[Cortodoxone (cortexolone) from hyodesoxycholic acid methyl ester].
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17-Hydroxycorticosteroids↗
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Topical corticosteroid therapy and pituitary-adrenal function.
Systemic absorption has been reported after the use of corticosteroid eye drops. Prolonged use could result in adrenocortical insufficiency and an associated adrenal crisis under stressful situations. For that reason, we studied the hypothalamic-pituitary-adrenal axis of patients receiving corticosteroid eye drope. Fifteen patients were given 0.1% dexamethasone sodium phosphate eye drops, one drop (approximately 1/30 ml) to each eye four times a day for six weeks. This dosage resulted in partial adrenal suppression, manifested by reduced levels of plasma cortisol. However, in each case, the hypothalamic-pituitary-adrenal axis, as evaluated with the use of the oral metyrapone tartrate test, was intact.
Administration, Topical↗
Decrease of ocular pressure with oral metyrapone. A double-masked crossover trial.
To examine the effect of a decrease in plasma cortisol level on intraocular pressure, 14 subjects with elevated ocular pressure were given oral metyrapone tartrate (an inhibitor of adrenal cortisol biosynthesis) and a placebo in a double-masked, two-period, crossover trial. Ocular pressure and the adrenal response were monitored over a seven-hour period. The decrease in ocular pressure after metyrapone administration was significantly greater than that after placebo. The 14 subjects could be designated as responders or nonresponders by decline of ocular pressure after metyrapone administration compared with response after placebo. The responders could be further differentiated from the nonresponders by a smaller decrease in ocular pressure over time in response to the placebo and by a smaller decrease over time of plasma cortisol level in response to metyrapone. These results provide further evidence that plasma glucocorticoids may play a role in the regulation of ocular pressure.
Administration, Oral↗
Transient adrenogenital syndrome due to exposure to danazol in utero.
We describe a premature female infant exposed in utero to danazol during the first trimester of pregnancy. She was first observed in the newborn period with marked degree virilization and clinical findings suggestive of salt-losing congenital adrenal hyperplasia. This was supported by the high plasma levels of 17 alpha-hydroxyprogesterone and adrenocorticotropic hormone and low plasma cortisol level. Levels of testosterone, androstenedione, 11-deoxycortisol, and renin were also elevated. An excessive increase in the levels of 17 alpha-hydroxyprogesterone and 11-deoxycortisol to corticotropin administration associated with impaired increase in plasma cortisol level strongly suggests a partial block in the 21-hydroxylation of 17 alpha-hydroxyprogesterone. However, the high levels of 11-deoxycortisol also suggest a block of the steroid 11 beta-monooxygenase. A year later she was found to have normal basal levels of the adrenal steroids and normal response to corticotropin administration, pointing out the transitory nature of these abnormalities. It may be hypothesized that danazol produced a transitory block of the steroid 21- and 11 beta-monooxygenases in this child.
Adrenal Hyperplasia, Congenital↗
Precocious puberty associated with neurofibromatosis and optic gliomas. Treatment with luteinizing hormone releasing hormone analogue.
Seven children with central precocious puberty and either neurofibromatosis and/or optic gliomas were referred to the National Institutes of Health, Bethesda, Md, for evaluation and treatment with the long-acting luteinizing hormone releasing hormone analogue (LHRHa) D-Trp6-Pro9-NEt-LHRH. Only six of the seven children chose to receive treatment. Four children presented with neurofibromatosis, three of whom also had optic gliomas; the remaining three children had isolated optic gliomas, without other neurocutaneous stigmas. All had central precocious puberty mediated by activation of the hypothalamic-pituitary-gonadal axis. Six months of LHRHa therapy caused suppression of gonadotropin and sex steroid levels, stabilization or regression of secondary sexual characteristics, and decreases in growth velocity and the rate of bone age maturation. We conclude that LHRHa therapy is effective in the treatment of central precocious puberty secondary to neurofibromatosis and/or optic gliomas.
