Benign and Malignant Breast Disease in South Wales: A Study of Urinary Steroids

The levels of aetiocholanolone, androsterone, and 17-hydroxycorticosteroids were measured in women without known disease of the breast, in women with benign breast disease, and in women with primary and advanced breast cancer. Statistical analysis showed there was no difference in the excretion of urinary 17-hydroxycorticosteroids in the various groups of patients. Detailed analysis of the aetiocholanolone and androsterone levels, however, indicated that patients with advanced localized disease excreted significantly less of these 11-deoxy-17-oxosteroids than those in the other groups.     

Study on the inactivation mechanism of androgens in rheumatoid arthritis: excretory rate of free and conjugated 17-ketosteroids.

Unconjugated, sulpho- and glucurono-conjugated androgen hormone metabolites have been determined in the urine of patients with rheumatoid arthritis. An increase in the excretory rate of unconjugated 5 beta-reduced 17-ketosteroids and a decrease in that of 17-ketosteroid conjugates, especially in dehydroepiandrosterone sulphate and in the sum of dehydroepiandrosterone, etiocholanolone and androsterone glucuronoside were observed. In contrast to unconjugated metabolites, there was less significant change in the 5 beta-metabolite conjugates in urine. Corticosteroid treatment resulted in an additional decrease of metabolite excretion by patients. Further study is necessary to determine the causative factors in the altered steroid pattern observed in this severe, non-endocrine disease.     

The gas–liquid chromatography of carboxylic acid esters of the urinary 11-deoxy-17-oxo steroids: Determination as n-butyrates

1. The gas-liquid-chromatographic separations of the acetate, propionate, n-butyrate, isobutyrate and n-valerate esters of androsterone, aetiocholanolone and dehydroepiandrosterone were studied on a 1% neopentyl glycol sebacate column. The n-butyrate, isobutyrate and n-valerate esters were well resolved. 2. The three steroids derived from hydrolysed urinary 17-oxo steroid conjugate extracts were analysed by gas-liquid chromatography after conversion into their n-butyrate esters. The results were compared with independent determinations involving chromatography on alumina.     

Thyroid function in lung cancer

Thyroid function was assessed at the time of initial diagnosis in 204 patients with lung cancer and compared with that of age and sex-matched patients with non-malignant lung disease. Abnormalities in thyroid function were found in 67 patients (33%). The most prevalent abnormality was a low T3 concentration; this was not associated with other clinical or biochemical evidence of hypothyroidism, but the short-term prognosis of these patients was worse than that of matched patients with lung cancer having normal T3 concentrations. Primary hypothyroidism occurred in three patients, low T4 concentrations and free thyroxine index (FTI) with normal thyrotrophin (TSH) concentrations in four patients, and moderately raised TSH with normal thyroid hormone concentrations in six patients; nine patients had a raised FTI with or without raised T4 concentration as the sole abnormality.Overall, the pattern of thyroid hormone metabolism in lung cancer was a tendency towards reduced T3 concentrations with significantly increased T4/T3 ratios and modestly increased 3,3′,5′-triiodothyronine (rT3) concentrations. The altered T4/T3 ratio was particularly noticeable in patients with anaplastic tumours of small (“oat cell”) and large cell types, but was not apparently related to detectable extrathoracic metastases.These data suggest that thyroid hormone metabolism is altered in patients with lung cancer by decreased 5′-monodeiodination of T4. The resulting low T3 concentrations and altered T4/T3 ratio may be partly responsible for the reduced ratio of androsterone to aetiocholanolone observed in lung cancer, which is known to be a poor prognostic sign.     

