Excretion Of Etiocholanolone Research Articles

Biomarkers for assessment of the polychemotherapy results in patients with adrenocortical cancer based on gas chromatography-mass spectrometry studies of urine steroid profiles

Background: The effectiveness of polychemotherapy (PCT) for adrenocortical cancer (ACC) is assessed by imaging tests with the RECIST 1.1 criteria. However, the presence of subclinical tumor foci does not allow for an objective measurement of the true tumor burden. As shown previously, postoperative assessment of the steroid metabolome by gas chromatography-mass spectrometry (GCMS) in ACC patients makes it possible to identify early signs of adrenal steroidogenesis abnormalities and of the recurrence of adrenocortical carcinoma.
 Aim: To identify biomarkers of response to PCT by GCMS study of the urine steroid profile in ACC patients after surgical resection of the tumor.
 Materials and methods: Urine steroid profiles were studied by GCMS (Shimadzu GCMS-TQ8050 gas chromatography-mass spectrometer) in 30 ACC patients (stages II, III and IV) after surgery and first line (combination of etoposide, doxorubicin and cisplatin with daily mitotane) and second line (gemcitabine combined with capecitabine and mitotane) PCT. The control group included 25 patients with hormonally inactive adenomas.
 Results: The response to PCT according to RECIST 1.1 criteria was obtained in 23 patients (Group 1, responders) and in 7 patients ACC progressed under PCT (Group 2, non-responders). In the responders, the urinary excretion of etiocholanolone, pregnanediol and pregnanetriol was lower than in the control group. The non-responders had higher urinary excretion of androgens, progestogens and tetrahydro-11-deoxycortisol (THS), compared to the responders and the control group. The patients with ACC progression under PCT had an increase in 3β,16,20-pregnenetriol (3β,16,20-dP3) levels and a decrease of the 3α,16,20-dP3/3β,16,20-dP3 ratio, compared to those in the PCT responders. The threshold values for urinary excretion of dehydroepiandrosterone (DHEA, ≤ 469 mcg/24h; AUC = 1.0), THS (≤ 223 mcg/24h; AUC = 1.0), and 3β,16,20-dP3 (≤ 130 mcg/24h; AUC = 0.986), as well as the 3α,16,20-dP3/3β,16,20-dP3 ratio (≥ 2.13; AUC = 1.0) had 100% sensitivity and specificity for the assessment of the PCT effectiveness.
 Conclusion: Different urine steroid profiles were obtained by GCMS in the ACC patients after PCT with and without treatment response. The 100% sensitivity and specificity of the threshold values for urinary excretion of DHEA, THS, 3β,16,20-dP3 and the 3α,16,20-dP3/3β,16,20-dP3 ratio for the assessment of PCT results indicate the potential to use these parameters as biomarkers of response or progression of the disease in the monitoring of PCT effects in ACC patients.

Evidence for decreased androgen 5 alpha-reduction in skin and liver of men with severe acne after 13-cis-retinoic acid treatment.

