Excretion Of Pregnanetriol Research Articles

Serum 170H-progesterone, serum cortisol and plasma ACTH in the management of congenital adrenal hyperplasia

17OH-progesterone (RIA), cortisol (isotope derivative technique), and ACTH (RIA) was measured at control visits during 18 months in 24 patients with cortisone treated CAH (all 21OH-deficiency, 14 were salt losers). - Treatment was not changed in 14 patients (dosage reduced in 1). 17OH-progesterone was increased in 2, cortisol and ACTH was normal in all 14 patients. In 9 patients the dosage was raised at 20 occasions. Pregnanetriol excretion was increased in all 20 occasions and 17-KS in 16. Contemporary blood values were abnormal: 17OH-progesterone was high in 14 of 20 occasions, cortisol was low in 7, and ACTH high in 2. - Taken as new diagnostic tests compared to the excretion of 17-KS and pregnanetriol, the predictive value of a positive test (I) and the predictive value of a negative test (II) was:

Management of congenital adrenal hyperplasia. Urinary steroid estimations--review of their value.

A retrospective study was made of 16 children with 21-hydroxylase-deficient congenital adrenal hyperplasia of the salt-losing variety, who were treated with fludrocortisone and prednisone and were in good health during the period under review. The height velocity of the children was subnormal, height achievement was poor, and their bone ages retarded. Urinary 17-oxosteroid and pregnanetriol excretion were used to monitor the therapy of the children and these data have been related to growth velocities. In spite of urinary steroid figures in excess of those published as desirable for monitoring therapy, the children failed to grow properly, probably as a result of glucocorticoid overdosage. Published urinary steroid criteria are considered too strict and in order to achieve them one would need to give unnecessarily high doses of steroid. Regular measurement of height velocity and skeletal maturation rate are better indicators of therapeutic control and should lead to more satisfactory growth and ultimate height.

Short-term culture of mouse Graafian follicles: the effect of steroids on oocyte maturation and atresia

Adrenal function has been studied in patients during prolonged treatment with Enovid, administered both continually and cyclically. No significant depression was noted in the excretion of urinary 17-hydroxycorticosteroids, 17-ketosteroids, pregnanetriol, or pregnanediol. Adrenal responsiveness, as determined by the increase in urinary excretion of these steroids during two days of corticotropin administration, was comparable to that of an untreated group of patients. Plasma levels of cortisol displayed the effect of estrogen by an increase in protein binding.

Urinary pregnanetriol excretion in hirsutism

Eighteen consecutive hirsute women attending an endocrine clinic have been studied by measurement of the urinary pregnanetriol excretion before and following the concurrent administration of corticotrophin and metyrapone. An abnormal increment in pregnanetriol excretion was observed in 11 of these 18 patients. It is suggested that this is evidence that an adrenal abnormality, probably operative at the 21-hydroxylase level, might be a factor responsible for the hirsutism in these 11 patients. Five adrenalectomized women who were also studied showed no significant increase in urinary pregnanetriol excretion in response to concurrent corticotrophin and metyrapone administration.

PARTIAL 11− AND 21-HYDROXYLASE DEFICIENCIES IN HIRSUTE WOMEN

NEWMARK, STEPHEN; DLUHY, ROBERT G.; WILLIAMS, GORDON H.; POCHI, PETER; ROSE, LESLIE I. Author Information

Treatment of congenital virilizing adrenal hyperplasia patients with single and multiple daily doses of prednisone

Six patients with congenital virilizing adrenal hyperplasia were evaluated on single- and multiple-dose prednisone schedules. Each of the treatment periods was for one month. Patients were evaluated by 24-hour urinary excretion of 17-ketosteroids and pregnanetriol, as well as 0900 plasma concentrations of 17-hydroxyprogesterone, progesterone, and testosterone. By the criteria of urinary excretion of KS and PNT appropriate for chronologic age, three of the six patients were adequately controlled on prednisone given once a day. Prednisone administered twice daily at 12-hourly intervals either in equally divided doses or with a larger dose in the evening, however, resulted in adequate suppression in all patients. Because of the marked diurnal variation of plasma 17-OHP, the time of day that the sample is drawn is critical. Afternoon samples are often misleadingly low. Plasma 17-OHP concentration may reflect escape from therapeutic control sooner than urinary KS and PNT excretion. There was no correlation between 17-OHP and P values. Plasma concentration of T was not a reliable indicator of good control, since T values were often at prepubertal levels when urinary KS and PNT were elevated.

