Bone mineral in prepubertal children: gender and ethnicity.

Previous reports of gender and ethnic differences in bone mineral in prepubertal children have been inconsistent due to different methodologies, the problematic nature of bone density by dual-energy X-ray absorptiometry (DXA) calculated as the ratio of bone mineral mass to projected bone area (BA), and the generally small study populations. The aim of this study was to test the hypothesis that gender and ethnic differences in bone mineral by DXA are present in prepubertal children. The subjects were 336 healthy Asian, black, and white prepubertal children (172 females and 164 males). Total body bone mineral content (TBBMC) was adjusted for total body BA (TBBA), age, height, and weight. Adjusted mean TBBMC was greater in males than in females (p = 0.01). The gender difference was independent of ethnicity. Adjusted mean TBBMC was different for black compared with nonblack children (p = 0.001). The ethnic difference was a function of TBBA and weight. This study in a multiethnic population of prepubertal children shows (1) a gender difference in TBBMC and (2) an ethnic difference in TBBMC.

Adrenal steroidogenic function in a black and Hispanic population with precocious pubarche.

Adrenal steroidogenic function was evaluated in 34 children with precocious pubarche (PP; onset of pubic hair, less than 8 yr in girls and less than 9 yr in boys). The adrenal steroid response to an iv bolus of ACTH-(1-24) in the patients (aged 9 months to 9 7/12 yr) was compared to that in 16 normal controls (prepubertal, n = 9; Tanner stage II pubic hair, n = 7). The patient population consisted of 20 Hispanics (17 from the Dominican Republic), 13 black Americans, and 1 black Haitian. All patients had normal stimulated levels of 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (compound S), and desoxycorticosterone, thereby ruling out 21-hydroxylase deficiency and 11 beta-hydroxylase deficiency, respectively. To evaluate for the presence of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency, the patients were classified on the basis of their 60-min delta 5-17-hydroxypregnenolone/17-OHP (delta 5-17P/17-OHP) ratio [PP1 (n = 13), less than or equal to 2 SD of Tanner I controls; PP2 (n = 17), greater than 2 SD above Tanner I controls and less than or equal to 2 SD Tanner II controls; and PP3 (n = 4), greater than 2 SD above Tanner II controls; 2.1 +/- 1.0, 6.1 +/- 1.7, and 16.1 +/- 3.3 for PP1, PP2, and PP3, respectively. delta 5-17P/17-OHP for PP1 vs. PP2, PP2 vs. PP3, and PP1 vs. PP3 were significantly different (P less than 0.05) by analysis of variance and multiple comparison testing using the Student-Newman-Keuls procedure. The four patients in PP3 were considered to have a possible nonclassical 3 beta-HSD deficiency. This diagnosis was supported by the fact that these patients had the greatest increment in delta 5-17P and dehydroepiandrosterone (DHEA) levels as well as the highest stimulated delta 5-17P/cortisol (delta 5-17P/F) ratio among the patient groups. In contrast to the ACTH-stimulated androgens there were no differences in the baseline delta 5-17P/170HP or androgens among the patient groups. Additionally, the 60-min delta 5-17P/17-OHP within the patient groups was highly correlated with the 60 min-values for delta 5-17P, DHEA, DHEA/delta 4-androstendione, and delta 5-17P/F. In the children with PP the mean bone age/chronological age (BA/CA) was 1.27 +/- .27, the mean BA/height age (BA/HA) was 1.09 +/- 0.25, and the mean HA/CA was 1.18 +/- 0.17. No differences were noted between the patient population groups in mean BA/CA, mean BA/HA, or mean HA/CA.(ABSTRACT TRUNCATED AT 400 WORDS)

Parallelism of 11 beta- and 18-hydroxylation demonstrated by urinary free hormones in man.