17-alpha-Hydroxyprogesterone↗
Russell-Silver syndrome and hypopituitarism. Patient report and literature review.
Russell-Silver syndrome (RSS) is a sporadic form of prenatal onset dwarfism with typical facial features, variable asymmetry, and linear growth 3 to 4 SDs below the mean. Endocrinologic studies are usually normal; however, six cases of RSS with growth hormone deficiency have been reported, three of which had additional pituitary abnormalities. We describe another case, a 7-year-old girl with RSS and deficiencies of growth hormone, corticotropin, and thyroid-stimulating hormone. Replacement therapy including growth hormone resulted in an improved growth velocity, though twice the usual dose of growth hormone was required and short stature persisted. Since growth hormone secretion is usually normal in RSS, the existence of individuals with RSS phenotype and hypopituitarism including growth hormone deficiency suggests etiologic heterogeneity. We recommend that those individuals with RSS phenotype and a continuous significant decline in height velocity be investigated for pituitary abnormalities. Unusually high replacement doses of growth hormone may be required to overcome deficiency.
Adolescent↗
Augmented pituitary corticotropin response to a threshold dosage of human corticotropin-releasing hormone in depressives pretreated with metyrapone.
We studied pituitary corticotropin response to exogenous corticotropin-releasing hormone infusion and attempted to control for the confounding effect of variable serum cortisol levels between depressed and control subjects. If metyrapone was given during the time of day when hypothalamic pituitary adrenal activity was otherwise low, the relative increase in the corticotropin concentration was small. Pituitary response to exogenous corticotropin-releasing hormone can be defined under conditions in which the amount of glucocorticoid-mediated negative feedback present at the level of the pituitary gland is equal in all subjects. When the ambient cortisol level was equalized (and suppressed) in all subjects at the time of study with a threshold dosage of corticotropin-releasing hormone, we found an augmented response to corticotropin-releasing hormone in depressives. This raises the possibility that either increased pituitary sensitivity to corticotropin-releasing hormone or an increased intracellular pool of corticotropin is available for release in subjects with major depressive illness.
Adrenocorticotropic Hormone↗
Increased evening activation of the hypothalamic-pituitary-adrenal axis in depressed patients.
OBJECTIVE: To determine whether depressed patients demonstrate hypothalamic-pituitary-adrenal (HPA) axis activation during the late afternoon and evening, a time when the HPA axis is usually quiescent in normal subjects. METHODS: We administered metyrapone, an 11-beta-hydroxylase inhibitor of cortisol synthesis, to normal controls and depressed patients between 4 and 10 PM. Metyrapone blockade of cortisol secretion would amplify any HPA axis secretion. RESULTS: In 10 normal control subjects, administration of metyrapone lowered plasma cortisol levels to a mean of 36 nmol/L. No rebound corticotropin or beta-endorphin secretion was seen in these normal controls between 4 and 10 PM, supporting the existence of a period of minimal endogenous corticotropin releasing factor drive. Compared with a group of placebo-treated depressed patients (n = 10), metyrapone-treated depressed subjects (n = 17) had significantly decreased plasma cortisol concentrations. However, in contrast to normal controls treated with metyrapone, metyrapone-treated depressed patients demonstrated rebound corticotroph secretion, particularly between 7:30 and 10 PM (P = .036 for patients vs normal controls for beta-endorphin secretion from 4:30 to 10 PM). CONCLUSION: These data support the hypothesis of increased corticotropin releasing factor drive in the evening in depressed subjects and are in agreement with the longstanding observation of "early escape" from dexamethasone suppression between 4 and 11 PM in depressed patients.
Adrenocorticotropic Hormone↗
Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial.