Inverse correlation between urinary 17-hydroxycorticosteroid (17-OHCS) excretion and thyrotropin-releasing hormone (TRH)-induced thyrotropin (TSH) response in disorders of adrenocorticotropic hormone (ACTH) and adrenal secretion

A TRH test was performed in patients with Cushing's syndrome and isolated ACTH deficiency, and serum TSH was measured. A TRH-induced TSH showed low response in patients with Cushing's syndrome but showed excessive response in patients with isolated ACTH deficiency. However, in both diseases TRH-induced TSH response showed a tendency to normalize after the treatment. Urinary 17-OHCS excretion was measured in patients with Cushing's syndrome and isolated ACTH deficiency before and after the treatment. There was a definite inverse correlation between ;the logarithm for urinary 17-OHCS excretion and the peak TSH response to TRH. These results suggested that glucocorticoids regulate not only ACTH but also TSH secretion.     

Hypertension,Increased Aldosterone Secretion and Low Plasma Renin Activity Relieved by Dexamethasone

A father and son are described with a condition characterized by benign hypertension, potassium deficiency, increased aldosterone secretion rate (ASR), raised plasma volume and suppressed plasma renin activity (PRA). There were intermittent elevations of urine 17-ketosteroids and 17-hydroxycorticoids (17-OHCS) but no increase in urine THS, normal circadian rhythm of plasma 17-OHCS, and normal urine 17-OHCS response to dexamethasone and intravenous ACTH. Plasma ACTH and corticosterone secretion were not elevated. Pregnanetriol excretion was normal but urine pregnanediol was increased. At operation on the father no adrenal tumour was found; the excised left adrenal weighed 7 g. and showed nodular cortical hyperplasia; juxtaglomerular cells showed only occasional granules. Following operation hypertension persisted and ASR was half the preoperative value. All abnormalities in father and son were relieved by dexamethasone (DM) 2 mg. daily. The condition recurred following cessation of DM but was relieved by a second course of treatment. No such response to DM was seen in a normal subject or in a patient with Conn''s syndrome. For a number of reasons it is suggested that patients with hypertension, increased ASR and low PRA be given a trial of dexamethasone treatment before undergoing adrenal surgery.     

Endogenous steroid concentrations in human breast tumours determined by high-resolution mass fragmentography (Short Communication)

A pilot study of the endogenous steroid concentrations in human breast tumours was performed. The technique of high-resolution molecular-ion monitoring during combined g.l.c.-mass spectrometry was used to determine oestrone, oestradiol-17beta and oestriol in concentrations above 1ng/g wet wt. of tissue, and dehydroepiandrosterone, testosterone, androsterone (3alpha-hydroxy-5alpha-androstan-17-one) and 3beta-hydroxy-5alpha-androstan-17-one in concentrations exceeding 5ng/g, in extracts of five primary breast tumours.     

Steroid glucuronides: Human circulatory levels and formation by LNCaP cells

We studied the relationship between circulating androsterone glucuronide, androstane-3,17β-diol glucuronide and androstane-3β,17β-diol glucuronide concentrations and adrenal as well as testicular C-19 steroids in men. Among the three 5-reduced steroid glucuronides, androsterone glucuronide is the predominant C-19 steroid measured in plasma and its levels are markedly elevated compared to those of the non-conjugated steroid. The marked rise in testosterone during puberty was strongly correlated with the increase in both androsterone glucuronide and androstane-3,17β-diol glucuronide, thus suggesting that testicular C-19 steroids are the main precursors of the steroid glucuronides. We also found that the presence of testicular androgen in plasma contributes to approx. 70% of plasma androsterone glucuronide and androstane-3,17β-diol glucuronide. Our data suggest that the adrenal C-19 steroids remaining in circulation after castration in men are converted into potent androgen which are then glucuronidated by UDP-glucuronyltransferase. We also demonstrated that the human prostate cell line LNCaP is capable of converting to a large extent androstenedione into androsterone glucuronide. Our data further confirm that glucuronidation is a major pathway of steroid metabolism in steroid target tissues.     

Circadian rhythms of electrolyte and 17-hydroxycorticosteroid excretion in hyperthyroidism and hypothyroidism.

