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The urinary levels of seven steroids, 5 alpha-androstane-3 alpha,17 beta-diol, 5 beta-androstane-3 alpha,17 beta-diol, androsterone, etiocholanolone, tetrahydrocortisone, tetrahydrocortisol and allotetrahydrocortisol were measured in both normal (n = 18) and hirsute (n = 24) women. The results confirmed 5 alpha-androstane-3 alpha,17 beta-diol as the most significant steroid with respect to discrimination between hirsute and normal subjects. Investigation of the inter-steroid relationships, using multivariate techniques established that the mode of steroid metabolism was different between the two groups. Whereas in normal women the strong correlation amongst all the androgen metabolites inferred a predominant hepatic route to 5 alpha-androstane-3 alpha,17 beta-diol formation, the same analogy was not applicable to the hirsute subjects. Excellent agreement was found for the predicted vs actual excretion of 5 alpha-androstane-3 alpha,17 beta-diol in normal women, based on a regression model involving the six other steroids as independent variables. When the same model was used for estimation of 5 alpha-androstane-3 alpha,17 beta-diol levels in thirteen hirsute subjects, misclassified as "normal", 50% gave values which were considerably less than actually measured. It is suggested that this discrepancy, with respect to these hirsute subjects is a reflection of extrahepatic production of 5 alpha-androstane-3 alpha,17 beta-diol due to increased 5 alpha-reductase activity.

The authors studied the relation of plasma testosterone and Sex-Hormone-Binding-Globulin levels to the urinary excretion of androsterone (A) and etiocholanolone (E) in three patients with the syndrome of testicular feminization. They found levels of SHBG in the upper female range, testosterone concentration in the normal male range and urinary excretion rate of A and E in the normal female range.

The increased urinary excretion of androsterone and aetiocholanolone, 17-oxosteroids, and oestrogens which occurs after the administration of human chorionic gonadotropin to normal men, was followed by measuring steroid to creatinine ratios in small samples of urine. For androsterone + aetiocholanolone, values of the ratio correspond closely with 24 h output (correlation coefficients: 0.91, 0.92, and 0.91 for first morning, mid-morning, and mid-afternoon urine specimens.) Comparable correlation coefficients for the 17-oxosteroids in urine were 0.90, 0.95, and 0.91; and for oestrogens, 0.88, 0.87, and 0.86.

Etiocholanolone levels have been measured in both premastectomy and postoperative urines from 86 women with early breast cancer. Levels did not differ between patients subsequently surviving five years following mastectomy and those dying from recurrent disease within this period.

To assess the validity of serum dehydroepiandrosterone sulphate (DS) radioimmunoassay instead of urinary total 17-ketosteroid (17-KS) or individual metabolite (dehydroepiandrosterone + etiocholanolone + androsterone; D + E + A) determination to control adrenal androgen function, a comparative study has been performed. Mathematical analysis of simultaneous estimates revealed significant correlation when normal or above normal 17-KS or D + E + A excretion relative to serum DS were considered. Poor correlation was observed when below normal metabolite excretion and serum DS were related. Furthermore, there was a significant correlation between estimates of 17-KS (or D + E + A) and those of serum unconjugated D also determined by radioimmunoassay. The serum DS radioimmunoassay appeared to be a reliable tool to assess adrenal androgen function, at least in patients exhibiting normal or high 17-ketosteroid values.

Gas-chromatographic analysis of the urinary steroids in an 18 year-old girl with primary amenorrhoea and hirsutism revealed markedly elevated excretion of androsterone, etiocholanolone, dehydroepiandrosterone, and androstendiole, both under basal conditions and after oral dexamethasone (0.5 mg q.i.d. for three days). Adrenal scintigraphy revealed the presence of a tumour of the right adrenal gland, which was subsequently removed by unilateral adrenalectomy. Histologically, the tumour showed marked anisocytosis, but since there was no evidence of capsular or angioinvasion or of mitotic activity, it was classified as an adrenocortical adenoma. Postoperatively the patient showed regression of the virilizing syndrome and normal menstrual bleeding. Urinary steroid excretion has remained normal for four years after adrenalectomy. Androgen-producing tumours must be considered as a possible cause of hirsutism in young females and should, thus, be excluded in each case. Analysis of urinary steroids by gas chromatography is a valuable tool in accomplishing this task.