BACKGROUND: Inhibitors of steroid synthesis have been reported to exert antidepressive effects, according to preliminary findings. OBJECTIVE: To test whether the addition of metyrapone to standard antidepressants induces a more rapid, more efficacious, and sustained treatment response in patients with major depression. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Hospitalized care. PATIENTS: Sixty-three inpatients with a DSM-IV diagnosis of major depression and a baseline score 18 points or higher on the Hamilton Rating Scale for Depression. INTERVENTIONS: Random allocation to 2 treatment groups receiving either placebo or metyrapone (1 g/d) for the first 3 weeks during a 5-week treatment with standard serotonergic antidepressants (nefazodone or fluvoxamine). MAIN OUTCOME MEASURES: Primary outcome criteria were the number of responders and the time to onset of action. Responder rates were considered twice after 3 and 5 weeks with a definition of treatment response as 30% and 50% reduction, respectively, of baseline Hamilton Rating Scale for Depression scores. Onset of action was defined as the time point at which at least a 20% reduction of baseline Hamilton Rating Scale for Depression scores occurred. RESULTS: Using intention-to-treat analysis, we found that a higher proportion of patients receiving metyrapone showed a positive treatment response at day 21 (23 of 33 patients) and at day 35 (19 of 33 patients) compared with placebo patients (day 21: 13 of 30 patients; Fisher exact P = .031; day 35: 10 of 30 patients; Fisher exact P = .047). The clinical course of patients treated with metyrapone showed an earlier onset of action (Kaplan-Meier analysis; log-rank test P<.006) beginning in the first week. The plasma concentrations of corticotropin and deoxycortisol were significantly higher during metyrapone treatment (multivariate analysis of covariance, P<.05), whereas cortisol remained largely unchanged. Metyrapone treatment was well tolerated without serious adverse effects. CONCLUSIONS: Metyrapone is an effective adjunct in the treatment of major depression, accelerating the onset of antidepressant action. A better treatment outcome compared with standard treatment and a sustained antidepressive effect were observed.
Adrenocorticotropic Hormone↗
Corticosteroid biosynthesis in vitro by testes of the grouper (Epinephelus coioides) after 17alpha-methyltestosterone-induced sex inversion.
This study reports the unique compartmentalization of cortisol and 11-deoxycortisol biosynthesis in vitro from [(3)H]17alpha-hydroxyprogesterone (17P) in testicular tissues of groupers after sex inversion induced by 17alpha-methyltestosterone (MT). Before MT implantation, the ovarian tissues produced only nonpolar metabolites. Following sex inversion some 6 months later, synthesis of these nonpolar metabolites was not detectable. Instead, cortisol and 11-deoxycortisol, with yields of about 3% and 14%, respectively, were synthesized together with two other polar metabolites. The corticosteroids and polar metabolites were distinctly nondetectable in ovarian tissues of the control fish throughout the experiment. While the significance of this testicular synthesis of corticosteroids is presently unclear, it could be related to the increased energy demands arising from the reorganization of gonadal tissues during sex inversion.
Animals↗
Evidence of 11 beta-hydroxylase deficiency in childhood adrenocortical tumors. The plasma corticosterone/11-deoxycorticosterone ratio as a possible marker for malignancy.
In search for a biochemical marker to differentiate between adrenocortical carcinoma (AC) and adenoma (AA), plasma levels of the following steroids were studied preoperatively and postoperatively: 11-deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S), and cortisol (F). Levels were measured by Sephadex LH-20 chromatography and specific radioimmunoassays. The subjects included eight children ages 2 years, 5 months to 9 years, 10 months. There were three girls and 5 boys with pseudoprecocious puberty due to adrenocortical tumors (histologically, four were AC and four, AA). The preoperative showed that DOC and S levels were elevated in all patients, F levels were elevated in four of eight children when compared with age-matched controls, whereas B was normal. Postoperatively, all levels returned to normal. The ratios of B/DOC and F/S as an index of adrenal 11 beta-hydroxylase activity were calculated. The preoperative ratios of B/DOC were markedly decreased in all patients with AC compared to controls (7.7,4.1,5.9,1.9 versus 23.5, median), but normal in three of four patients with AA (16.2, 29.6, 16.1). The F/S ratios were significantly lower in AC and AA when compared with controls. The data indicate a deficiency in 11 beta-hydroxylation in cases of adrenocortical tumors. Despite a still limited number of patients, the decreased B/DOC ratios may possibly indicate malignancy and could be helpful in distinguishing by biochemical means between benign and malignant adrenocortical tumors.