To investigate the effect of 13-cis-retinoic acid (13-cis-RA) treatment on androgen metabolism in men with severe nodulocystic acne, eight men with severe acne received an oral daily dose of 0.7 mg/kg 13-cis-RA over 3 months. Exploration of androgen metabolism in serum samples, 24-h urine collections, and skin biopsies obtained before and at the end of the treatment revealed no significant alterations in serum levels of either adrenal or gonadal androgens. However, the treatment did induce significant decreases in serum levels of the 5 alpha-reduced androgens: 5 alpha-dihydrotestosterone (P < 0.02), androsterone glucosiduronate (P < 0.04), and 5 alpha-androstan-3 alpha, 17 beta-diol glucosiduronate (P < 0.004). Unlike serum, the urinary 5 alpha-reduced metabolites 5 alpha-androstan-3 alpha, 17 beta-diol and androsterone did not vary significantly despite a decrease in the excretion of the latter. Moreover, a marginally significant increase in urinary excretion of etiocholanolone, very similar to the decrease in androsterone excretion, was observed. The ratio of androsterone to etiocholanolone decreased significantly (P < 0.004) after 13-cis-RA therapy and suggested a metabolic deviation from the androgen 5 alpha- to 5 beta-reduction pathway in the liver. The most pronounced effect was observed in skin biopsies, which lost 80% of their ability to form 5 alpha-dihydrotestosterone (P < 0.001). It is concluded that 13-cis-RA therapy in men with severe nodulocystic acne did not alter gonadal or adrenal functions, but it did induce 1) a highly significant decrease in 5 alpha-dihydrotestosterone formation by skin biopsies; 2) significant decreases in serum 5 alpha-dihydrotestosterone, androsterone glucosiduronate, and 5 alpha-androstan-3 alpha, 17 beta-diol glucosiduronate; and, finally, 3) deviation of the liver androgen 5 alpha- to 5 beta-reduction pathway. The effect of 13-cis-RA treatment on severe acne is consistent with the dramatic decrease in androgen 5 alpha-reduction observed mainly in the skin.

THE URINARY DEHYDROEPIANDROSTERONE, ANDROSTERONE AND ETIOCHOLANOLONE EXCRETION OF HEALTHY WOMEN AND WOMEN WITH BENIGN AND MALIGNANT BREAST DISEASE

The 24-h urinary excretion of dehydroepiandrosterone, androsterone and etiocholanolone was followed in healthy women (n = 50) and in women with benign-fibroadenoma (n = 32), microcysts (n = 32), macrocysts (n = 25) and malignant (n = 35) breast disease aged 35-50 years. The data were analysed in three groups each covering 5 years (35-39, 40-44 and 45-49). A significant decrease in the excretion of etiocholanolone and dehydroepiandrosterone was found in women with benign and malignant breast disease when compared to controls. There was no significant decrease in androsterone excretion in women with benign and malignant breast disease when compared to a control group. A high correlation was found between excretion of etiocholanolone and its precursor dehydroepiandrosterone both in women with benign-fibroadenoma (r = 0.7683) or macrocysts (r = 0.7337) and in women with malignant (r = 0.805) breast disease. Dehydroepiandrosterone and, in particular, etiocholanolone excretions were found to decrease significantly with age in women affected by malignant breast disease.

Identification of potential antiatherosclerotic/hypolipidemic agents by their effect on hepatic conversion of androst-4-ene-3,17-dione to etiocholanolone and androsterone

Clinical observations have shown that hypercholesterolemia is associated with abnormal androgen metabolism, viz. an increased excretion of etiocholanolone (E) relative to androsterone (A). Substances which restore the A E ratio to normal likewise lower serum cholesterol. Postulating that the abnormal steroid and sterol metabolism may be either causally related or dependent on the same metabolic defect, we have developed in vitro and in vivo models to select drugs which favorably effect the ratio of A to E produced from [4- 14C]androst-4-ene-3,17-dione [4- 14C]A-dione). The in vitro model employs a mixture of rat liver microsomal Δ 4-3-ketosteroid-5 α-reductase and cytosolic 3a-hydroxysteroid dehydrogenase and Δ 4-3-ketosteroid-5 α-reductase. Kinetic and mechanistic studies have been performed on active compounds using this in vitro assay. The in vivo model employs i.v. injection of [4- 14C]A-dione followed by collection of bile in anesthetized, hypophysectomized female rats. Many compounds preselected in the in vitro assay likewise reduced the A E ratio in vivo. One of these compounds (CGS 10614A) also lowered serum cholesterol and reduced the incidence and severity of atherosclerotic lesions in aortas of cholesterol-fed rabbits.

Some aspects of the circadian rhythm of the urinary excretion of etiocholanolone, androsterone and dehydroepiandrosterone.

The circadian rhythm in the urinary excretion of etiocholanolone, of androsterone and of dehydroepiandrosterone in normal menstruating women was studied. The excretion patterns of etiocholanolone and androsterone seem to be nearly synchronous, but not equal, thus resulting in a diurnal variation.