Seven anorexia nervosa (A.N.) patients had reduced urinary excretion values of tetrahydrocortisone (THE), androsterone (A) and 5alpha-tetrahydrocortisol (5alpha-THF). THE to tetrahydrocortisol (THF), A to aetiocholanolone (Ae) and 5alpha-THF to THF ratios were all significantly reduced. Six A.N. patients had oral metyrapone tests with quantitatively normal but delayed urinary 3alpha,17alpha,21-trihydroxy-5beta-pregnan-20-one (THS) response. The steroid determinations were done by capillary gaschromatography, which proves to be of value in the study of the above mentioned metabolic abnormalities.

[4-14C]-Dehydroepiandrosterone and [7 alpha-3H]-Dehydroepiandrosterone sulphate were injected simultaneously to normal and obese female subjects. The percentage recovery of 14C and 3H radioactivies in dehydroepiandrosterone sulphate, androsterone sulphate, etiocholanolone sulphate, androsterone glucuronoside and etiocholanolone glucuronoside was determined in the day-to-day urine collections for 72 hr. Results showed a normal total 3H recovery and a poor 14C recovery in urinary conjugates of obese patients. The rate of appearance of 3H activity was not identical in the individual metabolites of normal subjects, and it was not normal in obesity. Overweight subjects exhibited an acceleration in [7 alpha-3H]-Dehydroepiandrosterone sulphate metabolism to androsterone glucuronoside. The observation regarding the rate of appearance of urinary conjugates bearing 14C isotope correlate with our previous finding in which a glandular overproduction of free dehydroepiandrosterone was found and an uptake of this steroid by the adipose tissue was suggested. Our results showed that the poor recovery of 14C radioactivity in urine of obese female subjects was not an aspecific consequence of illness.

Serum concentrations of LH, FSH and testosterone, and urinary excretion of individual 17-ketosteroids, oestrogenic substances and free cortisol was investigated in 12 normal men after a daily administration of 50 mg clomiphene citrate for 14 days. A significant increase in the serum concentrations of LH, FSH and testosterone was seen after 8 days with a further increase when measured a week later. The percentual increase in urinary excretion of oestrogens and dehydroepiandrosterone was of the same order as the increase in serum testosterone concentrations whereas the increase in androsterone and a aetiocholanolone was significantly lower. The excretion of free cortisol was unaltered. The study that measurements of oestrogens in the urine might be used as a parameter of the stimulatory effect of clomiphene on the hypothalamic - pituitary - gonadal axis in man. In addition, of the results support the hypothesis of an independent effect of clomiphene on adrenal steroidogenesis, not related to the production of glucocorticoids.

Urinary aetiocholanolone levels have been measured in 417 women aged between 20 and 70 years. The women were drawn from South East Scotland and South Wales and consisted of patients with either benign or malignant disease of the breast and control patients suffering from no detectable breast disorder. The pattern of aetiocholanolone excretion with respect to age and menopausal status has been defined in each group of patients. No significant differences in urinary levels have been detected between patients with breast disease, whether benign or malignant, and control patients. More detailed examination of the 201 women with early cancer of the breast has also shown that there is no consistent correlation between pre-operative aetiocholanolone levels and factors of prognostic significance detectable at the time of primary treatment-tumour size, grade, round cell infiltration, histological involvement of nodes by tumour and the clinical palpability of lymph nodes. It would seem, therefore, that the prognostic value of pre-operative aetiocholanolone measurements is somewhat limited in patients with early breast cancer. It is noted, however, that low levels of aetiocholanolone are associated with post-menopausal patients, a group in which the prognosis is generally poorer than that in pre-menopausal women.

We report on the present views on disturbances regarding spermatogenesis caused by chronic abuse of alcohol which still are partly based on findings from the year 1910. We are also presenting results of semen analysis in alcoholics. There is some evidence that alcohol-toxic damage of the testes may occur immediately. Regarding alcohol-toxic effects, we discuss some biochemical conceptions as there are the metabolism of Vitamin A and possible effects on the steroid reductases in particular. Our own studies have revealed some disturbances with regard to the gestagen metabolism of chronic alcoholics.

