Urinary Excretion Of 17-ketogenic Steroids Research Articles

High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C

Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans. While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis. To study this, steroid hormone profiles in urine were assessed in male subjects suffering from functional mutations in ATP binding cassette transporter A1 (ABCA1) (n = 24), lecithin:cholesterol acyltransferase (LCAT) (n = 40), as well as in 11 subjects with low HDL cholesterol (HDL-C) without ABCA1/LCAT mutations. HDL-C levels were 39% lower in the ABCA1, LCAT, and low HDL-C groups compared with controls (all P < 0.001). In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27%, and 32% compared with controls (all P < 0.04). In seven carriers of either type of mutation, adrenocorticotropic hormone (ACTH) stimulation did not reveal differences from normolipidemic controls. In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin. These findings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans.

XYY males found in a general male population. Cytogenetic and physical examination.

Five males with karyotype 47,XYY were found among 3840 men examined for military service, giving a prevalence of 1.30 per 1000. The five XYY males had a normal male phenotype and no physical abnormalities, except for minor columna vertebralis aberrations. There was a slight increase of the β1 fraction of alkaline phosphatases. Testis histology showed impairment of spermatogenesis in all four in whom this examination was made. Electroencephalogram was slightly abnormal in two of the five males. There was a comparatively low urinary excretion of pituitary gonadotrophins, dehydroepiandrosterones and oestrogenes and a comparatively high urinary excretion of 17-ketogenic steroids; these deviations in hormone excretion were, however, not very pronounced.

Plasma prolactin response to submaximal stimulation by TRH and endogenous corticosteroids in man.

Recent studies suggest that submaximal plasma prolactin responses to TRH may reflect the effects of endogenous dopamine on prolactin release more accurately than basal plasma prolactin levels or maximal plasma prolactin responses to TRH. In the present study the plasma prolactin response to 12.5 micrograms i.v. TRH in 25 male subjects was significantly correlated with 24-hour urinary 17-ketogenic steroid excretion (= "total" 17-hydroxy corticosteroids). With regard to the basal plasma prolactin level or the prolactin response to 200 micrograms i.v. TRH, no such relation with corticosteroid excretion was detected. It is concluded that the plasma prolactin response to 12.5 micrograms i.v. TRH may provide a new, useful investigative tool with which to study corticosteroid-dopamine interactions and central dopamine activity in man.

SERUM TESTOSTERONE, FSH/LH AND URINARY EXCRETION OF ESTROGENS AND CORTICOIDS DURING TREATMENT WITH AN INJECTABLE, LONGACTING ESTROGEN‐DHEA PREPARATION

Ten weeks after total hysterectomy and bilateral salpingo-oophorectomy, nine women were treated with injections of Gynodian, composed of 4 mg estradiol valerate and 200 mg dehydroepiandrosterone enanthate, followed by injections of Primodian, composed of 4 mg estradiol valerate and 90.27 mg testosterone enanthate. Before commencement of treatment estimation of serum FSH, LH and testosterone, and analyses for total estrogen, 17-ketogenic steroids and fractionated 17-ketosteroids in 24-hour urine samples were carried out in all patients. The same serum and urine analyses were made 2 weeks after the first Gynodian injection and the first Primodian injection respectively. Serum testosterone concentrations did not change during treatment with Gynodian, whereas they rose markedly after administration of Primodian. Two weeks after the first injection of Gynodian and also of Primodian, the total estrogen excretion was only slightly increased in comparison with the value measured before start of treatment, and the serum FSH/LH ratio was only slightly depressed. The daily urinary excretion of 17-ketogenic steroids and of fractionated 17-ketosteroids were unchanged during treatment.

