgery.

Manejo con cinco antihipertensivos en paciente con pubertad precoz. Reporte de caso / Management with five antihypertensives in patient with precocious puberty. Case report

RESUMEN Introducción: la hiperplasia suprarrenal congénita por deficiencia de 11-beta-Hidroxilasa es una enfermedad autosómica recesiva poco frecuente, y en estadios avanzados sus complicaciones cardiovasculares exigen un manejo aún más complejo. Presentación del caso: paciente masculino que inicia pubarca a los 2 años de edad, por lo que se diagnostica hiperplasia suprarrenal congénita por deficiencia de 11-beta-Hidroxilasa, y subsecuente hipertensión desde sus 5 años. Consulta a los 8 años de edad por una intoxicación alimentaria que desencadena una insuficiencia adrenal. Adicionalmente se diagnostica pubertad precoz periférica, melanodermia, hipopotasemia e hipertrofia ventricular izquierda. Requiere manejo con hidrocortisona a dosis de estrés y uso de cinco antihipertensivos. Discusión: el tratamiento determina el pronóstico del paciente; al no realizarse el manejo oportuno puede producirse pubertad precoz e hipertensión arterial con complicaciones irreversibles como deterioro de la talla final y la hipertrofia ventricular izquierda respectivamente.

SUMMARY Introduction: Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is an infrequent autosomal recessive disease and the associated cardiovascular complications in the advanced stages make the management even more complex. Case presentation: A male patient who starts pubarche at 2 years old, therefore, he is diagnosed with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency, and subsequent hypertension from age 5. At eight-years-old, he is hospitalized for a foodborne illness that causes adrenal insufficiency. Additionally, he is diagnosed with peripheral precocious puberty, melanoderma, hypokalemia and left ventricular hypertrophy. He required stress dose of hydrocortisone and five antihypertensives. Discussion: Treatment determines a patient's prognosis. Therefore, once precocious puberty and hypertension produce irreversible complications such as deterioration of the final height and left ventricular hypertrophy respectively, the management is extremely difficult.

Height augmentation in 11ß-hydroxylase deficiency congenital adrenal hyperplasia.

CONTEXT: 11ß-hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia. Untreated, this enzyme deficiency leads to virilization, hypertension, and significant height impairment. PATIENT: We describe a patient from abroad who first presented to us at age 7 years for follow-up of ambiguous genitalia. He had been investigated and treated in Pakistan at 3-years-of-age following presentation for bilateral cryptorchidism. He was found to have 46, XX karyotype, elevated 17-OH progesterone and was diagnosed with congenital adrenal hyperplasia. In Pakistan, the patient had abdominal hysterectomy, bilateral salpingoophrectomy, and was started on corticosteroid replacement. At 7 years, shortly after immigrating to Canada, height was 138 cm and BMI 19.3 kg/m(2) (+2.9 SDS and +1.7 SDS, respectively, male growth chart) and blood pressure was greater than the 99th percentile for age and height. The patient had Prader stage III - IV genital anatomy. Bone age was significantly advanced, yielding a severely compromised predicted final adult height. Biochemical evaluation was consistent with 11ß-hydroxylase deficiency congenital adrenal hyperplasia. INTERVENTION AND OUTCOME: In an attempt to improve final height, in addition to glucocorticoid replacement, this patient was treated with recombinant growth hormone and a third generation aromatase inhibitor (Letrozole) with an improvement in final height attained as compared with predicted height. CONCLUSIONS: This case of a 46,XX patient raised as male with congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency highlights a number of unique and difficult treatment challenges; specifically, the role of new therapeutic options for optimization of growth in the context of prior suboptimal disease management.

MicroRNA-24 is a novel regulator of aldosterone and cortisol production in the human adrenal cortex.

Dysregulation of aldosterone or cortisol production can predispose to hypertension, as seen in aldosterone-producing adenoma, a form of primary aldosteronism. We investigated the role of microRNA (miRNA) in their production, with particular emphasis on the CYP11B1 (11ß-hydroxylase) and CYP11B2 (aldosterone synthase) genes, which produce the enzymes responsible for the final stages of cortisol and aldosterone biosynthesis, respectively. Knockdown of Dicer1, a key enzyme in miRNA maturation, significantly altered CYP11B1 and CYP11B2 expression in a human adrenocortical cell line. Screening of nondiseased human adrenal and aldosterone-producing adenoma samples yielded reproducible but distinctive miRNA expression signatures for each tissue type, with levels of certain miRNA, including microRNA-24 (miR-24), differing significantly between the 2. Bioinformatic analysis identified putative binding sites for several miRNA, including miR-24, in the 3' untranslated region of CYP11B1 and CYP11B2 mRNAs. In vitro manipulation of miR-24 confirmed its ability to modulate CYP11B1 and CYP11B2 expression, as well as cortisol and aldosterone production. This study demonstrates that Dicer-dependent miRNA, including miR-24, can post-transcriptionally regulate expression of the CYP11B1 and CYP11B2 genes. Normal adrenal tissue and aldosterone-producing adenoma differ significantly and reproducibly in their miRNA expression profiles, with miR-24 significantly downregulated in the latter. Adrenal miRNA may, therefore, be a novel and valid target for the therapeutic manipulation of corticosteroid biosynthesis.

Testosterone implants modify the steroid hormone balance and the gonadal physiology of gilthead seabream (Sparus aurata L.) males.