Calusterone (7beta, 17alpha-dimethyltestosterone) is a 17-alkylated, orally active androgenic steroid used in the treatment of breast cancer. The effect of this steroid on the metabolism of 14C-testosterone and the excretion of endogenous urinary androgen metabolites has been studied in four patients with breast cancer. Total glucuronide metabolites of the tracer decreased significantly, the andorsterone/etiocholanolone ratio rose by a factor of 2-4, and there was increased formation of uncharacterized polar metabolites. There was no significant change in either the sum of the excretion of endogenous androgen metabolites or the androsterone/etiocholanolone ratio. The changes resemble those we have seen in cirrhosis of the liver. It is concluded that the effects of Calusterone on testosterone metabolism, like its effects on cortisol or estradiol metabolism, represent nonspecific effects of an orally administered 17-alkylated steroid on hepatic structure and function, and probably bear no relationship to its therapeutic effect in breast cancer.

An extension of the logistic model (Cox, 1970) is applied to the prospective study of breast cancer in Guernsey (Bulbrook and Hayward, 1967). Four important risk factors, age at menarche, family history, age at first birth and etiocholanolone excretion, are identified and shown to have additive effects on a logistic scale for the probability of developing breast cancer. The feasibility of screening a high risk group of women is considered and shown unlikely to be of practical value.

The administration of human chorionic gonadotrophin (HCG) to dexamethasone-suppressed men caused parallel changes in the concentration of plasma testosterone and in the urinary output of androsterone+aetiocholanolone, total 17-oxosteroids and oestrogens. Discrepant results occurred in only four of the thirty-seven men tested. With these exceptions, the response to HCG could by followed as well by measuring androsterone+aetiocholanolone, 17-oxosteroid or oestrogen excretion rates as by following plasma testosterone levels. The most sensitive index of response was the rate of appearance of oestrogens in urine, and the next that of androsterone+aetiocholanolone.

Two kindreds with Marinesco-Sjögren's syndrome in three sibships are described. In five of the six affected, but in none of the unaffected sibs, a hypergonadotropic hypogonadism was observed. In one of the kindreds a high degree of inbreeding was revealed, and inbreeding likely also existed in the other kindred. The two families were not related. Marinesco-Sjögren's syndrome is known to be a distinct clinical entity, governed by autosomal recessive inheritance, and this also applies to hypergonadotropic hypogonadism. Several heredo-degenerative nervous disorders are accompanied by a hypogonadotropic hypogonadism, which is believed to be secondary to the neurological disorder, as in traumatic paraplegia. A hypergonadotropic hypoganadism cannot readily be explained in this way. We consider genetic linkage between two independent disorders as the most likely explanation for the observed concurrence.

Ketosteroids, the excretory metabolities of adrenal and gonadal steroids, can be analyzed individually in urine by a simple extraction procedure followed by separation and quantitation by the use of gas/liquid chromatography. The ketosteroids quantitatively detected by the technique are androsterone, etiocholanolone, dehydroepiandrosterone, 11-hydroxyandrosterone, 11-hydroxyetiocholanolone, 11-ketandrosterone, and 11-ketoetiocholanolone. Other steroid metabolities detected are pregnanediol, pregnanetriol, delta5-pregnenetriol, and 11-ketopregnanetriol. In comparison with concentrations of these steroids observed in urine specimens collected from healthy individuals, abnormal results occur in specimens from patients with testicular disease, Cushing's syndrome, adrenal hyperplasia, and several types of female hirsutism. Characteristic profiles for each of these diseases are presented.

Sexual function was studied in 76 patients with chronic bronchitis and in 17 healthy males. The study showed a decrease in sexual function of primary hypogonadism type which was in direct relation to the gravity of disease.

A method for gas-liquid chromatographic separation and quantitation of urinary steroid metabolites is described. A normal reference range has been established and classic examples of urinary steroid profiles of the major steroid disorders are given.

