A case of adrenal carcinoma with Cushing's syndrome was presented. Endocrinological and morphological investigations disclosed the presence of a functional adrenal carcinoma. This case was characterized by its unusual urinary <em>17</em>-<em>ketosteroid</em> (<em>17</em>-KS) fractionation, i.e. a marked elevation of <em>17</em>-KS was accompanied by the increments of etiocholanolone, but not of dehydroepiandrosterone (DHEA) or androsterone. Measurements of the plasma adrenocorticosteroids revealed normal DHEA and DHEA-S (sulfate) levels, moderately increased <em>17</em>-OH-pregnenolone, and markedly increased (less than 100 times the normal) 11-deoxycortisol (cpd S). Therefore, it seems plausible that the normal urinary DHEA level in this patient would have occurred as a result of remarkably low C<em>17</em>-20 lyase activity sufficient to hamper DHEA production, and that markedly increased etiocholanolone might possibly have been converted from cpd S as well as from DHEA and androstenedione through 5 beta-reduction.

A left ovarian gynandroblastoma in a 24-year-old woman was clinically manifest by prolonged (7 years) amenorrheas interrupted by metrorrhagies, with moderate hypertrichosis is presented. An important urinary elimination of estrogens (1.500 gamma/24 h) and of <em>17</em>-<em>ketosteroids</em> (25 gamma/24 h) with normal <em>17</em>-OH and gonadotrophins were evidenced. The microscopic examination of the operated tumor showed structures of a granulous tumor intermingled with arrhenoblastomatous structures. Restoration of the patient's sexual biological conditions.

5-(Trimethylstannyl)-2H-pyran-2-one (11) and 3-(trimethylstannyl)-2H-pyran-2-one (30), readily prepared from the corresponding bromo-2H-pyran-2-ones, undergo Pd(0)-catalyzed coupling reactions with a variety of enol triflates to give 5- and 3- substituted 2H-pyran-2-ones, respectively. This reaction is applicable to the enol triflates of 14beta-hydroxy-<em>17</em>-<em>ketosteroids</em>, and therefore may prove useful in convergent syntheses of lucibufagins and bufadienolides.

The course of oxidative side chain cleavage of two recently isolated <em>17</em> alpha-hydroxy C-18 oxygenated naturally-occurring corticosteroids differed in that 18-hydroxycortisol yielded a <em>17</em>-<em>ketosteroid</em> (Chu M. D., and Ulick S. (1982) J. biol. Chem. 257, 2218-2224) whereas 18-oxocortisol yielded a gamma-etiolactone (Ulick S., Chu M. D. and Land M. (1983) J. biol. Chem. 258, 5498-5502). In an analytic application of the periodic acid oxidative cleavage reaction to 18-oxocortisol, the finding of a second product of the reaction prompted a reinvestigation of its course. Both the delta 4,3-ketone secreted form of the steroid and its tetrahydro urinary metabolite were cleaved predominantly to <em>17</em>-<em>ketosteroids</em> along with smaller amounts of gamma-etiolactones, whose proof of structure is herein reported. This anomalous course of oxidative cleavage was considered to reflect an equilibrium between C-20 ketone and cyclic-hemiketal forms in which the glycerol-type side chain structure of the later becomes the precursor of a <em>17</em>-<em>ketosteroid</em>. Because of the similarities between in vitro oxidative side chain cleavage and in vivo corticosteroid metabolism, these findings suggest that C-18 oxygenated steroids may contribute to the <em>17</em>-<em>ketosteroid</em> fraction of human urine.

In eight normals, eight anxiety neurotics and eight patients of acute schizophrenic episode, twenty-four-hour urinary excretion of each of the following was measured: (1) <em>17</em>-<em>ketosteroids</em> (<em>17</em>-KS)-total, glucuronides) and sulphates, (2)<em>17</em>-hydroxycorticosteroids <em>17</em>-KS)-total, conjugated and free, (3) Vanilamendelic acid (VMA), and (4) total indoles. In case of schizophrenics, such measurements were made before starting treatment, and after 30 days of chlorpromazine therapy. The psychopathology of schizophrenic subjects were rated on Rockland and Pollir (R. P.) scale on both occasions. Correlating the psychopathology with the biochemical values, amongst schizophrenics, R. P. score was found to show significant positive correlation with VMA and, to a lesser extent with total indoles. Schizophrenics excrated greater amount of VMA than normals and this returned to near normal levels with treatment. On the other hand, schizophrenics excreted lower amounts of most steroid fractions than normals, but amongst schizophrenics, there was no significant correlation between R. P. score arid steroid excretion.