Partial 11- and 21-hydroxylase deficiencies in hirsute women

Thirty-one women with idiopathic hirsutism were evaluated for partial 11- and 21-hydroxylase adrenocortical enzyme deficiencies. Twenty-four hour urine collections for 17-ketosteroids, 17-hydroxycorticoids, tetrahydro compound S (THS), and pregnanetriol were obtained basally and following a continuous 24 hour infusion of α 1–24 ACTH (cosyntropin). The results were compared to those in eight normal, nonhirsute women studied under identical conditions. Normal control subjects and 18 of 31 hirsute female patients (Group I) showed similar small increments in the excretion of THS and pregnanetriol following the infusion of cosyntropin. Thirteen hirsute women (Group II) showed cosyntropin-stimulated increments in either THS and/or pregnanetriol that were significantly greater than the mean response of the control group. The cosyntropin-stimulated increments in 17-ketosteroid excretion and basal sebum production rates were also significantly greater in Group II. The results are consistent with partial 11- and/or 21-adrenocortical hydroxylase deficiencies in some hirsute women whose condition would have previously been designated as “idiopathic”. Thus, prolonged ACTH stimulation testing may identify patients who might benefit from glucocorticoid suppression therapy.

Bilateral Testicular Tumors in Congenital Adrenal Hyperplasia

A 22-year-old male with bilateral testicular tumors and the 21-hydroxylase variety of congenital adrenal hyperplasia (CAH) was studied. Preoperatively, on his usual glucocorticoid regimen, his urinary pregnanetriol excretion was increased (8.0-23.5 mg/day), serum LH and FSH were normal to increased (14.3-28.7 mIU/ml and 13.2-19.5 mIU/ml, respectively) and testosterone (T) was normal to decreased (176-600 ng/dl). At surgery, testicular vein concentrations of 17-alpha-hydroxyprogesterone (17-OHP) and adnrostenedione (delta) were increased (30.1 mug/dl and 38.3 mug/dl respectively) while T was decreased (1,503 ng/dl); a positive peripheral vein--testicular vein gradient was not seen for these steroids. Following injection of 10 U of crystalline ACTH into the testicular artery; testicular vein concentrations of 17-OHP, delta and T increased to 729 mug/dl, 2,390 mug/dl and 9,660 ng/dl respectively. Microscopic examination of the testes revealed multinodular tumors composed of polygonal or rounded eosinophilic cells, arranged in cords, nests and clusters. The tumors extended from the hilus and compressed the adjacent testicular tissue. Electron microscopic examination of the tumors showed features, common to steroid-secreting tissues, with abundant smooth endoplasmic reticulum in close proximity to mitochondria which was moderate in number. The adjacent testicular tissue was composed of immature tubules with normally developed Leydig cells in the interstitial tissues. From these data and a survey of previous works, it was postulated that these tumors were dependent upon ACTH for growth and steroid secretion. In view of the high serum LH concentration seen in association with incomplete suppression of adrenal steroid secretion in this study and the association of evidence of gonadotropin secretion with testicular tumors in other CAH patients, LH may also have contributed to the growth of these tumors.

The urinary excretion of pregnanetriol and pregnenetriol in patients with breast cancer. A postulation on the meaning of Bulbrook's discriminant

The ratio between 11 deoxy- 17 ketosteroids and 17-hydroxycorticosteroids (Bulbrook's discriminant) and the ratio between pregnenetriol and pregnanetriol were measured in the urines of forty-one patients with advanced cancer of the breast. It was found that the two ratios were very significantly correlated. The ratio pregnenetriol/pregnanetriol reveals the efficiency of adrenal 3β hydroxysteroid dehydrogenase, an enzyme known to be blocked by oestrogens. It is therefore presumed that the Bulbrook's discriminant, of prognostic value in breast cancer patients, is an assessment of endogenous oestrogen effect.

Pregnenolone, 17-OH-Pregnenolone, and Testosterone in Plasma of Patients with Congenital Adrenal Hyperplasia

Both pregnenolone and 17-OH-pregnenolone were found to be higher in the plasma of patients with poorly controlled congential adrenal hyperplasia than in normal subjects. The plasma levels of these precursor steroids were significantly correlated with urinary 17-ketosteroid and pregnanetriol excretion and with plasma testosterone. The mechanism where by plasma pregnenolone and 17-OH-pregnenolone levels are elevated in patients with 21-hydroxylase deficiency is unknown, but the phenomenon of product inhibition is suggested as a possible explanation. As 17-OH-pregnenolone in plasma is almost entirely of adrenal origin, its measurement promises to be useful in the management of patients with congenital adrenal hyperplasia. Acute stimulation with ACTH caused negligible changes in the plasma levels of pregnenolone and 17-OH-pregnenolone and failed to distinguish between overly, appropriately, and under-treated patients. However, following repeated stimulation with repository ACTH, the steroid levels rose. These findings indicate limited adrenal responsiveness to ACTH following chronic glucocorticoid treatment of congenital adrenal hyperplasia, even in under-treated patients, and suggest that normal precursor steroid levels in plasma and normal 17-ketosteroid and pregnanetriol excretion can only be achieved by the suppression of total steroidogenesis to less than that occurring in normal subjects.