The circadian rhythms of excretion of sodium, potassium, calcium, magnesium, phosphorus and 17-hydroxycorticosteroid (17-ohcs) were determined in five normal subjects, in six patients with hyperthyroidism and five with hypothyroidism. Constant diets with identical 3-hourly feedings were employed, and urine collections were made every 3 hrs during a 3-day study period. The circadian patterns of urinary excretion of sodium, potassium and 17-OHCS were similar in all three groups with distinct daytime peaks and nighttime nadirs. The total quantities of the ions and 17-OHCS excreted were greater in hyperthyroid than in hypothyroid patients with the greatest difference noted with the 17-OHCS. The rhythms for calcium, magnesium and phosphorus excretion were accentuated in hyperthyroid patients but similar to those in normal subjects with early morning calcium and magnesium peaks and a phosphorus peak approximately 12 hrs later. While a similar although blunted circadian pattern for calcium and perhaps magnesium excretion was noted in hypothyroid patients, their phosphorus rhythms were distorted and rather flat. These latter results confirm the observation of MINTZ et al. and are compatible with their interpretation that thyroid hormone is permissibly necessary for the expression of a normal phosphaturic rhythm and that the circulating level of thyroid hormone influences the amplitude of the phosphaturic rhythm.     

Excretion of 17-hydroxycorticosteroids under the effect of combined preparations containing separate progestagens: ethynodiol diacetate and chlormadinone

28 women were treated with .1 mg of mestranol + 3 mg of chlormadinone and 25 were treated with .1 mg of mestranol + 1 mg of ethynodiol diacetate. Examinations of the excretion of 17-corticosteroids in the urine were made and compared between the 2 groups. In the group treated with mestranol + chlormadinone here was no change in the excretion of 17-OHCS. The group of women treated with mestranol + ethynodiol diacetate showed a significant decrease of approximately 37%. The difference in the effects of these preparations is thought to be caused by their different chemical structure.     

Late-onset 21-hydroxylase deficiency: reliable diagnosis by steroid analysis of random urine collections

The feasibility of performing steroid analysis by capillary gas chromatography on random urine samples for the detection of mild late-onset 21-hydroxylase deficiency was evaluated. Comparisons were made of basal excretions of androgen and 17 alpha-hydroxyprogesterone metabolites with plasma levels (basal and stimulated) of 17 alpha-hydroxyprogesterone and testosterone in six patients with the disorder. The following steroid metabolite excretion ratios were determined for normal controls and affected individuals. 1) 17 alpha-hydroxypregnanolone/tetrahydrocortisone + tetrahydrocortisol + 5 alpha-tetrahydrocortisol (cortisol metabolites) (normal 0.017-0.10, affected 0.17-0.42); 2) pregnanetriol/cortisol metabolites (normal 0.03-0.15, affected 0.17-0.99); 3) pregnanetriolone/cortisol metabolites (normal 0.02-0.014, affected 0.08-0.20); 4) androsterone + etiocholanolone/cortisol metabolites (normal 0.26-1.02, affected 0.34-1.47). Among the 21-deoxy steroid ratios, there was no overlap between affected and unaffected individuals. Two of six affected individuals had androsterone + etiocholanolone/cortisol metabolite ratios in the normal range. This method provides excellent discrimination between normal and affected individuals, precluding the need for an ACTH-stimulation test. It is anticipated that it will be increasingly used for diagnosis of the condition.     

Relevance of the selective oestrogen receptor modulators tamoxifen, toremifene and clomiphene in doping field: endogenous steroids urinary profile after multiple oral doses