CONVENTIONAL PITUITARY IRRADIATION IN ACROMEGALY

Thirty-one patients who had been treated for acromegaly for 1-21 years with conventional pituitary irradiation were re-examined. Immunoreactive growth hormone (GH) was measured in connection with an oral glucose load. Adrenal and gonadal functions were assessed on the basis of plasma cortisol and the urinary excretion of 17-ketogenic steroids, 17-ketosteroids and gonadotrophins. In evaluating the thyroid-pituitary axis the thyrotrophin-releasing hormone stimulation test (TRH) was used. Initially 30 patients had experienced definite benefit from the treatment but at the time of re-examination 10 still had clinically active disease and required another type of treatment. Normal GH levels (less than 5 ng/ml/1) were seen in only 12 patients. Skin thickness was normal in 15 out of 30. Thus the remission rate can be evaluated as being 67% as regards clinical activity, 50% with regard to skin thickness and 39% in terms of GH levels. Hypogonadism occurred in 12 patients (39%) and adrenal and thyroid failure in 5 patients each (16%). The response to TRH was within the normal range in 2 of the hypothyroid patients. In 22 euthyroid patients the mean increment in serum TSH in response to 200 mug of synthetic TRH was only 5.8 mU/1 which was significantly below the normal mean 12.5 mU/1. Furthermore, in 7 of these patients (32%) the response was absent or subnormal (less than 3.0 mU/1). This indicated that the pituitary is capable of secreting enough TSH for maintenance of an euthyroid state but that its capacity is limited. Conventional pituitary irradiation is not a very effective treatment in acromegaly but may still be recommended in selected cases.

VIRILIZING ADRENOCORTICAL ADENOMA RESPONSIVE TO GONADOTROPHIN

A virilizing adrenocortical adenoma was demonstrated in a yound female. Urinary 17-ketosteroid excretion and subfractions, plasma testosterone level and urinary 17-ketogenic steroid excretion were markedly increased. Dehydroepiandrosterone was the main constituent of the androgen excess. Otherwise the adrenocortical function was found to be normal as evaluated from measurements of cortisol, corticosterone and their metabolites under basal conditions and during dynamic tests. The androgen excess showed an unexpected response to trophic hormones. Human chorionic gonadotrophin stimulation resulted in a pronounced increase in androgen production, whereas no gonadotrophin-dependency could be demonstrated by means of the oestrogen suppression test. Similarly, no corticotrophin-dependency could be demonstrated by corticotrophin stimulation and suppression tests. Removal of the tumour resulted in normalization of the androgen production and no abnormal response upon human chorionic gonadotrophin administration could now be found. The inappropriate response of tumours to trophic hormones is discussed. It is concluded that the reliability of stimulation and suppression tests in determining the site of excessive androgen production should be accepted with reservation.

Adrenal function in patients receiving medroxyprogesterone acetate

Adrenal and pituitary function studies consisting of ACTH stimulation and SU-4885 tests were performed on ten patients before and during medroxyprogesterone acetate injections for one year. Plasma cortisols and urinary excretion rates of 17-ketosteroid and 17-ketogenic steroids were measured before and during the test. The following observations were noted: (a) baseline plasma cortisol levels were lower after receiving medroxyprogesterone acetate injections; (b) with ACTH stimulation, 17-ketogenic steroids and plasma cortisol showed a normal response, whereas the excretion rates of urinary 17-ketosteroids showed variable responses; (c) with SU-4885, the increases in urinary 17-ketogenic steroid excretion rates in subjects receiving MPA was less than that observed prior to MPA, again, the 17-ketosteroid excretion rates were variable.

Familial moniliasis, defective delayed hypersensitivity, and adrenocorticotropic hormone deficiency

Five siblings, 2 normal and 3 with moniliasis, cutaneous anergy, and limited pituitary adrenocorticotropin reserve, were studied. The affected siblings failed to manifest delayed hypersensitivity. Endocrine studies showed that the affected siblings had almost no increase in urinary excretion of 17-ketogenic steroids after adrenocorticotropin infusion, and a significantly lower increase in 17-ketogenic steroid excretion during a metyrapone test as compared to control subjects. One sibling had hypoparathyroidism.

Hypopituitarism and ketotic hypoglycemia.

A 7-year-old patient presented with growth failure and early morning convulsions. The convulsions were associated with hypoglycemia and ketosis. Symptomatic hypoglycemia with ketosis occurred following the administration of a hypocaloric ketogenic diet. The diagnosis of hypopituitarism was established by failure of growth hormone response following administration of insulin and arginine hydrochloride, and failure of metyrapone to increase the urinary excretion of 17-ketogenic steroids. Thyroid function became abnormal. Therapy with thyroid extract alone and later combined with prednisone failed to decrease the frequency of ketotic hypoglycemic episodes. The administration of thyroid extract and human growth hormone, however, was followed by remarkable improvement which may have been due, in part, to increased insulin production.