Adenoma↗
Pituitary-adrenal axis function in sickle cell anemia and its relationship to leukocyte alkaline phosphatase.
The function of the pituitary-adrenal axis and leukocyte alkaline phosphatase activity were evaluated in eight patients with sickle cell disease during a painful crisis and when crisis-free. The leukocyte alkaline phosphatase (LAP) score did not increase during crisis; the scores were in the low-normal range during crisis and noncrisis periods. Insulin-induced hypoglycemia produced normal growth hormone responses during both crisis and crisis-free periods. Plasma cortisol concentrations were diminished in the crisis group. Also impaired was 11-deoxycortisol production in both groups after metyrapone. These findings indicate that a mild defect in the hypothalamic-pituitary-adrenal axis exists in sickle cell disease patients.
Adult↗
Continuous dehydrogenation of a steroid with immobilized microbial cells: effect of an exogenous electron acceptor.
Whole cells of Pseudomonas testosteroni, induced to synthesize steroid-transforming enzymes beforehand, have been immobilized by entrapment in polyacrylamide gel. The immobilized cells have been used to catalyze the continuous delta1-dehydrogenation of Reichstein's substance S under various conditions in the presence of phenazine methosulfate (PMS), an electron acceptor for the cell-free delta1-dehydrogenase. The presence of PMS substantially increases the rate of reaction when fed with the steroid substrate to a continuous stirred tank reactor containing the immobilized cells. The operational half-life of the delta1-dehydrogenase activity of the cells, about 103 hr under the best operating conditions, is essentially unaffected by the presence of PMS. Though the acceleration of the reaction may be due to PMS-mediated passage of electrons from some component in the electron transport chain to molecular oxygen, the lack of a similar effect with methylene blue is consistent with the conclusion that PMS functions directly as the electron acceptor for the delta1-dehydrogenase.
17-Hydroxycorticosteroids↗
[Contribution toward partial synthesis of 18-oxygenated cortexones I. Synthesis of 18-hydroxy-cortexone].
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17-Hydroxycorticosteroids↗
[Contribution toward partial synthesis of 18-oxygenated cortexones II. Synthesis of 18-oxo-cortexone].
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17-Hydroxycorticosteroids↗
Interaction of steroids with the transport system of glucose in human erythrocytes.
Steroids inhibit the exchange transport of glucose in human erythrocytes. The extent of inhibition is roughly correlated to the affinity of the steroids to the membrane lipids. All C-21-steroids tested show a competitive inhibition while the C-19-steriods show different types of inhibition. 5Beta-androstane-3,17-dione acts as a competitive inhibitor. The inhibition by testosterone is of mixed type, while with androst-4-ene-3,17-dione and 5alpha-androstane-3,17-dione a non-competitive inhibition is observed. In this case two inhibitor molecules can be bound per transport molecule. The "non-competitive" inhibitors compete also to some extent with the glucose binding. This effect, however, is at high inhibitor concentrations masked by the more powerful non-competitive inhibition. Competitive and non-competitive inhibitors compete with each other. The structural requirements for the different types of inhibition are discussed.
17-Ketosteroids↗
Factors involved in supporting the growth and steroidogenic functions of bovine adrenal cortical cells maintained on extracellular matrix and exposed to a serum-free medium.
