Alterations In Steroid Metabolism Research Articles

Characterisation of the urinary steroid profile of patients with nonfunctioning adrenal incidentalomas: A matched controlled cross-sectional study.

To identify alterations in steroid metabolism in patients with nonfunctioning adrenal incidentalomas (NFAIs) through the analysis of their urinary steroid profile (USP). Cross-sectional study with one study group (NFAIs, cortisol post dexamethasone suppression test [DST] ≤ 1.8 µg/dl [49.7 nmol/L]) and 2 control groups: patients with autonomous cortisol secretion (ACS group, cortisol post-DST > 1.8 µg/dl (49.7 nmol/L) and patients without adrenal tumours (healthy-adrenal group). Twenty-four-hoururine collections for USP measurement (total and free fraction of 51 24 h-urine specimens) were obtained from 73 participants (24 with NFAIs, 24 without AIs, and 25 with ACS). USP was determined by gas chromatography coupled to mass spectrometry. Patients of the three groups were matched according to sex, age (±5 years-old) and body mass index (±5 kg/m2 ). Compared to healthy-adrenal controls, patients with NFAIs had a lower excretion of androgen metabolites (230.5 ± 190.12 vs. 388.7 ± 328.58 µg/24 h, p = .046) and a higher excretion of urinary free cortisol (UFC) (54.3 ± 66.07 vs. 25.4 ± 11.16 µg/24 h, p = .038). UFC was above the reference range in 20.8% of patients in the NFAI, compared to 0% in the healthy-adrenal group (p = .018). Patients with ACS had a higher prevalence of hypertension, dyslipidemia, and diabetes than patients with NFAIs or the control group. A lower excretion of androgen metabolites (218.4 ± 204.24 vs. 231 ± 190 µg/24 h, p = .041) and a nonsignificant higher excretion of glucocorticoid metabolites (2129.6 ± 1195.96 vs. 1550.8 ± 810.03 µg/24 h, p = .180) was found in patients with ACS compared to patients with NFAIs. NFAIs seem to secrete a subtle, yet clinically relevant, excess of glucocorticoids. Future studies are needed to confirm our findings; and to identify metabolic alterations associated with an increased cardiometabolic risk.

Late Onset of Abiraterone Severe Hypokalemia Due to Unsuspected ACTH-Secreting NEC

Clinical Case: 68-year-old male, Active smoker (30-40 packs/year), and moderate alcohol drinker. An increase in urinary frequency, nocturia, and a PSA of 116 µg/L led to the diagnosis of disseminated castration-sensitive prostate cancer (CSPC), advanced Gleason score (3 + 4 pT2), with bone and retroperitoneal metastases (CT). By 02/2018, he started androgen deprivation therapy (ADT) with Abiraterone (AB) 1000 mg, prednisone, and LHRH agonist. 15 months later, PSA levels decreased to 0.75 ng/ml without side effects and normal K+(3.7 mEq/L), when a CT scan revealed both liver and bone metastasis. During the progression study, two months later, the patient was admitted to the hospital for severe hypoK+ (1.7 mEq / L), normal renal function and metabolic alkalosis. Although abiraterone was discontinued, up to 460 mEq iv per day of K+ and spironolactone were required to maintain serum K+ above 2.5. 3 days later, the hormonal study revealed TSH 1.13 mU /L, ACTH 162 pmol/L, cortisol 258 nmol/L, aldosterone 105 pmol/L, renin (protein) 0.7 µU/mL and deoxycorticosterone 507 pmol/L. 11 days later, plasma cortisol was 967 nmol/L, ACTH 132pmol/L, and cortisoluria 1456 nmol/d. The suppression test with 1 mg of DXM for cortisol was 1162,5 nmol/L. DHEAS was < 407 nmol/L. Liver biopsy showed a small cell neuroendocrine carcinoma (NEC), chromogranin (+), synaptophysin (+), CD56 (+), TTF-1 (+), PSA (-), Ki-67 90% and the granular cytoplasmic ACTH (+). The octreotide scan (+) revealed pathological uptake in L4, multiple uptakes in the liver, and in the axial skeleton. Treatment with Carboplatin plus Paclitaxel for NEC was started, completing 3 weekly doses with good tolerance and clinical benefit, but with the persistence of severe hypoK+ (2.5 mEq/L). Treatment with lanreotide 120 mg every 4 weeks was added, following a feeling of clinical improvement, the disappearance of edema, asthenia, and normalization of plasma K+ (3,4mEq/L). The patient died two months later from respiratory sepsis. Discussion: Several clinical trials have demonstrated that the combination of AB plus ADT prolongs overall survival in DCSPC. The CYP17 inhibition by AB increases ACTH leading to early secondary mineralocorticoid excess with hypokalemia and hypertension while the cortisol levels remain normal or low. Cortisol serum levels increased after AB was discontinued, whereas aldosterone serum levels remained low due to K+ regulatory feedback. The hormonal profile and the pathological and radiological studies revealed an ACTH-producing small cell NEC. In this patient, the previous treatment with BA has masked the clinical and hormonal profile of an ectopic Cushing syndrome. Therefore, Cyp17 inhibitors can mask adrenal or extra-adrenal processes characterized by alterations in steroid metabolism. This case has suggested a more thorough assessment of the adrenal hormonal profile including ACTH during BA treatment.

