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

A 25-year-old woman presented with an extensive adrenocortical carcinoma with severe virilization and mild Cushing's syndrome. In the tumour there was a primacy of the P450C17 (17,20-lyase) over the P450C21 (21-hydroxylase) route, favouring the synthesis of androgens over corticoids. Preoperatively, the patient was treated with the antimycotic agent ketoconazole, a known inhibitor of steroid synthesis, at a dose of 600 mg/day and after a week 1200 mg/day, to reduce operation risks and to achieve a better metabolic control. This treatment markedly decreased hyperandrogenism and normalized the hypercortisolism. The main effect of ketoconazole was at the 17,20-lyase level and probably at a locus prior in steroidogenesis, i.e. at the P450SCC and/or 17 alpha-hydroxylase level. In contrast with other studies no effect at all was seen on the 11-hydroxylase activity of P450C11. After removal of a massive adrenal carcinoma, extending into the vena cava, vena cava resection and hemihepatectomy because of liver invasion, plasma cortisol and androgen values normalized. Despite adjuvant chemotherapy with o,p'-dichlor-diphenyl-dichloretan (4000 mg daily) hyperandrogenism soon recurred and lung metastases became manifest. Within 2 months after starting combined chemotherapy with 5-fluorouracil, cisplatin, and doxorubicin lung metastases almost completely disappeared with clinical and biochemical resolution of the hyperandrogenic state.
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PMID:Favourable response of a virilizing adrenocortical carcinoma to preoperative treatment with ketoconazole and postoperative chemotherapy. 203 46

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

Aberrant adrenocortical function during the first trimester of human fetal development underlies the severe virilization of congenital adrenal hyperplasia due to cytochrome P450 21-hydroxylase (CYP21) deficiency. Although valuable information of human adrenocortical development after 12 weeks gestation is available, less is known earlier in pregnancy. In our studies, the adrenal cortex was first detected in human embryos by hematoxylin and eosin staining at 33 days post-conception (dpc) with distinction between the definitive and fetal zones possible at 52 dpc. Vascular development was apparent within the adrenal gland at 41 dpc. CYP11A and CYP17 were expressed centrally within the fetal zone at 50 dpc and all later time points during the first trimester. Weaker CYP11A immunoreactivity also was visible in the outer region of the adrenal cortex consistent with definitive zone expression. In this location, immunoreactivity was observed for 3beta-hydroxysteroid dehydrogenase and the proliferation marker, Ki67. These data raise the possibility of de novo cortisol biosynthesis during the first trimester of human development and are relevant to the pathophysiology of 46,XX virilization in CYP21 deficiency.
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PMID:Steroidogenic enzyme expression within the adrenal cortex during early human gestation. 1253 Jun 76

Masculinization depends on adequate production of testosterone by the fetal testis within a specific "masculinization programming window." Disorders resulting from subtle deficiencies in this process are common in humans, and environmental exposures/lifestyle could contribute causally because common therapeutic and environmental compounds can affect steroidogenesis. This evidence derives mainly from rodent studies, but because there are major species differences in regulation of steroidogenesis in the fetal testis, this may not always be a guide to potential effects in the human. In addition to direct study of the effects of compounds on steroidogenesis, information also derives from study of masculinization disorders that result from mutations in genes in pathways regulating steroidogenesis. This review addresses this issue by critically reviewing the comparative timing of production and regulation of steroidogenesis in the fetal testis of humans and of rodents and its susceptibility to disruption; where there is limited information for the fetus, evidence from effects on steroidogenesis in the adult testis is considered. There are a number of fundamental regulatory differences between the human and rodent fetal testis, most notably in the importance of paracrine vs. endocrine drives during masculinization such that inactivating LH receptor mutations block masculinization in humans but not in rodents. Other large differences involve the steroidogenic response to estrogens and GnRH analogs and possibly phthalates, whereas for other compounds there may be differences in sensitivity to disruption (ketoconazole). This comparison identifies steroidogenic targets that are either vulnerable (mitochondrial cholesterol transport, CYP11A, CYP17) or not (cholesterol uptake) to chemical interference.
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PMID:Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds. 1988 92