Bovine adrenal cortex cells maintained on extracellular matrix (ECM)-coated dishes will proliferate actively when serum is replaced by HDL (25 micrograms protein/ml), insulin (10 ng/ml), and FGF (100 ng/ml). The cells have an absolute requirement for HDL in order to survive and grow. The omission of insulin, FGF, or both results in a slower growth rate and lower final cell density of the cultures. A requirement for transferrin (1 microgram/ml) becomes apparent only when cells have been grown for at least four generations in the absence of serum. Early passage (P1-P3) bovine adrenal cortex cells cultured in serum-free medium responded to ACTH (10(-8)M) with increased 11-deoxycortisol production; this effect was not observed in later passage cells (P7-P15). The cells' ability to utilize LDL-derived cholesterol and to respond to db cAMP (1mM) by increased steroid release was preserved in cells cultured for over 60 generations in the serum-free medium. HDL, although also able to increase steroid production in early-passage cultures exposed to ACTH or to ACTH and dibutyryl cyclic AMP (db cAMP), was 10 fold less potent than LDL. It did not support steroidogenesis in cultures not exposed to these trophic agents. The life span of bovine adrenal cortex cells grown in the serum-free medium on fibronectin (FN)- versus ECM-coated dishes was compared. Cells seeded in serum-containing medium and grown in serum-free medium had a life span of 34 versus 60 generations when maintained on fibronectin- or ECM-coated dishes, respectively. Cells seeded in the complete absence of serum in the serum-free medium on ECM- or fibronectin-coated dishes could be passaged for 26 or 13 generations, respectively. While FGF was an absolute requirement for cells cultured on fibronectin-coated dishes, it was not required when cells were maintained on ECM. These observations demonstrate the influence of the ECM not only in promoting cell growth and differentiation but also on the life span of cultured cells.
Adrenal Cortex↗
Induction of maturation of Atlantic croaker oocytes by 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one in vitro: consideration of some biological and experimental variables.
We characterized the in vitro control of germinal vesicle breakdown (GVBD) by 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one (20 beta-S) in intact ovarian follicles of gonadotropin-primed Atlantic croaker. 20 beta-S-induced GVBD was determined in relation to ovarian (oocyte) morphology, duration of incubation, steroid metabolism, and interaction with other steroids. The rate of GVBD in vitro in the absence of exogenous steroid was positively correlated with initial stage of ovarian morphological development. Maximal responsiveness to 20 beta-S was seen in ovaries with oocytes showing the first signs of morphological maturation. Dose-response experiments with 20 beta-S and 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17 alpha,20 beta-P) over a range of incubation times yielded similar results for both steroids, suggesting that conversion of 17 alpha,20 beta-P to 20 beta-S is not required for 17 alpha,20 beta-P-induced GVBD. The ED50 of these steroids markedly decreased with increasing incubation times. Comparisons between patterns of follicular transformation of various radiolabelled steroids to 20 beta-S and their respective activities (using unlabelled steroids) in the GVBD bioassay suggested that, in addition to 17 alpha,20 beta-P, progesterone has some intrinsic maturational activity. However, the maturational effects of 11-deoxycortisol and pregnenolone may be explained by their conversion to 20 beta-S. For the first time in any vertebrate, we showed that the proposed maturation-inducing steroid (20 beta-S) is not significantly transformed to any extractable, potentially active metabolite by intact, maturing ovarian follicles. These findings strongly suggest that 20 beta-S is the terminal product of the MIS biosynthetic pathway in Atlantic croaker ovaries. Estradiol had no acute effects on 20 beta-S-induced GVBD. However, testosterone decreased and cortisol augmented the maturational activity of 20 beta-S. Excess progesterone reduced the activity of a maximally effective dose of 20 beta-S, but pregnenolone was without effect. The effects of these steroids on 20 beta-S-induced GVBD are discussed in relation to their possible interactions with 20 beta-S at the MIS receptor level.
17-Hydroxycorticosteroids↗