Steroid hormone synthetic pathways in prostate cancer.

While androgen deprivation therapy (ADT) remains the primary treatment for metastatic prostate cancer (PCa) since the seminal recognition of the disease as androgen-dependent by Huggins and Hodges in 1941, therapy is uniformly marked by progression to castration-resistant prostate cancer (CRPC) over a period of about 18 months, with an ensuing median survival of 1 to 2 years. Importantly, castration does not eliminate androgens from the prostate tumor microenvironment. Castration resistant tumors are characterized by elevated tumor androgens that are well within the range capable of activating the AR and AR-mediated gene expression, and by steroid enzyme alterations which may potentiate de novo androgen synthesis or utilization of circulating adrenal androgens. The dependence of CRPC on intratumoral androgen metabolism has been modeled in vitro and in vivo, and residual intratumoral androgens are implicated in nearly every mechanism by which AR-mediated signaling promotes castration-resistant disease.These observations suggest that tissue based alterations in steroid metabolism contribute to the development of CRPC and underscore these metabolic pathways as critical targets of therapy. Herein, we review the accumulated body of evidence which strongly supports intracrine (tumoral) androgen synthesis as an important mechanism underlying PCa progression. We first discuss the presence and significance of residual prostate tumor androgens in the progression of CRPC. We review the classical and non-classical pathways of androgen metabolism, and how dysregulated expression of these enzymes is likely to potentiate tumor androgen production in the progression to CRPC. Next we review the in vitro and in vivo data in human tumors, xenografts, and cell line models which demonstrate the capacity of prostate tumors to utilize cholesterol and adrenal androgens in the production of testosterone (T) and dihydrotestosterone (DHT), and briefly review the potential role of exogenous influences on this process. Finally, we discuss the emerging data regarding mechanisms of response and resistance to potent ligand synthesis inhibitors entering clinical practice, and conclude by discussing the implications of these findings for future therapy.

Cytochrome P450-mediated metabolic alterations in preeclampsia evaluated by quantitative steroid signatures

Although preeclampsia has been suggested potential risk factors including placental and systemic inflammation, oxidative stress, and abnormal steroid metabolism during pregnancy, the pathogenesis of preeclampsia has not fully been elucidated, particularly in steroid metabolism. The association between various cytochrome P450 (CYP)-mediated steroid metabolic markers and preeclampsia risk was therefore investigated. The serum levels of 54 CYP-mediated regioselective hydroxysteroids and their substrates were quantitatively evaluated from both pregnant women with preeclampsia (n=30; age, 30.8±4.5 years) and normotensive controls (n=30; age, 31.0±3.5 years), who were similar with respect to maternal age, gestational age, and body mass index. The levels of 6ß-, 7a-, and 11ß-hydroxymetabolites of androgens and corticoids were significantly increased in women with preeclampsia. In addition, the levels of oxysterols, including 7a-, 7ß-, 4ß-, 20a-, 24S-, and 27-hydroxycholesterol, were markedly higher, while the levels of 16a-OH-DHEA, 16a-OH-androstenedione, and cholesterol were significantly decreased in patients. The 6ß-hydroxylation of androgens and corticoids by CYP3A4 (P<0.01), the activation of 20,22-desmolase (a cholesterol side-chain cleavage enzyme) by CYP11A1 (P<0.00001), and the multi-hydroxylation of cholesterol at C-4ß, C-7a, C-7ß, C-24S, C-27, and C-20a (P<0.0001) by catalytic or enzymatic reaction (e.g. CYP3A4, CYP7A1, CYP27A1, and CYP46A1) were differed between preeclamptic women and control subjects. In particular, an increased oxysterols (induction>2.0-fold) were positively correlated with the conditions of preeclampsia. Our metabolic profiling suggests the CYP-mediated alterations in steroid metabolism and hydroxylation in pregnancy-induced hypertension. These multiple markers could serve as background information for improved clinical diagnosis and management during pregnancy.This article is part of a Special Issue entitled “Pregnancy and Steroids”.