The present study was performed to investigate the influence of the intake of selective oestrogen receptor modulators on the urinary endogenous steroids profile. For this purpose the circadian variability of luteinizing hormone, follicle-stimulating hormone, testosterone, 5α-androstan-3α,17β-diol, 5β-androstan-3α,17β-diol, epitestosterone, 4-androstenedione, androsterone and etiocholanolone were measured on eight subjects (four males and four females) by gas chromatography–mass spectrometry and chemiluminescent immunometric assay techniques before and after oral administration of multiple doses of either tamoxifen (80 mg for 2 days) or toremifene (120 mg for 2 days) or clomiphene (100 mg for 2 days). The individual baseline variability of the steroids studied was set up by collecting the urine samples every 3 h, for 3 days prior to the treatment; whereas the evaluation of the effects of the oral administration of multiple doses of selective oestrogen receptor modulators on the steroid urinary profile was assessed by collecting urine samples every three hours for at least five days from the first administration.The results of our measurements showed that, only in male subjects, the relative urinary concentrations of testosterone, epitestosterone and 4-androstenedione were significantly altered generally after the second day of drug administration. While no significant effects were recorded in both sexes on the luteinizing hormone, follicle-stimulating hormone, androsterone, etiocholanolone, 5α-androstan-3α,17β-diol and 5β-androstan-3α,17β-diol urinary levels and on testosterone/epitestosterone, 5α-androstan-3α,17β-diol/5β-androstan-3α,17β-diol and androsterone/etiocholanolone ratios.     

Determination of urine steroid profile in untrained men to evaluate recovery after a strength training session

Intense physical exercise is an important modifier of hormone metabolism. The aim of this study was to evaluate the variations in the urine profile of glucuroconjugated steroids (androgens, estrogens, and corticosteroids) as a consequence of a session of strength exercises. The subjects were a group (N = 20) of untrained male university students. They performed 3 sets of 10 repetitions, with a 3-minute recovery time between sets, at 70-75% of 1 repetition maximum (1RM). Four urine samples were collected per subject: before the session, immediately after, 3 hours after, and 48 hours after the session. They were assayed using a gas chromatograph coupled with a mass spectrometer. The concentrations of the different hormones were determined according to the urine creatinine level (ng steroid per mg creatinine). The substances assayed were testosterone, epitestosterone (Epit), androstenedione, dehydroepiandrosterone (DHEA), androsterone, etiocholanolone, beta-estradiol, estrone, tetrahydrocortisone (THE), and tetrahydrocortisol (THF). The results showed a significant decline after exercise with respect to the rested state in the urinary excretion of testosterone, Epit, DHEA, androsterone, and etiocholanolone. At 48 hours, there was a significant increase in the urinary excretion of Epit, androstenedione, androsterone, etiocholanolone, estrone, and THE. The androsterone + etiocholanolone/THE + THF ratio decreased after exercise, increased significantly (p < 0.05) at 3 hours, and returned to near resting levels at 48 hours. The data suggest that the performing a strength session at 70-75% of maximum strength provoked a state of fatigue in the subjects, from which they recovered 48 hours after the exercise.     

Effect of ethyl ether of p-chlorphenoxyisobutyric acid on the glucocorticoid function of the adrenal cortex of guinea pigs]

In administration to quinea pigs of ethyl-p-chlorophenoxyisobutyrate daily in a dose of 0.2 g/kg per os for 15-26 days decreased the 17-OHCS concentration in the peripheral blood plasma. A fall of the urinary excretion of individual 17-OHCS occurred chiefly at the expense of free unchanged cortisol, tetrahydrocortisol and tetrahydro-11-desoxycortisol. The zona fasciculate displays the abundance of the sudanophilic material. A test with ACTH demonstrated that the present functional reserves of the adrenal cortex failed to change under the effect of the preparation. The content of NEFA decreased in the blood serum; as to cholesterol level - it reamined unchanged. Possible mechanisms of the action of the preparation and prospects of its use for the treatment of hypercorticism are discussed.     