STEROID EXCRETION PATTERNS IN URINE FROM NEONATES WITH CONGENITAL ADRENAL HYPERPLASIA

Four neonates (2 boys, 2 girls) with congenital adrenal hyperplasia (CAH) was studied. All of the Children were saltlosers. Two of the children had a sister or brother with CAH. By means of paper and thin layer chromatography the urinary steroids were studied on the 3 to 14 day of life, when signs of adrenal disorder had appeared. Highly increased excretion of 3 beta-hydroxy Δ5 steroids was shown to be present in all 4 patients. Pregnanetriol was less dominant but increased in all the patients, During treatment with cortisone the excretion of the above mentioned steroids returned to normal levels. Repeated studies after 3 months of age showed a typical excretion pattern for 21-hydroxylase deficiency with increased excretion of pregnanetriol and negligible excretion of 3 beta-hydroxy Δ5 steroids. Our findings confirm the observations that newborn infants with 21-hydroxylase deficiency initially can be misdiagnosed to have a deficiency of the 3 beta-hydroxy-steroid dehydrogenase. The findings also support the theory of the existence of 2 separate 21-hydroxylase systems, one active on pregnenolone and one on 17-alfa-hydroxy-progesterone.

COMBINED MINERALCORTICOID - CORTISONE VERSUS CORTISONE TREATMENT IN CONGENITAL ADRENAL HYTERPLASIA

Growth was studied in 13 patients with the salt losing form of congenital adrenal hyperplasia. Present height for chronological age and for bone age at mean age 7.2 years (range 1.1 – 16.4 years) is −0.12 SD ± 1.16 and −0.16 SD ± 0.62. In seven patients treated with cortisone acetate (c) and NaCl alone 9 fluorohydrocortisone (F) was instituted. C doses could then be reduced to mean 21 ± 5 from 28 ± 9 mg/m2 and day with equal or better control as measured by urinary pregnanetriol excretion. These patients also showed a better growth with a mean height gain of 0.48 SD-scores after 1.5 years of treatment. Bone age advancement during this period was 0.9 ± 0.5 years/year. The increased height velocity and good metabolid control during combined F and C treatment suggests that this regime is superior to the conventional longterm treatment with C and NaCl alone. Values are means ± standard deviation.

Serum 17-α-hydroxyprogesterone, progesterone, estradiol, and testosterone in the diagnosis and management of congenital adrenal hyperplasia

The value of determining concentrations of serum 17-α-hydroxyprogesterone, progesterone, estradiol, and testosterone in the diagnosis and management of congenital adrenal hyperplasia was studied. The values recorded were compared with established criteria of control: growth rate, advancement of bone age, degree of virilization, and 24-hour urine excretion of 17-ketosteroids and pregnanetriol. Serum 17-OHP concentrations were diagnostic in five new patients with CAH; they ranged from 100–312 ng/ml (50 to 450-fold above normal); serum progesterone concentrations ranged from 7–24 ng/ml (2 to 50-fold above normal). In the long-term management no one serum steroid concentration alone could be relied upon to determine adequacy of control. It appears that several variables, including diurnal variation, timing of the sample in relation to the last dose of a glucocorticoid, and chronic suppression of the hypothalamic-pituitary-adrenal axis, in addition to the degree of control, may affect a single serum steroid determination. When an acceptable range of normal in CAH for concentration of serum 17-OPH was broadened to 4 ng/ml and for progesterone to 1 ng/ml, there was a fairly good correlation of serum steroid concentrations with degree of control.

Evidence for an underlying adrenocortical abnormality in hirsute women.

Urinary testosterone levels were measured in twenty‐eight hirsute women and ten control subjects before and after the administration of corticotrophin. Twenty‐four patients had elevated basal urinary testosterone levels, and of these, nineteen showed an abnormal response to corticotrophin stimulation. Ten hirsute women from the latter group of nineteen, and eight control subjects, were further studied by measurement of the urinary pregnanetriol excretion before and following the concurrent administration of corticotrophin and metyrapone. An abnormal increment in pregnanetriol excretion was observed in eight out of the ten hirsute patients. It is suggested that this is evidence that an adrenal abnormality may be responsible for certain cases of idiopathic hirsutism, which may be operative at the 21‐hydroxylase level.