To investigate whether the functions of 11 beta- and 18-hydroxylase are parallel in the human adrenal cortex, we measured urinary free deoxycorticosterone (DOC), free 18-hydroxy-DOC (18-OH-DOC), and free corticosterone (B) in 22 subjects (aged 3 6/12 to 19 yr) before and after metyrapone administration and ACTH infusion. The substrate to product ratio was used as an index of enzyme activity. There were parallel changes in the ratios of DOC to B (11 beta-hydroxylase) and DOC to 18-OH-DOC (18-hydroxylase) in all conditions, while the B to 18-OH-DOC ratio (product ratio) was relatively constant. The correlations between the ratios of DOC to B and DOC to 18-OH-DOC as well as between B and 18-OH-DOC were highly significant under all conditions (r = 0.89; P = 0.00001). These findings are consistent with previous in vitro studies and studies in patients with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency, suggesting that a single enzyme system is responsible for both 11 beta- and 18-hydroxylation of DOC in the adrenal zona fasciculata. As part of the metyrapone study, 18-OH-B was measured: 18-OH-B values decreased significantly, and the B to 18-OH-B ratio increased during metyrapone administration (from 0.38 +/- 0.09 to 1.79 +/- 0.04; P < 0.005), showing inhibition of 18-hydroxylation of B as well. Since 18-OH-B was suppressed without a decrease in PRA, we concluded that this inhibition is a primary metyrapone effect and not the result of increased DOC and suppressed PRA.

Serum androgens in normal prepubertal and pubertal children and in children with precocious adrenarche.

Serum androgens testosterone (T), testosterone-like-substances (TLS), delta4-androstenedione (delta4), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) were measured in 85 normal girls and 101 normal boys grouped according to pubic hair development in Tanner stages I to IV/V. The pattern of change with puberty differed for each androgen. In boys T and TLS rose with the onset of puberty but showed a more abrupt rise later in puberty. DHT also was higher in boys in late puberty but did not demonstrate a steep rise. The other androgens did not show a sex difference at any stage of puberty. While delta4 steroids did not show an increase in the years before onset of puberty, DHEA was significantly higher in prepubertal children over 7 years than in those under 7 years (mean +/- SD 166 +/- 110 vs. 31 +/- 25, P less than 0.005). The most rapid increase of DHEA concentrations was observed with the appearance of pubic hair (Stage II) in boys and girls. This contrasted with the more gradual rise of delta4 in both sexes. The oldest boys and girls (Tanner stages IV/V) had mean concentrations of all androgens in the adult range except for DHT. Twenty-two girls with precocious adrenarche (PA) aged 3-8 years had mean concentrations of T, DHT, delta4 and DHEA that were significantly higher (P less than 0.05) than in prepubertal children, but similar to those of girls in stage II and significantly lower (P less than 0.02) than in late pubertal girls (stage IV/V). Longitudinal studies in 12 of the girls indicated fluctuation of androgen concentrations, especially DHEA, but in general no increase during the years of followup. Precocious adrenarche appears to be a non-progressive disorder associated with an advanced maturation of adrenal androgen to an early pubertal stage. A rise in all androgens measured was correlated with the development of sexual hair.

Dehydroepiandrosterone sulfate (DS) levels, a rapid test for abnormal adrenal androgen secretion.

Dehydroepiandrosterone sulfate (DS) concentration was measured in the sera of premature and full-term infants and in children throughout puberty. Panhypopituitary, Addisonian, and virilized children were also studied. DS decreased slowly during the first weeks of life from a high level in neonates to the low levels observed between one to five years. After five years of age, DS concentration started to rise. A steeper increase was observed with the onset of puberty, and adult DS concentrations were reached in late puberty. There was no sex difference in DS concentration at any pubertal stage or bone age. Day-to-day variations were small in childhood and during puberty, but were considerable in premature infants. DS concentrations measured at 0900 h were not significantly different from those at 1700 h. There was a positive correlation of serum DS concentrations with the excretion of urinary 17-ketosteroids in boys and girls (r=0.789). Premature infants had DS concentration in or above the late pubertal range. Five panhypopituitary patients and five Addisonian patients had DS concentrations below normal. DS was markedly elevated in patients with congenital adrenal hyperplasia and in one girl with adrenal carcinoma, and was suppressible with dexamethasone in the former. The ease of measurement and the small amount of blood required make serum DS determination a useful guide for adrenal androgen secretion.

