Excretion Of Pregnanetriol Research Articles

Biomarkers for assessment of the polychemotherapy results in patients with adrenocortical cancer based on gas chromatography-mass spectrometry studies of urine steroid profiles

Background: The effectiveness of polychemotherapy (PCT) for adrenocortical cancer (ACC) is assessed by imaging tests with the RECIST 1.1 criteria. However, the presence of subclinical tumor foci does not allow for an objective measurement of the true tumor burden. As shown previously, postoperative assessment of the steroid metabolome by gas chromatography-mass spectrometry (GCMS) in ACC patients makes it possible to identify early signs of adrenal steroidogenesis abnormalities and of the recurrence of adrenocortical carcinoma.
 Aim: To identify biomarkers of response to PCT by GCMS study of the urine steroid profile in ACC patients after surgical resection of the tumor.
 Materials and methods: Urine steroid profiles were studied by GCMS (Shimadzu GCMS-TQ8050 gas chromatography-mass spectrometer) in 30 ACC patients (stages II, III and IV) after surgery and first line (combination of etoposide, doxorubicin and cisplatin with daily mitotane) and second line (gemcitabine combined with capecitabine and mitotane) PCT. The control group included 25 patients with hormonally inactive adenomas.
 Results: The response to PCT according to RECIST 1.1 criteria was obtained in 23 patients (Group 1, responders) and in 7 patients ACC progressed under PCT (Group 2, non-responders). In the responders, the urinary excretion of etiocholanolone, pregnanediol and pregnanetriol was lower than in the control group. The non-responders had higher urinary excretion of androgens, progestogens and tetrahydro-11-deoxycortisol (THS), compared to the responders and the control group. The patients with ACC progression under PCT had an increase in 3β,16,20-pregnenetriol (3β,16,20-dP3) levels and a decrease of the 3α,16,20-dP3/3β,16,20-dP3 ratio, compared to those in the PCT responders. The threshold values for urinary excretion of dehydroepiandrosterone (DHEA, ≤ 469 mcg/24h; AUC = 1.0), THS (≤ 223 mcg/24h; AUC = 1.0), and 3β,16,20-dP3 (≤ 130 mcg/24h; AUC = 0.986), as well as the 3α,16,20-dP3/3β,16,20-dP3 ratio (≥ 2.13; AUC = 1.0) had 100% sensitivity and specificity for the assessment of the PCT effectiveness.
 Conclusion: Different urine steroid profiles were obtained by GCMS in the ACC patients after PCT with and without treatment response. The 100% sensitivity and specificity of the threshold values for urinary excretion of DHEA, THS, 3β,16,20-dP3 and the 3α,16,20-dP3/3β,16,20-dP3 ratio for the assessment of PCT results indicate the potential to use these parameters as biomarkers of response or progression of the disease in the monitoring of PCT effects in ACC patients.

Testicular Adrenal Rest Tumors Develop Independently of Long-Term Disease Control: A Longitudinal Analysis of 50 Adult Men With Congenital Adrenal Hyperplasia due to Classic 21-Hydroxylase Deficiency

Testicular adrenal rest tumors (TARTs) and hypogonadotropic hypogonadism are the two most common causes for male infertility in classic 21-hydroxylase deficiency. Current hypotheses suggest the quality of disease control to be one of the main pathogenic factors for TART development. The aim was to study long-term predictors for TART development in a retrospective longitudinal study. Fifty men with classic 21-hydroxylase deficiency (31 salt wasting, 19 simple virilizing) were investigated. Testicular ultrasound at a median age at investigation of 27 years detected TARTs in 28 of 50 subjects (19 salt wasting, 9 simple virilizing). TART presence was correlated with long-term parameters of disease control during childhood and adolescence obtained from patients' charts: 24-hour urine pregnanetriol, serum 17-hydroxyprogesterone, onset and stage of pubic hair development, testicular growth, and bone age in relation to chronological age. There was no difference in pregnanetriol excretion over lifetime between patients with and without TARTs. Similarly, neither development of pubic hair and testicular volume (Tanner) nor bone age in relation to chronological age differed between the two groups. Furthermore, the two groups had the same body mass index and the same impairment of final height in relation to midparental target height. Our longitudinal analysis demonstrates no association between TART presence and parameters of disease control. These data, therefore, argue for other mechanisms more relevant for TART induction including those occurring during fetal development.