Wirkung von Spirolactonen auf die Ausscheidung der fraktionierten 17-Oxosteroide und von Pregnandiol im Urin

The effect of spirolactones on the urinary excretion of individual 17-oxosteroids and of pregnanediol in man was investigated under various conditions. After purification by thin-layer chromatography, the 17-oxosteroids and pregnanediol were determined by gas chromatography. Eleven male subjects (age 21-34 years) received a daily dose of 200 mg spironolactone (Aldactone) orally on seven consecutive days. Five female subjects (age 20-35 years) and ten pregnant women (age 20-35 years; 28th.-39th. week of gestation) were given a daily intravenous injection of 600 mg potassium canrenoate (Aldactone pro injectione) on three consecutive days. In the male subjects, the excretion of individual 17-oxosteroids and of pregnanediol was significantly reduced during administration of spironolactone. In the nonpregnant female subjects, the excretion of etiocholanolone and dehydroepiandrosterone was diminished, whereas in the pregnant women, the excretion of pregnanediol and dehydroepiandrosterone was decreased during treatment with potassium canrenoate. These results suggest that the reduced urinary excretion of steroids may be due to an inhibition of steroid metabolising enzymes by spirolactones. It seems likely that spirolactones affect the enzymatic conversion fo cholesterol to pregnenolone.

Tryptophan metabolism in breast cancer. Correlation with urinary steroid excretion.

Urinary excretion of t ryptophan metabolites, etiocholanolone, androsterone, and 17-hydroxycorticosteroids (17-OHc.s.), was measured in 25 patients with breast cancer a n d i n 12 similarly aged control women. Twelve of the 25 patients had elevated excretions of metabolites of the kynurenine-niacin pa thway, and, in these patients, t he excretion of etiocholanolone was significantly lower t h a n in controls or in patients with normal t ryp tophan metabolism.

Steroid excretion patterns in postmenopausal women with benign and neoplastic endometrium

Urinary steroid metabolite patterns were evaluated in patients with postmenopausal bleeding. There was no difference in the patterns exhibited by normal postmenopausal women and women who had postmenopausal bleeding of benign etiology. Subnormal excretion levels of androsterone were demonstrated in patients with endometrial hyperplasia and carcinoma. The excretion of etiocholanolone was decreased in patients with endometrial hyperplasia. Calculation of a discriminant function 80-80 (17-hydroxycorticosteroids, milligrams per 24 hr.) plus micrograms of androsterone revealed positive values for the control and benign postmenopausal bleeding groups and negative values for the hyperplasia and cancer groups. These observations are similar to those previously reported in breast cancer and suggest an alteration in androgen metabolism. Further studies of androgen kinetics and interconversion of the androgens to the estrogens are indicated in patients with endometrial cancer and its precursor states to clarify the possible mechanisms responsible for this abnormality in androgen metabolism.

Metabolism of exogenous dehydroepiandrosterone in man.

ABSTRACT To study the metabolism of dehydroepiandrosterone, 3 normal subjects ingested 50, 300, and 1000 mg of dehydroepiandrosterone for 3 day periods. Although the fraction of the administered dehydroepiandrosterone that appeared in the urine decreased with increasing doses, the amount of dehydroepiandrosterone excreted approached that seen in adrenal cancer. The excretion of etiocholanolone was greater than that of androsterone at the higher dehydroepiandrosterone levels suggesting increased activity of the enzyme, Δ4-5β-reductase. Conjugation of the C19O2-ketosteroid metabolites of dehydroepiandrosterone was examined at each dose level. The excretion of dehydroepiandrosterone glucuronoside remained a small, constant fraction of the total dehydroepiandrosterone excretion. Similarly, the excretion of androsterone sulfate and etiocholanolone sulfate was a fairly constant but minor fraction of the total excretion of androsterone and etiocholanolone.