Evidence for an unidentified ACTH-induced steroid hormone causing hypertension.

The hypothesis that hyperaldosteronism is not the sole cause of hypertension in dexamethasone-suppressible hyperaldosteronsim was tested in an 18-year-old male. After six years of little or no treatment, the hypertension and mild hyperaldosteronism were promptly decreased by a small dose of dexamethasone. During dexamethasone treatment, when aldosterone secretion was suppressed to less than normal and he was normotensive, steroids were given by constant infusion in an attempt to reproduce the hypertension of the dexamethasone-free state. Neither five days of aldosterone or 18-hydroxydesoxycorticosterone (18-OH-DOC) at 1 mg/day, nor desoxycorticosterone (DOC) at 30 mg/day caused hypertension. However, sodium retention and potassium loss was observed during aldosterone and DOC infusion. Hypertension was produced within five days during infusion with ACTH or oral metyrapone. The hypertensive effect of the latter was abolished by addition of aminoglutethimide treatment. These studies suggest that a steroid other than aldosterone, 18-OH-DOC, or DOC may be the cause of the ACTH-induced hypertension in this patient. The aminoglutethimide data suggest that the ACTH effect on blood pressure is due to a steroid, and the metyrapone studies suggest that the steroid may be an 11-desoxysteroid. Urine and blood collected under ACTH stimulation and metyrapone treatment may be a rich source from which we may characterize this hormone.

Juvenile hyperthyroidism with elevated thyrotropin (TSH) and normal 24 hour FSH, LH, GH and prolactin secretory patterns.

An 11 year old boy was found to have hyperthyroidism and elevated serum TSH concentrations. Hyperthyroidism was first diagnosed at 4 years of age. After antithyroid drug therapy, a subtotal thyroidectomy was done when he was 7 years old. Goiter and hyperthyroidism gradually recurred, and an elevated serum TSH concentration (90 microU/ml) was found when first measured at age 12 years. There was no evidence of a pituitary tumor. Thyrotropin-releasing hormone (TRH) administration resulted in a marked increase in serum TSH concentrations. Triiodothyronine, thyroxine and dexamethasone administration lowered the serum TSH concentration. There was diurnal variation in TSH secretion. Growth hormone (GH) and prolactin responses to provocative stimuli and 24 h secretion patterns were normal. FSH and LH secretion was normal for age and stage of sexual development. The 24 h cortisol pattern demonstrated normal episodic secretion, although the mean 24 h concentration was high (10.5 microgram/dl). These data suggest that this patient's TSH hypersecretion is due to partial resistance of the thyrotrophs to the inhibitory action of thyroid hormone.

Adrenal androgen response to metyrapone, adrenocorticotropin, and corticotropin-releasing hormone stimulation in children with hypopituitarism.

We determined the adrenal steroid responses to metyrapone, ACTH, and CRH in 12 ACTH-intact and 5 ACTH-deficient hypopituitary children to determine the mechanisms that control adrenal androgen secretion. Serum adrenal androgen concentrations [dehydroepiandrosterone (DHEA) and delta 4-androstenedione (delta 4-A)] rose in response to oral administration of metyrapone (450 mg/m2 X dose, every h for 7 doses) in ACTH-intact hypopituitary children with multiple or isolated pituitary hormone deficiencies [mean postmaryrapone level: DHEA, 225 ng/dL (range, 27-566); delta 4-A, 313 ng/dL (range, 105-651)], except in 2 young children in whom DHEA did not rise. These adrenal androgens did not rise in all ACTH-deficient hypopituitary children [mean postmetyrapone level: DHEA, 11.0 ng/dL (range, 3-16); delta 4-A, 6.2 ng/dL (range, 3-10)]. The increases in both serum cortisol and adrenal androgens, including DHEA sulfate, in response to short term ACTH infusion (40 U in 6 h) in ACTH-intact hypopituitary children were normal or above normal, while these steroid responses were significantly (P less than 0.05-0.01) lower in ACTH-deficient hypopituitary children compared to normal values. However, prolonged administration of ACTH (40 U/day, or im) for 6 days to 2 ACTH-deficient hypopituitary children resulted in normal DHEA responses to the 6-h ACTH stimulation test (DHEA levels after the first test, 14 and 30 ng/dL, after priming, 80 and 50 ng/dL). Furthermore, CRH administration to 4 ACTH-deficient patients caused a rise in serum DHEA and cortisol in patients with a normal ACTH response, while those with a poor ACTH response had a lesser rise in DHEA and cortisol. These data suggest that ACTH is the major tropic hormone for adrenal androgen secretion.