Effects of aerobic exercise on urinary estrogens and progestagens in pre and postmenopausal women

The purpose of this study was to elucidate the effect of 6 months of aerobic exercise on urinary excretion of female steroid hormones in pre and postmenopausal women and to check the basal values of urinary steroid. To this end, 20 premenopausal (age 45.56 ± 4.06 years) and 20 postmenopausal (age 52.27 ± 3.80 years) women, all sedentary, were studied before and after a supervised 6-month exercise training program (at 60-70% of maximal heart rate, 60 min/day, 3 days/week), based on aerobic dance. The exercise included standing on one leg, squatting, walking, and touching their heels. Before and after the program, anthropometric data and VO(2max) were measured and urine samples were collected and analyzed by gas chromatography/mass spectrometry (GC/Q-MS). Both, pre and postmenopausal women, improved their VO(2max) after the aerobic exercise program. Regarding the urinary steroids, on the one hand, important differences were observed between urinary estrogens and progestagens in pre and postmenopausal women in basal values. Estrone (P < 0.05), pregnanediol (P < 0.01), pregnanetriol (P < 0.05), and estriol (P < 0.01) levels were lower in postmenopausal women than in premenopausal women. On the other hand, the aerobic exercise program did not affect postmenopausal women in the same way as premenopausal women. After the exercise program, no changes in urinary steroid levels were observed in premenopausal women. However, the aerobic exercise program caused an increase in urinary excretion of pregnanediol (P < 0.05) and pregnanetriol (P < 0.05) in postmenopausal women.

Androglottia in a young female adolescent with congenital adrenal hyperplasia and 21-hydroxylase deficiency.

Vocal disturbances in women with congenital adrenal hyperplasia and androgen excess should be extremely rare today since effective substitution with glucocorticoids is available. We present a 17 year-old female with congenital adrenal hyperplasia due to 21-hydroxylase deficiency and severe virilization because of long-term insufficient therapy. Laboratory data showed elevated serum levels of testosterone, 17-hydroxyprogesterone, plasma ACTH and a high excretion of urinary pregnanetriol. The phoniatric aspect showed a masculine voice. We discuss the different effects of androgens on the pubertal larynx and various hormonal disturbances that may cause voice changes as well as therapeutic options of voice therapy. From the pediatric point of view it might be important to perform a phoniatric examination in girls with congenital adrenal hyperplasia during puberty in order to monitor androgen effects.

A possible defect in the inter-conversion between cortisone and cortisol in prepubertal patients with congenital adrenal hyperplasia receiving cortisone acetate therapy