Alteration of [14C]-testosterone metabolism after chronic exposure of Daphnia magna to tributyltin.

Tributyltin (TBT) is a marine biocide that has been shown to alter the activity of cytochrome P450 monooxygenases and elicit toxicity indicative of androgenization in some species. The present study was conducted to determine whether TBT altered P450-, reductase-, and transferase-mediated testosterone metabolic processes in Daphnia magna at sublethal exposure concentrations. Two generations of daphnids were continuously exposed for 21 days to nominal TBT concentrations ranging from 0.31 to 2.5 microg/L TBT. The highest TBT concentration (2.5 microg/L) was lethal to 60% of the exposed organisms. Lower TBT concentrations elicited no adverse effects on molting or reproduction of the daphnids. No differences were observed in the response of the first- and second-generation daphnids to the toxicity of TBT. The ability of daphnids to metabolize [14C]-testosterone in vivo was assessed following exposure of each generation to TBT. Production of hydroxylated, reduced/dehydrogenated, and glucose-conjugated metabolites of testosterone were all elevated following exposure of both generations to 1.25 microg/L TBT. These findings indicate that, under these conditions, TBT elicits no discernible effects on molting and reproduction of daphnids at sublethal concentrations, and testosterone metabolism is enhanced at concentrations approaching those that are lethal to organisms. Alterations of steroid metabolism by xenobiotics can be used as a more sensitive indicator of sublethal exposure in daphnids than reproductive endpoints.

Effect of testosterone replacement on the alteration of steroid metabolism in the hypothalamic-preoptic area of male hamsters treated with melatonin

Adult male hamsters were maintained under 14 hours of light per day and randomly assigned to groups that received daily afternoon melatonin (25 μg) or vehicle injections. Animals from both groups were killed following 4, 8, and 12 weeks of treatment. By 12 weeks, the melatonin-treated hamsters had significant reductions in the weights of the testes and seminal vesicles, serum testosterone levels, and hypothalamic-preoptic area (HPOA) aromatase activities. Hypothalamic-preoptic area 5α-reductase activities did not differ between groups. In a second experiment, hamsters were again treated with melatonin or vehicle for 12 weeks prior to being killed. After 10 weeks of treatment, groups of melatonintreated animals received subcutaneous silastic capsules (5, 10, or 20 mm) filled with testosterone. Animals in two other groups were given blank implants or no implants at all. Two weeks later, at autopsy, reproductive organ weights, serum testosterone levels, and HPOA aromatase activities were significantly suppressed by melatonin administration. 5α-Reductase activity in the HPOA was not affected. Hamsters that had been given the 10- and 20-mm testosterone implants exhibited normal seminal vesicle weights and HPOA aromatase activities. These results suggest that melatonin-induced reduction of HPOA aromatase activity is mediated by decreased circulating levels of testosterone.

Intratesticular and plasma steroid profiles in fertile and infertile men.

In 24 apparently healthy men who requested sterilization by vasectomy, we have measured the intratesticular and peripheral plasma levels of 9 unconjugated and 5 sulphoconjugated steroids. These steroid levels were then compared with those found in a group of 18 men, admitted to the hospital with complaints of infertility. With the exception of higher dihydrotestosterone levels in the infertile group, no differences were found between the two groups with regard to the peripheral plasma levels of the unconjugated or sulphoconjugated steroids studied. On the other hand, the intratesticular levels of cortisol, pregnenolone, androstenedione, dihydrotestosterone, pregnenolone sulphate and testosterone sulphate (but not those of testosterone) were significantly diminished in the infertile group. With the exception of dehydroepiandrosterone levels in the fertile group, and dehydroepiandrosterone sulphate and dihydrotestosterone sulphate in the infertile group, the intratesticular steroid levels were uncorrelated with the plasma levels. The data are interpreted as suggesting that a) male infertility may be associated with intratesticular alterations of steroid metabolism which are not reflected by the peripheral steroid levels; b) the plasma and intratesticular levels of testosterone are not sensitive enough indices for the endocrine evaluation of male infertility; c) the role of the sulphoconjugated forms of steroids in the maintenance of male fertility deserves further investigation.

Biochemical endocrinology of prostatic tumors.