Pseudohypoaldosteronism: multiple target organ unresponsiveness to mineralocorticoid hormones.

The first report of a 7-month-old male with pseudohypoaldosteronism in which unresponsiveness to mineralocorticoids has been demonstrated in the kidney, colon, and sweat and salivary glands is presented here. This is documented by urinary, salivary, and sweat sodium wasting in the presence of elevated urinary aldosterone excretion, plasma aldosterone concentration, and PRA. There was no mineralocorticoid response in the kidney or salivary or sweat glands to the administration of high doses of 9 alpha-flurocortisol. Furthermore, in this patient, the colonic mucosal cells failed to respond to exogenous aldosterone administration. Repeat evaluation at 25 months of age showed persistence of the sodium wasting and multiple target organ insensitivity to administered mineralocorticoid. Since this patient has defective mineralocorticoid response in the major sodium-conserving organs, the only therapy possible was administration of sodium to compensate for total sodium loss.

"Acquired" adrenal hyperplasia with 21-hydroxylase deficiency is not the same genetic disorders as congenital adrenal hyperplasia.

Hormonal studies and HLA genotyping were performed on the family of a patient with "acquired" adrenal hyperplasia (AAH) due to 21-hydroxylase deficiency. The results of these studies suggest that "AAH", is not the same genetic disease as CAH.

The 21-hydroxylase activity in the glomerulosa and fasciculata of the adrenal cortex in congenital adrenal hyperplasia.

In the two clinical syndromes of congenital adrenal hyperplasia due to a 21-hydroxylation defect of adrenal steroidogenesis, the simple virilizing and the salt-wasting forms, the 21-hydroxylase activity was studied considering the zona fasciculata and the zona glomerulosa of the adrenal cortex as two separate glands under different regulation. To test this hypothesis, we stimulated adrenal steroidogenesis by ACTH infusion or dietary sodium restriction in eight patients with congenital adrenal hyperplasia (four patients with the simple virilizing form and four with the salt-wasting form of congenital adrenal hyperplasia) and in six normal children. Both the 17-hydroxy and 17-deoxy pathways of adrenocortical steroid biosynthesis were examined by measuring serum concentrations of 17-hydroxyprogesterone, cortisol, progesterone, deoxycorticosterone, corticosterone, and aldosterone and the excretion of free deoxycorticosterone, 18-hydroxydeoxycorticosterone, corticosterone, 18-hydroxycorticosterone, cortisol, and aldosterone. We considered the steroids 18-hydroxycorticosterone and aldosterone to be primarily of zona glomerulosa origin. These studies indicated that the zona fasciculata of both the salt-wasting and the simple virilizing forms is defective in 21-hydroxylation of 17-hydroxy and 17-deoxy steroids. The zona glomerulosa demonstrated deficient 21-hydroxylation only in the salt-wasting form, whereas in the simple virilizing form, the glomerulosa was spared this defect.

Evidence for an unidentified steroid in a child with apparent mineralocorticoid hypertension.