Oral administration of cortisone acetate is widely used to treat prepubertal patients with congenital adrenal hyperplasia (CAH). However, efficient ‘first pass’ hepatic conversion of the biologically inactive cortisone (E) to cortisol (F) by the 11-reductase component of the 11β-hydroxysteroid dehydrogenase (11β-HSD) system is required for suppression of the hypothalamic—pituitary—adrenal (HPA) axis. 11-β-HSD activity can be assessed by measurement of urinary tetrahydroderivatives of E (tetrahydrocortisone, THE) and F (tetrahydrocortisol, THF), formed in separate hepatic compartments by reduction of the A ring. Inadequate HPA axis suppression is frequently encountered in peripubertal CAH patients receiving cortisone acetate therapy. In this paper, we describe THE and THF concentrations in 24 h urine samples collected every 3–6 months from 14 prepubertal patients with simple virilizing CAH. The patients had been receiving cortisone acetate and 9α-fluorohydrocortisone since diagnosis and were investigated for 2–4 years during which there was marked intra- and inter-individual variation in the level of suppression. Good and poor control of HPA axis suppression were defined on the basis of a profile of early morning serum 17-hydroxyprogesterone, androstenedione, plasma renin activity and 24 h urinary excretion of pregnanetriol, pregnanetriolone and 5β,17α-hydroxypregnanolone. Serum steroids were measured by RIA and urinary metabolites quantitated as methyloxime—trimethylsilylimidazole derivatives by gas chromatography and GC-mass spectrometry. There were no significant differences in the THE/THF ratio between male ( n = 9) and female ( n = 5) patients during either good or poor therapeutic control. The data were therefore analyzed without consideration of patient sex. Urinary THE/THF (mean ± SD) was significantly higher in patients during periods of poor control (6.56 ± 2.51, P < 0.001) compared with periods of good control (3.73 ± 0.96) in the same patients. THE/THF levels were also significantly ( P < 0.001) higher in CAH patients, irrespective of the level of control, than those for the normal subjects (1.79 ± 0.20). Furthermore, THE excretion was significantly higher during periods of poor control compared with good control at all doses of cortisone acetate administered (10–50 mg/day). There were no significant differences in THF excretion. THE levels also rose significantly ( P < 0.001) in response to increasing total dose during periods of poor control. The increase in THF excretion was slight and significant only at doses >40 mg/day compared with doses <15 mg/day. A significant linear correlation could be drawn between THE excretion and total daily dose during periods of both poor ( r = 0.67, P < 0.05) and good ( r = 0.68, P < 0.005) control. Excretion of 5α-THF, cortols and the cortolones, unlike that for normal subjects, was very low in cortisone acetate treated CAH patients. In contrast, the ratios of 5α 5β C19 steroid metabolites were no different from normal. The results from this study suggest that poor therapeutic control is unlikely to be due to: (i) failure of compliance with therapy; (ii) inefficient absorption from the intestine; or (iii) inefficient acetate group removal. The data are consistent with a hypothesis of rapid tetrahydroderivitization of E, present in excess of the capacity of 11β-HSD to form F; i.e. a preferential reduction of the A ring rather than the 11-keto group as a consequence of hepatic ‘first pass’ uptake of the exogenously administered E. The ability of prednisolone and dexamethasone, both of which are bioactive and not subject to significant A ring reduction, to suppress the HPA axis of patients poorly suppressed by cortisone acetate, lends support to this hypothesis.

Ketoconazole and plasma and urine steroid levels in Cushing's disease.

1. Plasma and urine steroid and plasma ACTH levels were measured for 2 weeks in eight subjects (six female, two male) with Cushing's disease with each given 200 mg ketoconazole orally four times daily. 2. Treatment was associated with major falls in excretion of free cortisol and the cortisol metabolites tetrahydrocortisol, 5 alpha-tetrahydrocortisol and tetrahydrocortisone. 3. Plasma cortisol and ACTH levels did not change significantly. 4. Excretion of the androgen metabolites, androsterone, 11 beta-hydroxyandrosterone and aetiocholanolone was also reduced but there was no significant fall in plasma testosterone. Plasma levels of progesterone, 17 alpha-hydroxyprogesterone and 11 beta-deoxycortisol and excretion of pregnanediol, pregnanetriol and tetrahydrodeoxycortisol rose with treatment. 5. Analysis of steroid precursor/product ratios indicated that ketoconazole significantly inhibited 11 beta-hydroxylase and 17,20-lyase but not 17 alpha-hydroxylase in these patients with Cushing's disease.

Normal ACTH levels in saltlosing congenital adrenal hyperplasia (CAH) with elevated plasma renin concentration (PRC). The effect of mineralocorticoid treatment

Eleven patients with salt losing CAH (21 OH deficiency), aged 5-19 years were treated with cortisone 20-55 mg/m2/24 h in 3 divided doses and supplementary salt. Normal (< 60 m.i.u./1) and moderately raised (133, 140 m.i.u./1) PRC values in 4 patients were compatible with good control - normal excretion of pregnanetriol (Ptriol). High PRC values (153-522 m.i.u./1) were found in connection with high values of Ptriol (6.5-34.8 μmol/24 h). Plasma Aldosterone (PA) was 3-11 (control values <18) ng/100 ml. Normal ACTH values (11-82 pg/ml) were found in all patients - in one pt. with high PRC (522 m.i.u./1) ACTH was 99 pg/ml. During maintenance of cortisone therapy, mineralocorticoid (Florinef(R) was added to the treatment. The dose was gradually increased over a period (median 15 months) up to 1-4 μg/kg/24 h (2 doses) and normal PRC values were established. PA decreased significantly to values below 4 ng/100 ml. Ptriol excretion decreased markedly (to 0.4 -69 μmol/24 h). ACTH values were still in the normal range. During the observation period no change in growth velocity could be demonstrated.