P53抗体联合CYFRA21-1和CEA在非小细胞肺癌中的应用

目的：研究血清P53抗体在非小细胞肺癌临床病理特征之间的关系,并结合血清中的癌胚抗原、角质蛋白21-1以指导对临床上肺癌复发和转移的分析,用来选择合理的治疗方案。方法：正常组30例,肺良性疾病组10例,肺癌组45例,肺癌全组分别于手术前1天、术后10、30、60和90天时抽取清晨空腹静脉血2ml,23例肺癌病例于手术后120天,15例病例于手术后180天抽取清晨空腹静脉血2ml,肺良性疾病组分别于手术前1天、抽取清晨空腹静脉血2ml。正常组清晨空腹采集静脉血2ml。采用酶联免疫吸附法（ELISA）检测血清P53抗体和角质蛋白21-1,采用荧光酶标免疫法检测血清癌胚抗原。结果：血清P53抗体、CYFRA21-1和CEA在正常人组、良性疾病组、肺癌组术前阳性率的比较三种肿瘤标志物阳性率经X2检验,在肺癌组分别与正常人组和良性病例组有显著性差异（P〈0.05）,良性病例组和正常人组之间无显著行差异（P〉0.05）。并与手术后复发与转移相关。结论：联合检测癌胚抗原、角质蛋白21-1及血清P53抗体水平有助于肺部良恶性疾病的诊断;手术前后动态测定肺癌患者血清P53抗体和角质蛋白21-1的变化规律,有助于判断疗效,监测预后和指导肺癌术后的综合治疗。     

Effects of sulpiride on levels of FSH, LH and steroid hormones

In order to study the effects of prolactin upon the gonadotrophins and steroid hormones, hyperprolactinaemia was induced by the administration of sulpiride. 12 men between the ages of 18 and 20 were given 3 capsules of 50 mg of sulpiride daily for a period of 15 days, and the following parameters being measured before and after the treatment: (prolactine, FSH, LH, testosterone, estradiol, ACTH and DHEA-S) by RIA, (cortisol) by fluorimetry and (etiocholanone, androsterone, pregnandiol, pregnantriol, pregnantriolone, 11-keto etiocholanone and 11-OH androsterone) by gas chromatography. Our results show that on termination of the treatment there was a significant rise in the prolactin and DHEA-S serum levels and a drop in the FSH serum levels but not of LH. In addition there was a marked increase in all the androgen levels studied, (etiocholanone, androsterone and 11-keto etiocholanone) with the exception of testosterone.     

Clinical chronopharmacology of ACTH 1-17. I. Effects on plasma cortisol and urinary 17-hydroxycorticosteroids

The aim of the investigation was to study the effects of ACTH 1-17 on both plasma cortisol and urinary 17-OHCS in health adult young males with regard to the time (clock hours) at which this polypeptide was injected. Eight healthy adults (males from 18-30 years) volunteered for the study. They were synchronized with a diurnal activity from 0700 to 0000 and a nocturnal rest. Each week, during 6 consecutive weeks (January 19 to February 25, 1980), a 3-day test was performed on Saturday, Sunday and Monday. On Sundays 3 control-tests and 3 ACTH-tests were programmed during which either saline or 100 micrograms ACTH 1-17 were injected i.m. at respectively 0700, 1400 and 2100. During each 3 day-test (72 h) the urinary excretion of 17-OHCS was determined every 4 h at fixed clock hours. In addition, on Sundays, venous blood was sampled prior to control or ACTH injections at respectively 0700, 1400, and 2100 and 20, 40, 60, 90, 120, 150 and 180 min thereafter. Plasma cortisol (radioimmunoassay) was determined in samples thus collected. Both conventional and cosinor methods were used for statistical analyses. A strong and statistically significant rise of plasma cortisol was observed after all of the ACTH 1-17 injections. The obtained mean response curves were observed after all of the ACTH 1-17 injections. The obtained mean response curves were similar in form and parallel. The highest plasma cortisol curve corresponded to ACTH injected at 0700, the lowest to ACTH injected at 2100. The curve corresponding to ACTH injected at 1400 went in-between. The 24-h urinary excretion of 17-OHCS after ACTH 1-17 was approximately 4 times greater than the control value when injected at 0700, approximately 3 times greater than control when injected at 1400 and only twice greater than control when injected at 2100. In terms of changes in plasma cortisol and 17-OHCS the greatest best benefit of ACTH 1-17 is achieved when this polypeptide is injected at 0700, rather than at 1400 or 2100 in diurnally active subjects.     