A unique syndrome in a three-year-old American Indian girl was characterized by signs and symptoms of mineralocorticoid excess in the absence of excessive secretion of any known sodium-retaining steroids. Hypertension and hypokalemic alkalosis were corrected by spironolactone or a low sodium diet. Plasma renin activity was suppressed but the secretion of aldosterone was undetectable and was not stimulated by salt depletion. There was no evidence of abnormal accumulation of aldosterone precursors and metabolism of a tracer dose of the hormone was normal. Secretion rates of cortisol, corticosterone, deoxycorticosterone, deoxycortisol and aldosterone were very low and did not increase normally with ACTH administration. However ACTH administration aggravated hypertension and hypokalemia. Dexamethasone did not improve hypertension. Despite low secretion of glucocorticoids and mineralocorticoids, the patient showed no addisonian features and survived severe illness. Secretion of a factor of adrenocortical origin was suggested by the exacerbation of the syndrome of ACTH. The unidentified factor appears to be both a potent glucocorticoid and mineralocorticoid.

Steroid response to adrenocorticotropin stimulation in children with human immunodeficiency virus infection.

To evaluate whether frank or subtle disorders of adrenal steroidogenesis exist in human immunodeficiency virus (HIV)-infected children, the adrenal steroid response to an iv bolus of ACTH-(1-24) (0.25 mg Cortrosyn) was determined. Ten children (six males and four females, aged 7 months to 7.5 yr) were studied. Five underwent repeat testing 3-5 months after initial assessment. Nine patients were classified as P2 or symptomatic according to the Center for Disease Control criteria for HIV infection in children. Eight had failure to thrive, six had opportunistic infections and neurological deficits, and two were receiving ketoconazole at the time of ACTH testing. Only one patient had a neonatally acquired transfusion-related HIV infection. Three of the children died 2-5 months after ACTH testing. All patients had normal or slightly elevated baseline and stimulated cortisol levels compared to the control population. The mean post-ACTH cortisol level was significantly higher than the mean post-ACTH level in the control population. No patient demonstrated an impaired aldosterone response to ACTH. The basal and ACTH-stimulated dehydroepiandrosterone levels were normal. Although individual deoxycorticosterone and corticosterone levels were variable, the mean stimulated deoxycorticosterone and corticosterone levels in the patients were suggestive of a selective defect of the 17-desoxy pathway in the adrenal fasciculata. No changes were noted in the patients' cortisol, dehydroepiandrosterone, and aldosterone responses on repeat ACTH testing. In HIV-infected children we have demonstrated that cortisol and aldosterone synthesis is intact. Thus, the chronic debilitation observed cannot be explained on the basis of adrenal insufficiency. However, a selective deficiency of 17-desoxysteroid hormone production from the adrenal fasciculata may be present.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth, growth hormone, insulin-like growth factor-I, and prolactin secretion.

To assess further the relationship between gonadal sex steroids and PRL, GH, and insulin-like growth factor-I (IGF-I) secretion and to help clarify the mechanism underlying the pubertal growth spurt, we studied 11 children (10 girls) with central precocious puberty before and during gonadal suppression with the GnRH agonist (GnRH-a) leuprolide acetate. Nocturnal sampling for plasma levels of GH and PRL, GH response to GH-releasing factor-(1-44), and plasma IGF-I levels were determined before and 3-6 months after pituitary-gonadal suppression. Treatment caused a significant decrease in the LH and FSH responses to GnRH (P less than 0.01) and the plasma concentration of estradiol (P less than 0.05). The patients' mean height velocity SD score for chronological age, initially 3.8 +/- 1.9, decreased significantly to 0.9 +/- 0.9 with treatment (P less than 0.005). Nocturnal GH secretion (mean GH concentration, sum of GH pulse areas, sum of GH pulse amplitudes, and GH pulse frequency) and mean IGF-I levels (1.38 +/- 0.6 vs. 1.72 +/- 0.34 U/mL) were not significantly altered by treatment. However, the mean peak GH response to GH-releasing factor-(1-44) was 29.2 +/- 6.8 micrograms/L before treatment and declined significantly to 17.7 +/- 3.4 micrograms/L after gonadal suppression (P less than 0.05). PRL secretion was similar before and after GnRH-a-induced suppression. These results indicate that the decrease in height velocity noted during GnRH-a treatment occurred independently of changes in nocturnal GH secretion and IGF-I levels. These data are consistent with the premise that sex steroids can modulate growth by a direct action on skeletal growth.