Serum corticotrophin, plasma cortisol and urinary excretion of 17-ketogenic steroids in the elderly (age group: 66-94 years).

ABSTRACT The serum corticotrophin concentrations was determined in 28 elderly subjects (70–94 years) by the radioimmunochemical double-antibody-technique. In 5 elderly subjects, the corticotrophin concentration was studied throughout the 24-hour period. The plasma cortisol concentration was determined by means of a double-isotope-derivative technique in 69 elderly subjects (66–94 years). In 10 elderly and 8 younger subjects the concentration was checked throughout the 24-hour period. The urinary excretion of 17-ketogenic steroids was determined in a total of 80 elderly subjects (66–94 years). For comparison corticotrophin and cortisol measurements in young volunteers assayed by identical methods were used and partly carried out in cooperation with other investigators. At 8 a. m. the average corticotrophin concentration was 101.8 ± 55.0 (sd) pg/ml of serum and the average cortisol concentration was 15.0 ± 4.60 (sd) μg/100 ml of plasma. No significant age or sex variation could be detected. With regard to both hormones, the circadian variations were marked with parallel changes in the concentrations of corticotrophin and cortisol. The highest concentration was measured in the morning and the lowest in the evening. The urinary excretion of 17-ketogenic steroids showed a tendency to decrease with increasing age. The regression equation for females was ȳx = −0.07x + 11.42, for males ȳx = −0.22x + 26.59.

Hypokalemia with normal blood pressure, aldosterone and renin levels secondary to a renal or adrenal tumor

A normotensive forty-two year old Negro woman had persistent hypokalemia (2.6 to 3.1 mEq per L) with high urine potassium levels (30 to 60 mEq per day) which improved with spironolactone but not with sodium restriction. On a 150 mEq sodium diet, aldosterone excretion was 4.6 and 8.6 μg per day (normal 5 to 19), aldosterone secretion was 91.6 μg per day (normal 50 to 250), and plasma renin (supine) was 103 plasma renin activity (PRA) units per 100 ml (normal 30 to 220); while on a 10 mEq sodium diet, renin levels (ambulatory) were 1,760 and 840 PRA units per 100 ml (normal 390 to 1,200). Urinary excretion of 17-ketogenic steroids was 3.4 to 7.2 mg per day, excretion of compounds “B” and tetrahydro-DOC was not increased. Differential ureteral potassium excretions were equal, urinary acidification following the administration of ammonium chloride was normal, the creatinine clearance was normal. Angiotensin infusion (0.0083 to 0.1 μg per kg per minute) produced normal pressor response. An intravenous pyelogram and aortogram revealed a mass in the right kidney. The right kidney, containing a large cystic renal cell carcinoma (cyst fluid renin 60 PRA units per 100 ml), and the adrenal gland, containing a 1.5 cm diameter cortical adenoma, were removed. The uninvolved kidney was normal histologically, without juxtaglomerular cell hyperplasia. Postoperatively, the serum potassium level (3.8 to 5.4 mEq per L) returned to normal and plasma renin levels were 128 and 1,590 PRA units per 100 ml on a high and low sodium diet. This unique syndrome may be due to secretion of a nonsodium-retaining, potassium-losing hormone by the renal or adrenal tumor.

Radioimmunoassayable ACTH in dexamethasone nonsuppressible Cushing's syndrome.