Linear growth rate, bone maturation and growth hormone secretion in prepubertal children with congenital adrenal hyperplasia.

SummaryThis study was designed to evaluate the effect of various oral hydrocortisone dosages on linear growth and bone maturation in a group of 21 children with congenital adrenal hyper‐plasia between the age of 3 and 10 years. Treatment was monitored on urinary pregnanetriol excretion. When considering the individual annual height increment, a normal growth rate was achieved with dosages between 15 and 36 mg/per 24 hours, and a reduced growth rate with dosages between 27 and 55 mg/ per 24 hours. The same range of dosages was found when bone maturation increments were considered separately. In order to study the dose‐response relationship, the slopes of individual linear growth curves (considered for minimal periods of two years) were correlated with hydrocortisone dosages. A significant negative correlation was found which assesses the growth reducing activity of hydrocortisone for dosages up to 45 mg/per 24 hours. Linear growth of children overtreated during early infancy did not show a normal catch up rate in some cases, suggesting a permanent damage of growth. In all cases growth hormone secretion was in the normal range. In late treated children, dosages between 30 and 45 mg/ per 24 hours reduced predominantly the skeletal maturation and allowed some linear growth.

Rapid quantitative gas-chromatographic fractionation of the major urinary i7-oxosteroids and i7-oxogenic steroids

A rapid gas-chromatographic method for the fractionation of the major 17-oxosteroids and 17-oxogenic steroids in urine is presented. The method utilises borohydride reduction, periodate oxidation and gas-liquid chromatographic (GLC) separation of steroid formate esters on SE 30. A single estimation may take less than 4 h, providing estimates of the urinary excretion of pregnanetriol and THS (together); allopregnanetriol and allo-THS (together); aetiocholanolone; androsterone; THE, THF, cortols and cortolones (as a group); allo-THE, allo-THF, allo-cortols and -cortolones (as agroup); pregnanediol; 11-oxygenated aetiocholanolone; 11-oxygenated androsterone. The method has been evaluated by comparing 17-oxosteroid (17-OS) and 17-oxogenic steroid (17-OGS) values calculated from the individual GLC values with those obtained by group estimations on the same urine. The correlation coefficients between the GLC values and the group values did not differ significantly from 1.000 (17-OS, 0.979; 17-OGS, 0.976). Recovery experiments using reference steroids and available steroid glucuronides indicated quantitative recoveries. Steroid sulphates were not measured. Reproducibility was of the order of 10% (coefficient of variation). The specificity of the method was examined by trapping GLC peaks which were. subjected to mass spectroscopy and chromatographed in other GLC systems. In only one case so far examined has a GLC peak proved to be other than the expected steroid formate.

Urinary excretion of pregnanetriol and 5 -pregnenetriol in two forms of congenital adrenal hyperplasia.

Although congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase deficiency generally reveals a predominance of Delta(5)-3beta-hydroxysteroids, on occasion substantial quantities of pregnanetriol have been found as well. It appears that the latter steroid more often occurs in the subjects who have survived beyond infancy. The use of the measurement of pregnanetriol alone may therefore not be relied upon as a sole determinant of the specific form of defective steroidal biogenesis. It is more characteristic of the 21-hydroxylase deficiency. However when both Delta(5)-pregnenetriol and pregnanetriol are measured the ratio of the former to the latter is always considerably below 1.0 in 21-hydroxylase deficiency and always above 1.0 in 3beta-hydroxysteroid dehydrogenase. Furthermore, 11-ketopregnanetriol has been found only in the urine of subjects with the 21-hydroxylase deficiency. Thus, these two forms of defective steroidal biogenesis may be distinguished by the measurement of these three urinary steroidal metabolites.