Low adrenal androgenic-anabolic steroids in women with rheumatoid arthritis (RA): Gas-liquid chromatographic studies of RA patients and matched normal control women indicating decreased 11-deoxy-17-ketosteroid excretion

Using GLC, multiple adrenal corticosteroid urinary metabolites, including androgenic-anabolic, glucocorticoid, pregnanediol, and pregnanetriol, were measured in eight ambulatory female RA patients and eight matched normal control subjects on baseline, ACTH-, and metyrapone-stimulation days under carefully monitored clinical research center protocol. Neither group had been treated previously with any steroid hormones. The 11-deoxy-17-KS metabolites, derived from adrenal androgenic-anabolic steroids, and comprising androsterone, etiocholanolone, and DHA, were significantly lower in RA patients on baseline (P less than .001), ACTH (P less than .005)-, and metyrapone (P less than .02)-stimulation days. To the contrary, the 11-oxy-17-KS metabolites, derived mainly from glucocorticoids, showed some lowered excretion at baseline (P less than .05), but none on ACTH- or metyrapone-stimulation. RA patients had lower tetrahydrocortisone (P less than .001) and tetrahydro-11-deoxycortisol (P less than .01) excretion at baseline, but not during ACTH- or metyrapone-stimulation, than control subjects. Pregnanetriol excretion was lower (P less than .005) in RA patients than control subjects only during ACTH-stimulation. No difference was found between groups in tetrahydrocortisol or pregnanediol excretion on any day studied. Under conditions of oral metyrapone administration (750 mg every four hours for seven doses) each control subject increased their DHA excretion, but no RA patient showed an increase over baseline excretion (P less than .02). Except for 11-deoxy-17-KS, no difference was found in the other metabolites studied during metyrapone stimulation, ie, pregnanediol, pregnanetriol, tetrahydro-11-deoxycortisol, and tetrahydrocortisol. The 24-hour oral metyrapone test provided a greater stimulus to total 11-deoxy-17-KS excretion than an eight-hour intravenous ACTH test in control and particularly RA (P less than .01) subjects even though the DHA excretion decreased in the RA groups. Our findings of lower adrenal androgenic-anabolic metabolite excretion in female RA patients than normal matched control subjects under various conditions and other supportive androgenic hormone and metabolite studies reviewed in the English reports suggest an abnormality of adrenal androgen synthesis or metabolism in RA, whether it be a primary predisposing or secondary factor in disease. The recognized female sex preponderance and age-specific patterns of occurrence of RA are consistent with adrenal androgenic function in adrenarche, adrenopause, and later changes in aging. Metabolite excretion patterns at baseline, ACTH-, and metyrapone- stimulation indicate the greatest relative

Urinary and serum steroid concentrations in the management of congenital adrenal hyperplasia. Lack of physiologic correlations.

Serum concentrations of 17-hydroxyprogesterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, progesterone, testosterone, and androstenedione and 24-hour excretion of 17-ketosteroids and pregnanetriol were measured serially in 18 children with congenital adrenal hyperplasia (21-hydroxylase deficiency) during a two-year period. Correlations were sought between results of measurements of these steroids and clinical progress assessed by physical examination and skeletal maturity to determine if measurement of concentration of these substances at a single point in time could be used to gauge the dose of corticosteroids for optimum treatment. We found that these measurements of steroids were generally not useful indicators of optimum control of the disease. Repeated careful clinical examination and assessment of changes in growth velocity and skeletal maturation seem to be the best criteria on which to base dosage of corticosteroids used for therapy.