Metabolic and blood pressure responses to hydrocortisone in the syndrome of apparent mineralocorticoid excess.

A syndrome of low renin hypertension in childhood with apparent mineralocorticoid excess associated with a defect in the peripheral metabolism of cortisol has been described previously in 2 patients. In these patients, decreased secretion rates of glucocorticoids, mineralocorticoids, and sex steroids have been demonstrated. In a 10(10/12)-yr-old girl with this disorder, continuous iv administration of hydrocortisone in doses of 5, 10, 15, and 20 mg/day resulted in an increase in blood pressure and a decrease in serum potassium concentration. The addition of spironolactone during the continued administration of 20 mg/day hydrocortisone did not result in a decrease in blood pressure. Withdrawal of hydrocortisone and continued administration of spironolactone alone resulted in a decrease in blood pressure, a rise in serum potassium concentration, and a fall in serum sodium concentrations. These studies suggest that an abnormality in cortisol action or metabolism causing cortisol to behave as a potent mineralocorticoid may account for this syndrome of apparent mineralocorticoid excess.

Altered sensitivity to low dose dexamethasone in a subset of patients with premature adrenarche.

During adrenarche, levels of adrenal androgens increase. Although the regulatory mechanisms of adrenarche and premature adrenarche (PA) are not fully understood, it has been suggested that, unlike the cortisol (F) response to glucocorticoid suppression, which is not age dependent, before adrenarche the major adrenal androgen, dehydroepiandrosterone sulfate, is not suppressible by glucocorticoid. As these studies were performed using long term, high dose glucocorticoids, we sought to evaluate the F and adrenal androgen or androgen precursor suppression in response to low dose glucocorticoids [a single evening dose of dexamethasone (DEX), 0.3 mg/m2]. Twenty-four children (aged 1.3-8.75 yr; 4 males and 20 females) known to have PA, as determined by their response to ACTH-(1-24) (Cortrosyn; 0.25 mg, given by iv bolus), were studied. The children with PA could be divided into two groups, as defined by their morning F level after DEX administration: group I (n = 12), F levels below 5 micrograms/dL; and group II (n = 12), F levels of 5 micrograms/dL or more. Although the mean baseline values of F, testosterone, dehydroepiandrosterone, delta 4-androstenedione, 17-hydroxyprogesterone, and delta 5-17-hydroxypregnenolone did not differ between groups I and II, the mean levels in group I vs. group II of dehydroepiandrosterone, delta 4-androstenedione, and delta 5-17-hydroxypregnenolone were significantly greater in response to ACTH and lower in response to DEX (P < 0.05). Although no clinical difference was noted between the 2 groups, the mean SD for bone age adjusted for chronological age was greater and approached significance in group I, suggesting a greater degree of biological maturity in this group. These results suggest an increased sensitivity of the hypothalamic-pituitary-adrenal axis to changes in ACTH secretion in this subgroup of patients with PA.

Virilizing adrenal tumor in a child suppressed with dexamethasone for three years. Effect of o,p'-DDD on serum and urinary androgens.

Extensive hormonal evaluation was performed in a girl with adrenal carcinoma during the primary tumor stage, following adrenalectomy, during the period when metastases were evident and while on treatment with o,p'-DDD. At the age of 14 months a diagnosis of congenital adrenal hyperplasia was made and treatment with dexamethasone (0.125 to 0.25 mg/day) resulted in a fall-off in growth rate, normal advancement in bone age, decrease in virilization and suppression of 17- ketosteroid excretion which continued until 4 3/12 years of age when virilization increased. At five years of age elevated serum and urinary androgen levels unsuppressible with dexamethasone were noted. Following removal of a large right adrenal carcinoma, serum and urinary hormone levels returned to normal. There months following surgery, liver metastases were documented associated with elevated levels of serum androgens. With o,p'-DDD treatment, serum dehydroepiandrosterone sulfate (DS) and urinary 17-ketosteroid (17-KS) excretion fell rapidly while there was a delay in the fall of free androgens. The persistence of free steroid secretion with decreased formation of DS suggests that the o,p'-DDD may have altered sulfatase activity before causing tumor necrosis and total decrease in steroidogenesis.