Androgens can induce complete spermatogenesis in immature or prepubertal teleost fish; however, many aspects of the role of androgens in adult teleost spermatogenesis remain elusive. We used the in situ forming microparticle (ISM) system containing 1mg of testosterone (T)/kg body weight (T-ISM) in a homogenous population of gilthead seabream at testicular involution stage to study in vivo the effects of T on the sex steroid hormone balance and on the physiology of the gilthead seabream gonad. The levels of T, 11-ketotestosterone (11KT) and 17ß-estradiol (E2) in plasma, gonad and liver were determined in T-ISM implanted specimens after 7, 14, 21 and 28 days. The effect of T-ISM was evaluated on (i) de novo synthesis and metabolism of T in the gonad and liver by measuring the gene expression levels of the main steroidogenic proteins involved, (ii) the progress of spermatogenesis, (iii) the presence of different leukocyte cell types in the gonad, and (iv) the mRNA expression of some genes involved in the leukocyte migratory influx into the gonad and of some immune-relevant molecules. T-ISM implants promote an increase of T up to supra-physiological levels which induce a depletion of E2 levels and maintain the 11KT levels at physiological concentrations. The gene expression profile of some steroidogenic enzymes in gonad and liver ruled out the transformation of T into estrogenic compounds following T-ISM implantation. Moreover, androgens may also be involved in the leukocyte migratory influx, which occurred even when cytokine, chemokine and cell adhesion molecule gene expressions were down-regulated. Moreover, T-ISM implants block germ cell proliferation, although increased dmrt1 gene expression may prevent the complete depletion of germ cells in the gonad. Furthermore, T down-regulated the expression of several tlr genes, which may result in the inhibition of the immune response in the gonad through the impaired ability to recognize and respond to pathogens.

Small interference RNA-mediated CYP 1B 1 gene silencing inhibits the proliferation of human breast cancer MDA-MB-231 cells induced by polyunsaturated fatty acids / 肿瘤

Objective: To investigate the effect of CYP 1B 1 (cytochrome P-450 1B1) gene silencing induced by small interference RNA (siRNA) on the proliferation of MDA-MB-231 cells treated with EPA (eicosapentaenoic acid) and AA (arachidonic acid). Methods: The proliferation of MDA-MB-231 cells treated with EPA or AA was detected by CCK-8 (cell counting kit-8) assay. The expression of CYP1B1 was interfered by RNAi (RNA interference) technique. The transfection efficiency was examined by realtime fluorescence quantitative PCR (RFQ-PCR) and Western blotting, respectively. The expression levels of CYP1B1 and COMT (catechol-O -methyltransferase) mRNAs and proteins in MDA-MB-231 cells interfered with siRNA and treated with EPA or AA were determined by RFQ-PCR and Western blotting, respectively. The viability of breast cancer MDA-MB-231 cells interfered with siRNA and treated with EPA or AA was detected by CCK-8 assay. Results: The cell number of EPA-treated group was lower while the cell number of AA-treated group was higher than that of the control group (P <0.05). The expression levels of CYP1B1 mRNA and protein were decreased in MDA-MB-231 cells transfected with CYP1B1 siRNA, while the expression levels of COMT mRNA and protein were increased. The proliferation of MDA-MB -231 cells transfected with CYP1B1 siRNA was inhibited, and the number of MDA-MB -231 cells treated with EPA was significantly higher than that of the negative control group (P <0.05). Conclusion: CYP 1B 1 gene silencing inhibits the proliferation of MDA-MB-231 cells and reverses the inhibitory effect of EPA on the cell proliferation. EPA probably inhibits the cell proliferation through regulating the expression of CYP1B1 in breast cancer. © 2012 by Tumor.

Genetic analyses of the chimeric CYP11B1/CYP11B2 gene in a Korean family with glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inheritable form of hyperaldosteronism with early onset hypertension. GRA is caused by unequal crossing-over of the steroid 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropin. Here, we describe three cases of GRA in a Korean family. The proband-a 21-yr-old female-was incidentally found to have high blood pressure (170/108 mmHg). Her 46-yr-old father had been treated twice for cerebral hemorrhage at the ages of 29 and 39 yr. Her 15-yr-old brother had a 2-yr history of hypertension; however, he was never treated. Their laboratory test results showed normokalemia, hyporeninemia, hyperaldosteronism, and a high plasma aldosterone concentration-to-plasma renin activity ratio. Normal saline loading failed to suppress aldosterone secretion. However, dexamethasone administration effectively suppressed their plasma aldosterone concentrations. Following genetic analyses with PCR and direct sequencing to document the chimeric gene and crossover site, respectively, we identified CYP11B1/CYP11B2 and determined the breakpoint of unequal crossover to be located between intron 2 of CYP11B1 and exon 3 of CYP11B2.

Genetic Analyses of the Chimeric CYP11B1/CYP11B2 Gene in a Korean Family with Glucocorticoid-Remediable Aldosteronism

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inheritable form of hyperaldosteronism with early onset hypertension. GRA is caused by unequal crossing-over of the steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropin. Here, we describe three cases of GRA in a Korean family. The proband-a 21-yr-old female-was incidentally found to have high blood pressure (170/108 mmHg). Her 46-yr-old father had been treated twice for cerebral hemorrhage at the ages of 29 and 39 yr. Her 15-yr-old brother had a 2-yr history of hypertension; however, he was never treated. Their laboratory test results showed normokalemia, hyporeninemia, hyperaldosteronism, and a high plasma aldosterone concentration-to-plasma renin activity ratio. Normal saline loading failed to suppress aldosterone secretion. However, dexamethasone administration effectively suppressed their plasma aldosterone concentrations. Following genetic analyses with PCR and direct sequencing to document the chimeric gene and crossover site, respectively, we identified CYP11B1/CYP11B2 and determined the breakpoint of unequal crossover to be located between intron 2 of CYP11B1 and exon 3 of CYP11B2.