A new method for identifying human urine stains utilizing high-performance liquid chromatographic (HPLC) analysis of five major <em>17</em>-<em>ketosteroid</em> conjugates: dehydroepiandrosterone sulfate, etiocholanolone sulfate, etiocholanolone glucuronide, androsterone sulfate, and androsterone glucuronide was examined. Samples of urine stains were extracted with borate buffer solution (pH 9.3) and the extracts were applied onto a Sep-Pak tC18 cartridge. The analytes were eluted from the cartridge with methanol. The eluates were prelabeled with 2,4-dinitrophenylhydrazine in trichloroacetic acid-benzene solution and were separated by HPLC on a reversed-phase ODS column using a mobile phase of 80% methanol in a buffer consisting of 25 mM sodium acetate in 2% acetic acid. The eluates were monitored by a spectrophotometer at 380 nm. While all five <em>17</em>-<em>ketosteroid</em> conjugates were clearly detected in the human urine stain samples, traces of only some of these conjugates were detected in the animal samples. Therefore, the presence of all five <em>17</em>-<em>ketosteroid</em> conjugates indicated human specificity. In addition to the above finding, the properties of those five <em>17</em>-<em>ketosteroid</em> conjugates were confirmed by electrospray ionization liquid chromatography-mass spectrometry (ESI-LC-MS).

The use of bismuth(III) triflate as catalyst for the direct conversion of corticosteroids into highly functionalized <em>17</em>-<em>ketosteroids</em> by cleavage of the C<em>17</em>-dihydroxyacetone side chain is reported. This catalytic process is very chemoselective, since functionalities of the starting corticosteroids, such as Delta(4)-3-keto, Delta(1,4)-3-keto, 11beta-hydroxyl, and 9beta,11beta-epoxide, remained intact.

Steroidogenesis in dispersed fetal zone cells of midtrimester human fetal adrenal was stimulated acutely by ACTH. Polypeptide hormones such as hCG, alpha MSH, ovine PRL, and LH did not produce a similar stimulation of steroidogenesis. The principal steroid products of ACTH-stimulated fetal adrenal cells were dehydroisoandrosterone sulfate, pregnenolone, pregnenolone sulfate, and <em>17</em> alpha-hydroxypregnenolone. Only minimal production of the delta 4-3-<em>ketosteroids</em>, cortisol, corticosterone, and progesterone, was observed. Cyanoketone (2 alpha-cyano-4,4,<em>17</em> alpha-trimethyl-<em>17</em> beta-hydroxyandrost-5-en-3-one; an inhibitor of 3 beta-hydroxysteroid dehydrogenase activity) treatment of the cells caused only a minor increase in 3 beta-hydroxysteroid formation, confirming that 3 beta-hydroxysteroid formation is the principal steroidogenic fate of cholesterol in these cells. SU-10603 [7-chloro-3,4-dihydro-2-(3-pyridyl)naphthalen-1-(2H)one; a steroid <em>17</em> alpha-hydroxylase inhibitor] treatment of the cells caused a marked accumulation of pregnenolone sulfate, indicating that the C-19 steroids are produced from C-21 steroids in this tissue and possibly that dehydroisoandrosterone sulfate is synthesized directly from pregnenolone sulfate. ACTH-stimulated pregnenolone synthesis was inhibited by AY-9944 [trans-1,4-bis-(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride; an inhibitor of cholesterol biosynthesis]. Thus, cholesterol synthesized de novo was the likely steroidogenic precursor in the acute hormonally stimulated fetal adrenal cells.

The urinary excretion of 14 neutral steroids was measured by gas-liquid chromatography in women with early and advanced breast cancer, in women with early uterine cancer, and in healthy women from urban and rural districts. The premenopausal patients with early breast cancer excreted subnormal amounts of five steroids (11-hydroxyandrosterone, 11-hydroxyetiocholanolone, pregnanediol, pregnanetriol, and tetrahydrocorticosterone) and increased amounts of tetrahydrocortisol as compared with the normal subjects of corresponding ages. From our findings, a new parameter was proposed by which a premenopausal breast-cancer patient was separated from the control. Postmenopausal breast-cancer patients excreted greater amounts of five steroids (one steroid from <em>17</em>-<em>ketosteroids</em> and four from <em>17</em>-hydroxycorticoids) than the corresponding controls. The discrepancy between premenopausal and postmenopausal breast cancer was tentatively related to ovarian-adrenal dysfunction in the course of aging. Oophorectomy induced a long-lasting tumor regression only in patients with a high value for the ratio of 11-deoxy-<em>17</em>-<em>ketosteroid</em> to <em>17</em>-hydroxycorticosteroid in urine taken before surgery; the ratio in the responsive patients decreased remarkably after surgery. A constitutional change in <em>17</em>-<em>ketosteroids</em>, as observed in a postmenopausal breast-cancer patient and a premenopausal healthy woman of urban origin, favored the geographic importance in the genesis of breast malignancy. The steroid abnormalities in uterine cancer were distinguishable from those of breast cancer in both premenopausal and postmenopausal women.