Treatment of menstrual irregularities with dexamethasone in congenital adrenal hyperplasia

Abnormal menstrual patterns occur frequently in adolescent girls with congenital adrenal hyperplasia (CAH). In this report, two sisters with CAH secondary to the 21-hydroxylase defect are described in whom the administration of dexamethasone, a long-acting glucocorticoid, initiated or regulated their menstrual cycles. Plasma levels of 17-hydroxyprogesterone and androstenedione were elevated while on therapy with 80 mg/day of hydrocortisone, and became normal after treatment with daily dexamethasone, 1.5 mg. Urinary excretion of 17-ketosteroids and pregnanetriol showed a similar pattern. Plasma steroid levels remained suppressed after lowering ther dexamethasone dose to 0.75 mg daily, an amount equivalent to less than the original hydrocortisone dose. These data suggest that dexamethasone has a potential role in the management of patients with CAH who have menstrual irregularities, particularly if conventional therapy does not suppress adrenal steroid production.

Virilizing Testicular Tumor: In Vivo Studies of Steroid Secretion

Findings in a six‐year‐old boy with a virilizing tumor of the left testis are presented. His bone age was 14 years. Serum testosterone (5.9 nglml), urinary 17‐ketosteroid (29 mg/24 hr), and pregnanetriol (14 mg/24 hr) excretion was elevated. These values were not suppressed after the administration of dexamethasone. Spermatic‐peripheral vein concentration differences showed that the tumor secreted 17‐hydroxy‐pregnenolone, dehydroeplandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA‐S), progesterone, 17‐hydroxyprogesterone, androstenedione, testosterone, estrone, estradiol, 11‐desoxycortisol, and corticosterone. The tumor did not secrete cortisol. Electron microscopy study of the tumor revealed a dimorphic population of light and dark cells with many features seen in Leydig cell tumors. However, these were not distinct from those of adrenal rest tumors. Reinke crystalloids were not found. True precocious puberty developed five months after tumor removal, ie, the right testis increased in size, and serum gonadotropins increased. Seven months after tumor removal, the patient was demonstrated not to have impaired cortisol synthesis, ie, urinary 17‐hydroxysteroids increased from 1.8 to 38.0 mg/24 hr In response to adrenocorticotropic hormone (ACTH) administration. The differential diagnosis of virilizing testicular tumors lies between Leydig cell adenoma and adrenal rest tumor in California congenital adrenal hyperplasla. The demonstration that the patient did not have Impaired cortisol synthesis is consistent with his tumor being a Leydig cell adenoma.

Reinstitution of mineralocorticoid therapy in congenital adrenal hyperplasia. Effects on control and growth.

The results of reintroduction of mineralocorticoid substitution therapy (9-alpha-fluorohydrocortisone) in five children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are described. All children had shown a salt-losing syndrome in infancy, but were off mineralocorticoids during several years; at the start of this study they all had elevated plasma renin activity (PRA). Four of them had increased and fluctuating pregnanetriol excretion during the year preceding reintroduction of mineralocorticoids, indicating poor control despite substantial substitution with hydrocortisone: 26 +/- 1.9 mg/m2/day (mean +/- S.E.M.). Reintroduction of mineralocorticoid therapy at ages 5.0-9.4 years resulted in a marked improvement of control, significant reduction in hydrocortisone requirements (to 17.6 +/- 1.4 mg/m2/day) and improvement in linear growth. The data suggest that, in all children with CAH and elevated PRA, continuation throughout childhood of mineralocorticoid therapy in addition to glucocorticoid therapy is necessary for optimal control and linear growth.

Circadian patterns of plasma cortisol, 17-hydroxyprogesterone, and testosterone in congenital adrenal hyperplasia.

In 11 children aged between 2 and 17 years with (nonsalt-losing) congenital adrenal hyperplasia (21-hydroxylase deficiency) blood was drawn at 90-minute intervals during a 24-hour period and levels of 17-hydroxyprogesterone, testosterone, and cortisol were measured. Levels of 17-ketosteroids and pregnanetriol were measured too in 24-hour urine samples. These measurements were taken under different regimens of treatment and after interruption of treatment. Cortisol level rose and fell rapidly after administered corticosteroid, and reached unphysiologically high levels. Testosterone levels showed pronounced variations but stayed in the normal range for most of the time even in untreated patients; thus testosterone provides a poor control parameter. Levels of 17-hydroxyprogesterone showed extreme fluctuations and very high peak levels in untreated patients; standard treatment with two or three daily doses of corticosteroids did not prevent a pronounced rise in its level after midnight. After the first morning dose of hydrocortisone a very steep fall was observed. The 24-hour pregnanetriol excretion correlated well with the corresponding total integrated 17-hydroxyprogesterone area. It is concluded that single 17-hydroxyprogesterone values are unlikely to give adequate information about the quality of treatment.