The actions of exogenous corticotrophin (ACTH) and human choriogonadotrophin (HCG) were assessed by measuring cyclic adenosine 3',5'-monophosphate (cAMP), 17-ketosteroids (17-KS), 17-ketogenic steroids (17-KGS), androsterone (A), etiocholanolone (E), dehydroepiandrosterone (DHEA) and pregnanetriol (P3) in 24 h urine. ACTH was infused intravenously into six healthy women. A dexamethasone (DXM) suppression test was also performed, and continued when HCG was injected intramuscularly. The effects of intramuscular injection of ACTH and administration of DXM on urinary cAMP, 17-KS and 17-KGS were also studied in an adrenalectomized and ovariectomized patient. ACTH, 250 microgram (25 i.u.), increased excretion of cAMP in the healthy women and also in the patient. In the six controls there was a simultaneous normal increase in 17-KS, 17-KGS, A, E, DHEA and P3 excretion. DXM did not cause the excretion of cAMP to fall below the basal level in any of the subjects examined but the excretion of all the steroids studied decreased significantly. The only effect of HCG was to increase P3 excretion. The results indicate that the increment in cAMP is probably related to an extra-adrenal effect regulated by ACTH.

Comparative investigations of the urinary excretion of different 17-ketosteroids in healthy women and patients suffering from mastopathia fibrocystica and/or mammary carcinomas had the following results: 1. A clear age dependency of the excretion of 17 ketosteroids during the regenerative period has been shown in all groups investigated, but it could not be observed during the postmenopausal phase. 2. There are no hints by the excretion values for a remarkable contribution of mammary carcinomas to the hormone metabolism of the host. 3. The excretion values of patients suffering from mastopathia fibrocystica confirm epidemiological results, which consider this from of mastopathia a precancerous one.

In order to study the hypophyseal-testicular axis in males with complete absence of germinal epithelium, the urinary total hypophyseal gonadotrophins (HG), urinary follicle stimulating hormone (FSH) and urinary luteinizing hormone (LH) were measured by specific bioassays in 12 males with classical Sertoli-cell-only syndrome and compared with HG, FSH, and LH in normal and castrated men. HG and FSH were significantly higher than HG and FSH in normal men (P smaller than 0.0025, P smaller than 0.0005, respectively), but significantly lower than in castrated men (P less than 0.001, P less than 0.01, respectively). LH was not different from LH of normal men, but significantly lower than in castrated men (P less than 0.0005). All patients had normal excretion of androgen metabolites (androsterone plus aetiocholanolone) but a dexamethasone suppression test, performed in 8 subjects, revealed that in 2 cases of testicular origin, the values were below the normal range. The excretion of oestrogens was within the normal range. The presented data support the concept that the germinal epithelium produces a substance capable of inhibiting FSH secretion from the hypophyses, the Sertoli cell itself, however, having a basal production of this inhibitor. The finding of low excretion of testicular androgen metabolites in some of the patients and normal urinary LH, indicates that disturbances in the LH-testosterone feedback mechanism in such patients may occur and that the previous concept of isolated defects of spermatogenesis in all such patients was erroneous.

Gas-liquid chromatography was applied to the analysis of urinary steroids of women. In the statistical analysis, quantitation of all steroid excretions and ratios among them were transformed to give a normal frequency distribution. The influence of the host's age and the menstrual cycle on 24 hours' excretion was investigated for each of 14 identified neutral steroids, of which four in our fraction 2 (11-hydroxyandrosterone, 11-hydroxyetiocholanolone, pregnanediol, and pregnanetriol) were menstruation dependent. The 14 neutral steroid excretions were generally correlated with one another within the host, and the use of a steroid ratio rather than quantitation of steroid excretion was often more sensitive in the characterization of the hormonal status.

Urinary excretion of 11-deoxy-17-ketosteroids was studied in 20 to 22 women with normal menstrual cycles on the 7, 10, 14 and 20th days of their cycles. The fraction studied showed a significant cyclic variation with a type of pattern for Androsterone and Aetiocholanolone and another one for the Dehydroepiandrosterone. The possibity of one metabolic path for the former metabolites and a different one for the latter, plus its close conection with the functional changes of the ovary, were arrived at.