Increased intracelullar hormone concentration levels have been shown to be the cause of several endocrine-related cancers including breast, prostate, endometrial, ovarian, cervix, testicular, thyroid, and osteosarcoma. Deregulated expression of steroidogenic enzymes in these tumors seems to be the source of a positive balance in active steroids that bind to the corresponding nuclear receptor, thus ultimately stimulating cell proliferation. Among these enzymes, <em>17</em>β-hydroxysteroid dehydrogenases catalyze the interconversion between <em>17</em>-<em>ketosteroids</em> and <em>17</em>-hydroxysteroids on the last steps of sex hormones biosynthesis and metabolism. To date, 14 isoforms have been identified in vertebrates although only 13 are present in humans. Development and clinical evaluation of specific inhibitors to block their activity is currently under progress especially against the best characterized members 1 to 5. Selectivity and potency of these drugs constitute the main challenge in this new approach to cancer and steroid-dependent diseases treatment at the "pre-receptor level". Here we review the current state of knowledge regarding the deregulation of the expression of some of these enzymes in endocrine-related tumors.

A 64-yr-old female presented with severe osteoporosis and easy bruisability of over 2-yr duration. Biopsy of a neck mass revealed medullary carcinoma of the thyroid. Subsequently, lymphangitic pulmonary metastases were demonstrated which had been present radiographically for at least 4 yr. Basal serum calcitonin was markedly elevated and increased during calcium infusion. The diagnosis of ectopic ACTH syndrome was first entertained when hypokalemic alkalosis was observed during evaluation of her carcinoma. Elevated urinary <em>17</em>-hydroxycorticosteroids, <em>17</em>-<em>ketosteroids</em>, plasma cortisol, and immunoreactive plasma ACTH levels were documented. Adrenal steroidogenesis seemed to suppress on high dose dexamethasone. The primary tumor and its metastases contained high concentrations of immunoreactive ACTH and beta-melanocyte-stimulating hormone. Hepatic metastases contained extremely high concentrations of calcitonin. In contrast to the usual presentation of the ectopic ACTH syndrome as primarily hypokalemic alkalosis and glucose intolerance, patients with relatively benign and indolent ACTH-secreting tumors, such as certain cases of medullary carcinoma of the thyroid, may present with more typical signs and symptoms of Cushing's syndrome. The more pronounced cushingoid features in this latter group presumably reflects a more prolonged period of exposure to elevated glucocorticoid levels. Ten cases of ACTH-secreting medullary carcinoma of the thyroid from the literature are discussed. Extopic ACTH production by such tumors should be considered in the evaluation of patients with Cushing's syndrome or unexplained severe osteopenia.

A 35-year-old Japanese woman was referred for further examination of persistent hypertension with hypokalemia. Her serum aldosterone levels were high and her plasma renin activity markedly suppressed. Radiological examinations revealed the presence of a 3-cm diameter left adrenal tumor. (131)I-adosterol was specifically accumulated in the left adrenal tumor, whereas the accumulation in the right adrenal was completely suppressed. Low-dose dexamethasone failed to suppress cortisol secretion although the serum cortisol levels were within the normal range. Urinary excretion of <em>17</em>-hydroxycorticosteroids but not <em>17</em>-<em>ketosteroids</em> was increased. Levels of plasma adrenocorticotropin (ACTH) and serum dehydroepiandrosterone sulfate (DHEAS) were decreased. Upon diagnosis of left aldosteronoma with autonomous secretion of cortisol, left adrenalectomy was performed by laparoscopy. In the resected adenoma tissues, clear cells expressed P450c<em>17</em> protein and the ratio of CYP<em>17</em>/CYP11B2 mRNA evaluated by quantitative real-time polymerase chain reaction (PCR) was apparently higher than that of typical aldosteronomas. Based on the corticotropin-releasing hormone (CRH) loading tests, the contra-lateral adrenal functions were restored 3 months after surgery. These results indicate that evaluation for autonomy of cortisol secretion and contra-lateral adrenal function is clinically important to avoid the risk of adrenal failure after surgery for primary aldosteronism.