Plasma progesterone, 17-hydroxyprogesterone, androstenedione and testosterone in prepubertal, pubertal and adult subjects with congenital virilizing adrenal hyperplasia as indicators of adrenal suppression.

To determine whether a single morning plasma level of 17-hydroxyprogesterone (17OH-P), androstenedione, testosterone and progesterone reflected the degree of control of 21-hydroxylase congenital virilizing adrenal hyperplasia (CVAH) as indicated by 24-hour urinary 17-ketosteroid and pregnanetriol excretion, 142 simultaneous 24-hour urine and morning blood collections were made from 65 patients with CVAH. Patients were grouped into five categories on the basis of age, skeletal age, and sex. Paired blood and urinary data were analyzed. The results suggest that androstenedione is the most reliable indicator for all patient categories. Testosterone is an excellent indicator for children of both sexes and for adolescent and adult females. Levels of 17OH-P are difficult to interpret, as they can be several fold higher than the normal values when adrenal suppression appears adequate on the basis of urinary data. In general, progesterone is a poor indicator.

Dissociation of plasma renin activity and plasma aldosterone level during dexamethasone suppression test in non-salt-losers with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

We have studied plasma renin activity, the plasma aldosterone level and urinary metabolites of glucocorticoid precursors before and during a dexamethasone suppression test in three non-salt-losers with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, who had never been treated with glucocorticoid. Plasma renin activity, the plasma aldosterone level and urinary pregnanetriol excretion were found to be abnormally elevated before dexamethasone administration. After 7 days' dexamethasone administration, plasma renin activity still remained high above the normal level, while the plasma aldosterone level as well as urinary 17KS and pregnanetriol excretion were lowered to the normal ranges. Several possible mechanisms for this discordant suppression of plasma renin activity and aldosterone level were discussed and the presence of mineralocorticoid resistance, which is not related to ACTH dependent aldosterone antagonists, was suggested in the case of these patients.

Combined virilizing 17-21 hydroxylase deficiency in siblings

Female pseudohermaphroditism with skeletal abnormalities (cranial and antebrachial) was observed in 3 siblings. Marked hirsutism was observed during pregnancies in the mother. Ambiguous genitalia were present at birth but further virilization did not occur. Saltwasting, hypokalemia or hypertension was not present during long-term observation. Adrenal function studies were performed in 2 of the patients. Basal values of urinary cortisol-metabolites and 17-ketosteroids were normal but the excretion of corticosterone-metabolites and pregnanetriol was increased (ratio cortisol-/corticosterone-metabolites 1:1). After ACTH stimulation additional excretion of pregnanetriol and corticosterone-metabolites was found. Also urinary cortisol-metabolites were increased as were 17-ketosteroids, allthough only moderate. Basal ACTH and 17-OH progesterone values were only slightly increased. These observations suggest the presence of a combined partial 17-21 hydroxylase deficiency with skeletal defects. This clinical entity has not previously been described.

Increased urinary excretion of 16α-hydroxy-pregnenolone in newborn infants with 21-hydroxylase deficiency.

Urinary excretion of total 16α-hydroxypregnenolone (16α-OH-P'O), pregnanetriol (PT) and 11-oxopregnanetriol (11-0-PT) were determined by capillary gas chromatography in 18 healthy neonates and 3 newborn infants with congenital adrenal hyperplasia (CAH) during the first three weeks after birth. In the 4th week of life all CAH-infants demonstrated salt loosing crisis. Conclusion: The determination of urinary excretion of 16α-OH-P'O is a valuable tool in the reliable detection of 21-hydroxylase deficiency during the first weeks of life when conventional tests may fail. Supported by DFG SFB 87 Project C-3

Management of Congenital Adrenal Hyperplasia Using Serum Dehydroepiandrosterone Sulfate and 17-Hydroxyprogesterone Concentrations