PARTIAL 3β-HYDROXYSTEROID DEHYDROGENASE (3β-HSD) DEFICIENCY IN A FAMILY WITH CONGENITAL ADRENAL HYPERPLASIA: EVIDENCE FOR INCREASING 3β-HSD ACTIVITY WITH AGE

In the siblings reported, two affected boys have perineal hypospadias and bifid scrotum, and two affected girls have slight clitoral enlargement with otherwise normal genitalia. All are mild "salt losers" with spontaneous crises occurring late (3 months and 2 years) in the boys. The girls had negative sodium balance and hyponatremia only when stressed by salt deprivation at age 3 weeks and 4 years respectively. All had elevated 17-ketosteroid excretion when diagnosed, and in the two youngest, urinary dehydroisoandrosterone (DHA) exceeded androsterone. Cortisol production and/or 17-hydroxycorticosteroid excretions were normal. Steroid excretion patterns showed an increase of 3β-hydroxysteroid dehydrogenase (3-βHSD) activity with increased age, but with a persisting high excretion of pregrienetriol. At 2 months of age, one girl excreted per 24 hours: pregnanetriol–0.23 mg, pregnenetriol–1.2 mg, 17α- OH-pregnenolone–-2.6 mg, 16α-OH-pregnenolone– 8.2 mg, 16α-OH-DHA–5.4 mg, and DHA–0.5 mg. Her sister, at age 10 years, during withdrawal of cortisone therapy, excreted per 24 hours: pregnanetriol– 24 mg, pregnenetriol–14 mg, DHA–1.2 mg, and no 16αOH-pregnenolone or 16α-OH-DHA. We conclude that these patients have partial 3β-HSD deficiencies on the basis of inadequate fetal virilization and persistent postnatal excretion of large amounts of pregnenetriol. Possible explanations for the preponderance of urinary C-21 over C-19 steroids and for the large excretion of pregnanetriol are presented.

副腎皮質疾患及び睾丸機能低下症における尿中Δ<sup>5</sup>-Pregnenetriol 及び Pregnanetriol の Gas Chromatography による測定

Urinary Δ5-pregnenetriol (Δ5-pregnane-3β, 17α, 20α-triol) and pregnanetriol (5β-pregnane-3α, 17α, 20α-triol) were measured by the previously reported gas chromatographic method in the following subjects: 26 normal adults (male 16, female 10), 5 cases with primary aldosteronism, 13 with Cushing's syndrome (bilateral adrenal hyperplasia 5, adrenal adenoma 4, adrenal carcinoma 4), 9 with adrenogenital syndrome (congenital adrenal hyperplasia 7, virilizing adrenal adenoma 2) and 5 cases with male hypogonadism. In normal adults, mean values for urinary excretion of Δ5-pregnenetriol and pregnanetriol were 0.15±0.09 (S. D.) mg/day and 0.29±0.17 (S. D.) mg/day, respectively. These two steroids were increased by ACTH. The response of Δ5-pregnenetriol to ACTH suggests that there exists a biosynthetic pathway of cortisol which goes through 17α-hydroxypregnenolone. Our observation that urinary Δ5-pregnenetriol and pregnanetriol increased by the administration of human chorionic gonodotropin appears to suggest that these two urinary steroids are of testicular origin.The two steroids were within normal ranges both in primary aldosteronism and in male hypogonadism. Among patients with adrenogenital syndrome, urinary Δ5-pregnenetriol and pregnanetriol were equally high in congenital adrenal hyperplasia and in virilizing adrenal adenoma. However, the urinary excretion of pregnanetriolone (5β-pregnane-3α, 17α, 20α-triol-11-one) and pregnanetetrol (5β-pregnane-3α, 11β, 17α, 20α-tetrol) is characteristically high in congenital adrenal hyperplasia, while these steroids were not detected in virilizing adrenal adenoma. With regard to cases of Cushing's syndrome, urinary Δ5-pregnenetriol and pregnanetriol were within normal limits in patients with adrenal hyper-plasia or adrenal adenoma. However, it was noteworthy that patients with adrenal adenoma excreted lesser amounts of Δ5-pregnenetriol compared to those with adrenal hyperplasia. On the other hand, patients with adrenal carcinoma excreted outstandingly large amounts of Δ5-pregnenetriol and pregnanetriol, especially the former. From these data it is concluded that the measurement of Δ5-pregnenetriol is advisable in cases of Cushing's syndrome, especially in cases with adrenal tumor and that the steroid is characteristically high in carcinoma to an extent enough to warrant differential diagnosis from adenoma.

XO-XX-XXX mosaicism with possible congenital adrenal hyperplasia.

ABSTRACT A female pseudohermaphrodite is described with XO/XX/XXX mosaicism. A raised 17-ketosteroid excretion in 1962 and a raised pregnanetriol excretion in 1965 suggest that congenitial adrenal hyperplasia is the most likely cause of the patient's masculinization. A spontaneous fall in 17-ketosteroid excretion during the period 1962–1969 also suggests that the adrenal cortex has become refractory to the increased level of ACTH resulting from an inherited block in cortisol biosynthesis.