Lung volumes after an increase in lung distension in pneumonectomized ferrets

To investigate the role of lung distension in compensatory lung growth, the right lung of each of 21 adult male ferrets was replaced with a silicone rubber balloon filled with mineral oil. Three to thirteen weeks after surgery, the oil was removed through a subcutaneous port. Lung volumes were measured serially until 3-6 wk after balloon deflation. With pneumonectomy the total lung capacity (TLC) decreased to less than 50% of the preoperative value and remained essentially unchanged while the balloon was inflated. At balloon deflation, TLC and vital capacity did not change immediately, whereas functional residual capacity increased by 44%, indicating a change of 2-3 cmH2O in end-expiratory transpulmonary pressure. TLC increased by 10% within 3 days and continued to increase over the subsequent 3-5 wk by a total of 25% over TLC at balloon deflation. There was little difference in this response between animals whose balloons were deflated 3 wk after surgery and those in which deflation was delayed up to 13 wk. After pneumonectomy in the adult ferret, the remaining lung increases in volume in response to an increase in lung distension even weeks or months after surgery. The extent to which this volume increase involves lung tissue growth or depends on previous lung resection is at present unknown. This model may be useful for studies of the mechanisms by which lung distension influences lung volume and compensatory lung growth.     

Lung and vascular function during chronic severe pulmonary ischemia

Bronchial vascular angiogenesis takes place in a variety of lung inflammatory conditions such as asthma, cystic fibrosis, lung cancer, and chronic pulmonary thromboembolic disease. However, it is unclear whether neovascularization is predominantly appropriate and preserves lung tissue or whether it contributes further to lung pathology through edema formation and inflammation. In the present study we examined airway and lung parenchymal function 14 days after left pulmonary artery ligation. In rats as well as higher mammals, severe pulmonary ischemia results in bronchial vascular proliferation. Using labeled microspheres, we demonstrated an 18-fold increase in systemic blood flow to the ischemic left lung. Additionally, vascular remodeling extended to the tracheal venules, which showed an average 28% increase in venular diameter. Despite this increase in vascularity, airways resistance was not altered nor was methacholine responsiveness. Since these measurements include the entire lung, we suggest that the normal right lung, which represented 78% of the total lung, obscured the ability to detect a change. When functional indexes such as diffusing capacity, in situ lung volume, and vascular permeability of the left lung could be separated from right lung, significant changes were observed. Thus when comparing average left lung values of rats 14 days after left pulmonary artery ligation to left lungs of rats undergoing sham surgery, diffusing capacity of the left lung decreased by 72%, left lung volume decreased by 38%, and the vascular permeability to protein increased by 58%. No significant differences in inflammatory cell recruitment were observed, suggesting that acute ischemic inflammation had resolved. We conclude that despite the preservation of lung tissue, the proliferating bronchial neovasculature may contribute to a sustained decrement in pulmonary function.     

Glycoprotein hormone alpha subunit as a marker of pituitary adenoma

Blood serum FSH, LH, prolactin and testosterone as well as urinary excretion of 17KS and 17-OHCS were determined in 8 patients with chromophobe pituitary adenomas treated by transphenoidal microsurgical removal or craniotomy with or without subsequent telecobalt therapy. It was found te disease tends to recur in the majority of patients despite the type of therapy. Recurrence is accompanied by gonadotropins hyposecretion, increase in prolactin secretion, secretory disorders in the gonads and adrenals; an increase in prolactin secretion is proportional to the intensity of the compression symptoms. Bromocriptine in a daily doses ranging from 5.0 to 7.5 mg decreases prolactin levels in the recurrent chromophobe pituitary adenomas and does not affect their proliferation.