Simultaneous serum concentrations of dehydroepiandrosterone sulfate (DHEA-S) and 17-hydroxyprogesterone (17-OHP) were compared with urinary 17-ketosteroid (17-KS) and pregnanetriol (PT) excretion during therapy in 18 prepubertal patients with the 21-hydroxylase deficiency form of congenital adrenal hyperplasia (CAH). Patients were classified into those in good, poor, or questionable control on the basis of clinical examination, skeletal age, and 17-KS and PT excretion. During therapy, use of serum steroid concentrations was found to be nearly as accurate in judging adequacy of control as use of urine steroid concentrations. Of 34 evaluations, a definite assessment of adequacy of control could be arrived at 25 times using urinary values and 22 times using both serum DHEA-S and 17-OHP concentrations. DHEA-S concentration responded sluggishly when treatment was not adequate, being greater than 100 microgram/dl only in patients significantly undertreated. It was never elevated in well-controlled patients. Mid-afternoon 17-OHP concentrations were less than 200 ng/dl in well-controlled patients but readily escaped suppression and could not be used to differentiate poor from borderline control or from temporary noncompliance. Therefore, an increases DHEA-S concentration indicated poor control and a suppressed 17-OHP concentration indicated good control. The combination of normal DHEA-S level with elevated 17-OHP level, however, did not permit exact evaluation of the degree of control. Of significance is that not all patients with CAH present with an elevated DHEA-S concentration, and only in those in whom an elevated level has been documented can DHEA-S level be used as an index of control during therapy.

341 EARLY CLINICAL FEATURES OF CONGENITAL ADRENAL HYPERPLASIA (CAH)

The newborn male with salt-losing CAH is at risk for mortality before recognition of the disease. To better define the clinical features of CAH in the newborn period, we have reviewed the records of 45 children with CAH diagnosed before age 4 weeks. In 14 of 27 (52%) families with older children there was a history of early death of a male infant. Affected infants had significantly greater birth length and birth weight than a group of 66 control term infants, and their upper-to-lower segment ratio (U/L) was significantly lower than that found in controls.In 17 of 19 salt-losing infants the initial sign of a metabolic abnormality was a decline in CO2 content. Urinary 17-Keto-steroid excretion rose progressively from admission to initiation of therapy, but urinary Pregnanetriol excretion was uniformly low in the first week of life and did not permit distinction between different forms of CAH. The large for dates male infant with a low upper-to-lower segment ratio merits early diagnostic evaluation for CAH despite a negative family history of unexplained neonatal deaths.

PLASMA PREGNENOLONE AND 17-OH-PREGNENOLONE IN HIRSUTE AMENORRHOEIC PATIENTS

ABSTRACT This study was designed (a) to examine the involvement of the Δ5-pregnenes, pregnenolone and 17-OH-pregnenolone in the abnormal steroidogenesis present in hirsute patients; and (b) to examine the possibility that suppressed adrenal 21-hydroxylase activity may frequently underlie the abnormal steroidogenesis in hirsute women. Basal plasma pregnenolone and 17-OH-pregnenolone levels were significantly elevated in hirsute women. The levels of these steroids following treatment with dexamethasone and the decrement induced by this treatment were also significantly greater in hirsute patients than in normal subjects. These precursor steroids were also excessively responsive to stimulation with HCG in the hirsute patients. Urinary 17-hydroxycorticosteroid excretion was significantly higher in hirsute patients than in normal subjects. In contrast, the urinary excretion of pregnanetriol, either under basal conditions or following stimulation with ACTH was not significantly higher than in normal women similarly treated. In a further attempt to identify any limitation in 21-hydroxylase activity, the steroidogenic response to ACTH plus metyrapone was measured in hirsute and in normal women. Neither the urinary pregnanetriol response nor the ratio of pregnanetriol to 17-hydroxycorticosteroids was elevated in hirsute women. These observations document that plasma pregnenolone, and 17-hydroxypregnenolone are elevated in hirsute patients. The excess appears to be derived both from the adrenals and the ovaries. However, we were unable to demonstrate any limitation in adrenal 21-hydroxylase activity in hirsute patients.