Detailed studies of urinary steroids in patients with breast cancer and normal controls have shown that abnormal aging processes and depressed corpus luteum function were associated with the presence of this form of cancer. The ratio of androsterone to tetrahydrocortisol, an index of the aging process, was significantly lower in a breast cancer group than in a normal group at both premenopausal and postmenopausal stages. In premenopausal women, the ratio decreased in the order of rural controls, urban controls, and patients with breast cancer. It was indicated that the ratio may serve as a measure of risk for breast cancer. Aside from the general depression of menstruation-dependent steroids, breast cancer was associated with disproportionately low excretions of prenanediol and pregnanetriol within the menstruation-dependent steroid family. The notion that this finding reflects the delay or complete failure of ovulation was supported by a reduced parturition rate of our patients with breast cancer as compared with that of our normal controls. The physiologic significance of steroidal disturbances was considered in relation to the genesis of breast cancer.

26 women with secondary disturbance of sexual responsiveness were treated mainly with dehydroepiandrosterone preparations. The sexual tonus was tested before and after treatment by a sexual score system previously described. Urinary 17-ketosteroid and plasma testosterone fractions were controlled in 17 patients; these values were, in general, below the normal range before treatment. Treatment was considered to be successful in 17 patients, while in the remaining 9, who mainly belonged to the group of younger patients, no success was achieved. However, the results point out that therapeutic success with hormones of low biological activity can be expected only after numerous months of treatment. The pattern obtained on determination of hormonal parameters usually corresponded to the results of treatment.

1. Urinary 17-oxosteroid conjugates were measured by gas-liquid chromatography in five patients with hereditary coproporphyria. 2. Three patients were in an acute attack and showed significantly increased excretion of sulphate or glucuronide conjugates of aetiocholanolone. There was increased excretion of several other related steroids but no consistent pattern was apparent. 3. In the two patients in remission, excretion of urinary 17-oxosteroids was not increased. 4. The ratio of total urinary aetiocholanolone to androsterone (5beta:5alpha) was found to be significantly elevated for the three patients in an acute attack. Serial measurements were made in two of these patients and showed a highly significant linear correaltion between this ratio and the urinary content of delta-aminolaevulic acid and porphobilinogen. 5. These observations suggest the involvement of the 17-oxosteroids, espically aetiocholanolone, in the pathogenesis of hereditary coproporphyria.

It was shown experimentally that in old dogs a sharp reduction of testosterone and androstendion secretion by the testes was accompanied by a marked reduction of their metabolites (androsterone and ethiocholanolone) excretion. In the presence of a general reduction of the testicular androgen secretion and their urinary metabolite excretion there was noted a relative prevalence of fractions with low activity: of androstendion over testosterone in the blood, and of ethiocholanolone over androsterone in the urine. As postulated, in aged dogs hormonal background was characterized not only by quantitative, but also by qualitative changes, prerequisites for the development of visceral and metabolic disturbances.

Patients with Cushing's syndrome may be discriminated from normal subjects on the basis of their respective neutral urinary steroid profile. In the former group, evidence is presented that lowered levels of T3 secondary to hypercortisolism, decrease the liver enzymes associated with 5 alpha-reductase and 11 beta-hydroxy steroid dehydrogenase activity. As a result the metabolism of cortisol and androstenedione in Cushing's syndrome yields a unique pattern dominated by 5 beta and 11 beta-hydroxy steroid metabolites.

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 17-ketosteroid (17-KS) fractionation, i.e. a marked elevation of 17-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 17-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 C17-20 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.

Twelve patients with histologically verified polycystic ovary syndrome were investigated with special regard given to the effect of wedge resection on androgen status. Adrenal disorders were excluded in every case by determination of cortisol and corticosterone metabolites. Prior to and at least 6 months after surgery all patients were subjected to adrenal stimulation followed by adrenal suppression and ovarian stimulation. Comparison between pre- and postoperative studies revealed that only an insignificant reduction in the excretion of 17-ketosteroid had occurred and, although at lower levels, the stimulatory effect of hCG on ovarian androgens was still present. Clinically, 10 patients had had regular periods at followup, and 3 had become pregnant. In no case had hair growth slowed, bu the rate had declined. Seemingly, wedge resection does not significantly influence the biochemical pattern connected with the polycystic ovary syndrome.