This chapter discusses the biochemical endocrinology of prostatic tumors. The hormone dependency of benign and malignant tumors of the prostate in man is well-established. Concerning benign prostatic hypertrophy (BPH), controversial theories have been proposed with respect to both androgens and estrogens as the most important factors for the development of the disease. The etiology and pathogenesis of both types of prostatic tumors are still far from being understood. The chapter focuses on the data obtained from studies in human subjects by which induction and growth of both human tumors can be studied. In untreated patients with either BPH or prostatic cancer, blood hormone levels generally fluctuate in the normal range. Their determination, therefore, does not substantially improve the understanding of either the etiology or the pathogenesis of the disease in question. Recent data point in the direction of alterations in steroid metabolism at the cellular level of the BPH and prostatic cancer. The idea of an acquired error of metabolism as a possible cause of BPH, though highly speculative, seems to be attractive and promising.

Adrenal steroidogenesis in “low renin” or hyporeninemic hypertension

Suppressed plasma renin activity (PRA) and volume dependent hypertension have been associated with adrenocortical structural abnormalities, excessive deoxycorticosterone, 18-hydroxydeoxycorticosterone (18-OH-DOC) hypersecretion or non-suppressible aldosterone secretion and may be observed in patients thought to have “essential” hypertension. Dale and Melby (1973) encountered an additional alteration in steroid metabolism in two such patients while studying steroidogenesis in vitro by their sectioned adrenals. Conversion of labeled 18-OH-DOC to a new structure 16α,18-dihydroxydeoxycorticosterone was demonstrated to be greatly accelerated by the adrenal tissue in these patients as compared to normal adrenal tissue (70–80% vs 15% conversion). Hypersecretion of 16α,18-dihydroxy-deoxycorticosterone occurred in each. This steroid exerted no effect on sodium metabolism in adrenalectomized rats and in the toad bladder assay, but markedly enhanced activity of subthreshold doses of aldosterone in reducing sodium excretion in urine of adrenalectomized rats. We have concluded that excessive 16α,18-dihydroxydeoxycorticosterone secretion may be important in the genesis of suppressed renin in some patients with hypertension because of the unique activity of this steroid which appears to function as a cooperative or positive allosteric effector of aldosterone.

Adrenocortical function in alcoholics

The diminished adrenocortical responsiveness of chronic alcoholics to surgical trauma has been investigated. It is concluded that alterations in steroid metabolism and not adrenal cortical function are important accompaniments of chronic alcoholism.

Oral and intravenous suppression tests in the diagnosis of Cushing's syndrome.

SUMMARY Adrenocortical suppression tests, based on the fall in urinary 17-hydroxy-corticosteroid excretion during the oral administration of dexamethasone, were found to be of value in the diagnosis of Cushing's syndrome, but less useful in differentiating bilateral adrenal hyperplasia from adrenal tumour. Such tests have the disadvantage of requiring accurate urine collections and of taking several days to perform. A test is described, based on the decrease in plasma cortisol concentration during i.v. infusion of dexamethasone at a rate of 1 mg./hr. The results obtained in 12 patients with Cushing's syndrome and bilateral adrenal hyperplasia differed from those found in control subjects in that there was a delay between the start of the infusion and the fall of plasma cortisol, and the rate of fall was less rapid. The values found after 180 min., expressed either as μg./100 ml. or as a percentage of the resting level, differed significantly (P &lt; 0·001) in the two groups. The test proved valuable as an aid to the diagnosis of Cushing's syndrome, was easy to perform, and could be completed in 3 hr. In some patients with Cushing's syndrome, the administration of synthetic glucocorticoids appeared to result in an increased urinary steroid excretion. A transient increase in plasma cortisol levels was also observed in some of these patients during the early period of dexamethasone infusion. It is thought that this finding reflects an alteration in steroid metabolism induced by dexamethasone and fluorocortisol.

DETERMINATIONS OF URINARY 17-HYDROXYCORTICOSTEROIDS AND THEIR RELATION TO CORTISOL SECRETION.

A method for the determination of 17-hydroxycorticosteroids employing periodate oxidation was studied for reliability, and the secretion rate of cortisol was then compared with urinary steroid excretion in a number of subjects. The urinary assay was found to be satisfactory in terms of precision and accuracy. The correlation between urinary steroid excretion and secretion rate was acceptable in the normal range, but became poor as the secretion rate increased. Two patients with Cushing's syndrome showed elevated cortisol secretion rates as compared to the control subjects, but urinary steroid excretion was within the normal range. Examination of the percentage conversion of cortisol to urinary 17-hydroxycorticosteroids suggests there is a progressive decrease in the proportion converted as the secretion rate rises. It is concluded that a progressive alteration in steroid metabolism occurs as the secretion rate of cortisol rises, with the formation of metabolites which are not included in the urinary assay. This finding may impose some limitation on the interpretation of urinary steroid excretion values as an index of cortisol secretion rates.