Radioimmunoassayable serum ACTH has been measured in a patient with Cushing's syndrome due to bilateral adrenal hyperplasia showing failure of dexamethasone suppression of plasma and urinary steroids with up to 32 mg of dexamethasone/day. Plasma ACTH was consistently elevated and showed an abnormal diurnal pattern which altered with increasing doses of dexamethasone. On extremely high doses of dexamethasone, urinary 17-ketogenic steroid excretion doubled over base line at a time when ACTH seemed to lose its diurnal pattern and remain at a relatively high level. The patient's ACTH response to metyrapone was similar to that of a patient with suppressible Cushing's syndrome and adrenal hyperplasia. The intravenous infusion of hydrocortisone produced a dramatic fall in serum ACTH concentration not noted during the administration of dexamethasone. The study suggests a derangement in the feedback receptor for dexamethasone as the cause of this anomalous response of ACTH and adrenal steroids during dexamethasone administration.

Simplified dexamethasone suppression test.

ABSTRACT This is an investigation of the practical clinical value of the one mg dexamethasone suppression test of Nugent et al. (1963). The results, evaluated from the decrease in fluorimetrically determined plasma corticosteroids in normal subjects, as well as in cases of exogenous obesity, hirsutism and in Cushing's syndrome, confirm the findings reported in previous studies. Plasma corticosteroid reduction after one mg of dexamethasone in cases of stable diabetes was not significantly different from that observed in control subjects, but in one third of the insulin-treated diabetics only a partial response was observed, indicating a slight hypercorticism in these patients. An insufficient decrease in plasma corticosteroids was observed in certain other conditions (anorexia nervosa, pituitary adenoma, patients receiving contraceptive or anticonvulsive treatment) with no hypercorticism. The physiological significance of these findings is discussed. It is concluded that the test, together with a determination of the basal urinary 17-ketogenic steroid excretion, is suitable as the first diagnostic test in patients in whom Cushing's syndrome is suspected. In cases of insufficient suppression of plasma corticosteroids, further studies, including the suppression test of Liddle (1960), must be carried out.

Adrenal-pituitary responsiveness during therapy with an oral contraceptive.

The effect of the oral contraceptive Norinyl (1 or 2 mg norethindrone 100 mcg mestranol) on the hypothalamic-pituitary-adrenal response to Piromen (Pseudomonas polysaccharide complex) methopyrapone and exogenous ACTH was investigated in 8 subjects. Norinyl use significantly (p less than .001) lowered both urinary excretion of 17-ketogenic steroids (KGS) and 17-ketosteroids. The response to methopyrapone was markedly impaired during Norinyl treatment though the hypophyseal-adrenal response to Piromen was normal. The results indicate that Norinyl and presumably other progestational agents do not affect the pituitary-adrenal response to stress even though the response to methopyrapone was impaired.

CORTISOL SECRETION RATE AND URINARY CORTICOID EXCRETION IN NORMAL AND OBESE SUBJECTS

ABSTRACT The adrenocortical function has been studied in 18 obese patients and in 20 normal subjects. The cortisol secretion rate and the urinary excretion of 17-ketogenic steroids are significantly higher in the obese than in the normal subjects. Yet a great deal of overlapping exists among the groups. Highly significant correlations are found between cortisol secretion or 17-ketogenic excretion on the one hand, and body weight, body surface area or degree of obesity on the other, among pooled normal and obese individuals. When the values are related to body surface area or to actual body weight, the figures for normal and obese people are not significantly different. These data suggest that the increased cortisol secretion in moderately obese people is a function of the increase in their tissues mass.

Biological effects of urban air pollution. II. Chronic exposure of guinea pigs.

Rodents exposed to the ambient atmosphere of Los Angeles throughout their lives have been studied in comparison with animals maintained in smog-filtered atmospheres. In aging inbred mice of certain strains, there was an increased incidence of pulmonary adenoma. In one strain mortality of males (but not females) during the first year of life was increased. Severe smog episodes caused lung tissue alterations at the ultrastructural level, especially in mice older than 15 months. Severe episodes produced transient increases in pulmonary resistance in old guinea pigs but no demonstrable chronic or cumulative effects on this parameter. In guinea pigs sensitized by prior stress treatment, urinary excretion of 17-ketogenic steroids was enhanced by ambient atmosphere exposure. After two or three years of exposure, rabbits exhibited reduced activity of glutamic oxalacetic transaminase in blood serum.

A FOUR DAY CORTICOTROPHIN-SUPPRESSION TEST

ABSTRACT A four day ACTH-suppression test was performed in 58 patients showing symptoms often associated with hypercorticism and in 25 cases of Cushing's syndrome. The non Cushing patients suffered from obesity, hypertension, plethora, diabetes and mental disturbances in various combinations and/or conditions related to hypertrichosis and menstrual disorders. Some of them also showed an increased basal excretion of 17-ketosteroids. Triamcinolone, in doses of 4 mg and 8 mg every six hours or 2 mg of dexamethasone every six hours, induced a good suppression of adrenocortical function in the non Cushing patients. This was demonstrated by chromatographic analysis of 24 different 24-hour urine samples collected on the third or fourth day of the test. In these cases – selected at random from the 58 non Cushing patients – the mean excretion of tetrahydroderivatives of cortisone and cortisol was &lt; 0.3 mg/day (range 0.0–1.2 mg/day). Only traces of dehydroepiandrosterone and 11-oxy-17-ketosteroids were found. In all cases, 17-ketogenic steroids, Porter-Silber chromogens and 17-ketosteroids were determined by routine methods and the results are discussed with regard to the presence of non specific chromogens. There was no difference in the urinary excretion of steroids during the administration of 16 mg and 32 mg respectively of triamcinolone and of 8 mg of dexamethasone daily. In 9 of 11 cases of non-tumourous Cushing's syndrome, triamcinolone in a dose of 4 mg every six hours did not suppress the urinary excretion of 17-ketogenic steroids, Porter-Silber chromogens or 17-ketosteroids normally. In two cases, however, there was a normal suppression according to the criteria chosen. In one case of non-tumourous Cushing's syndrome, suppression could not be demonstrated during the administration of triamcinolone in a dose of 16 mg every six hours for four days. Because of the varying degrees of suppression found in Cushing's syndrome, the diagnostic conclusions drawn from the ACTH-suppression test should be made with caution. Marked variation in the basal excretion of steroids adds to the difficulties as do the limitations of the test imposed by unspecificity of the methods used in evaluating the adrenocortical function.

CLINICAL VALUE OF THE CORTISOL SECRETION RATE.

The isotopic estimation of the cortisol secretion rate in man is now an accepted and reliable method of assaying adrenal cortical function.Seven years' experience with its clinical use is reviewed and some practical aspects of technique are considered. The mean normal resting cortisol secretion rate is 16.2 +/- 5.7 mg. daily. In all of 14 cases of hypopituitarism studied secretion has been less than 2.1 mg. daily. In all of 26 cases of established Cushing's syndrome, the cortisol secretion was above 36 mg. The method can be used to follow day-by-day changes in adrenal cortisol activity and examples of such use are given. The urinary 17-ketogenic steroid excretion frequently gives results which conflict with secretion rate estimates, and can lead to erroneous clinical conclusions.

Response of obese patients to an 11beta-hydroxylase inhibitor, methopyrapone (SU-4885).

SummaryObese subjects exhibit 2 different responses to an 11β-hydroxylase inhibitor, methopyrapone (SU-4885), depending upon the level of the base-line urinary 17-ketogenic steroid excretion. Subjects with a normal base-line 17-KGS excretion have a normal response to methopyrapone, whereas subjects with base-line elevated urinary 17-KGS give a markedly impaired response to this inhibitor.

Pituitary-adrenal stimulation by sound of different frequencies.

ABSTRACT Nine healthy young men and 17 psychiatric patients were stimulated with pure sound for 1-hr periods. Sound frequencies of 125, 1,000, 5,000 and 10,000 cycles per second (cps) were tried, with intensities of 65–93 decibels. Substantial elevations in the free plasma 17-hydroxycorticoids (17-OHCS) were observed in the normal subjects with all frequencies, and higher values, between 20 and 24 μg (twice the normal levels), with 10,000 cps sound. Urinary 17-ketogenic steroid excretion also was markedly elevated. Particularly striking elevations in the plasma 17-OHCS levels were observed in psychoneurotic patients with anxiety, although depressive cases had either no elevation or a reduction c f corticoids. It is concluded that adrenal cortical function in man may be remarkably sensitive to auditory stimulation, probably through the effect of ACTH released by intense sound.