Late-onset adrenal steroid 3 beta-hydroxysteroid dehydrogenase deficiency. I. A cause of hirsutism in pubertal and postpubertal women.

To investigate the adrenal cause of hyperandrogenism in peri- and postpubertal hirsute women, baseline and ACTH-stimulated serum concentrations of delta 5-17-hydroxypregnenolone (delta 5-17P), dehydroepiandrosterone (DHEA) and its sulfate, 17-hydroxyprogesterone (17-OHP), cortisol, delta 4-androstenedione, and testosterone were determined in 116 women with hirsutism or acne of peri- and postpubertal onset with or without menstrual abnormalities. The results were compared with the same steroid concentrations in 30 normal age-matched women. Sixteen of the 116 women with hirsutism whose ACTH-stimulated 17-OHP levels (mean +/- SD, 5404 +/- 3234 ng/dl; normal, 334 +/- 194) were markedly elevated while their ratios of delta 5-17P to 17-OHP (0.4 +/- 0.2; normal, 3.4 +/- 1.5) were low were diagnosed as having nonclassical symptomatic 21-hydroxylase deficiency. Seventeen other hirsute women, including 3 siblings, had very high responses of delta 5-17P (2276 +/- 669 ng/dl; normal, 985 +/- 327) and DHEA (2787 +/- 386 ng/dl; normal, 1050 +/- 384) to ACTH stimulation, with significantly elevated ratios of delta 5-17P to 17-OHP (11 +/- 2.0; normal, 3.4 +/- 1.5) and DHEA to delta 4-androstenedione (7.5 +/- 2.3; normal, 4.6 +/- 1.5). In these hirsute women, the morning serum delta 5-17P and DHEA concentrations were elevated, had a diurnal variation, and were suppressed with dexamethasone administration. We propose that partial adrenal 3 beta-hydroxysteroid dehydrogenase deficiency is the cause of hirsutism in these women. This may represent an allelic variant at the genetic locus for 3 beta-hydroxysteroid dehydrogenase deficiency similar to that reported for symptomatic nonclassical 21-hydroxylase deficiency producing peripubertal excess androgen syndrome.

A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol.

A syndrome is described whose features, suggestive of primary mineralcorticoid excess, included hypertension, hypokalemia, low PRA, and responsiveness to spironolactone. Aldosterone levels were subnormal but as yet there has been no evidence of overproduction of other mineralocorticoids by chemical analysis or by bioassay of plasma and urinary extracts. The steroidal abnormalities that were observed involved peripheral matabolism rather than secretion. One patient exhibited a transient delay in reduction of the 3-keto group in the A ring, and both patients exhibited a decrease in the metabolism of cortisol to biologically inactive cortisone. This was shown by the marked decrease in the excretion of urinary metabolites bearing an 11-keto group and a decrease in the oxidation of 11 alpha-[3H]cortisol to tritiated water. The defect appeared not to be a deficiency of the 11 beta-oxidoreductase system itself, since the reverse reaction of conversion of cortisone to cortisol proceeded normally, but, rater, an alteration in the equilibrium position of 11 beta-oxidoreduction in favor of the reduced form. This was also expressed by a prolongation of the half-time of disappearance of cortisol. The decrease in the MCR permitted the maintenance of normal cortisol plasma levels and normal glucocorticoid function at a diminished rate of secretion. The decreased rate of conversion of cortisol to cortisone serves as a biochemical marker of this hypertensive syndrome.

Adrenocortical function, electrolyte metabolism, and blood pressure during prolonged adrenocorticotropin infusion in juvenile hypertension.

The effect of a continuous 5-day ACTH infusion (40 U/24 h) on adrenocorticoid function, electrolyte metabolism, and blood pressure was investigated in eight normotensive children and eight patients with hypertension of unknown origin. There was a continuous rise of plasma cortisol and deoxycorticosterone in all patients. Plasma aldosterone rose transiently in the normotensive and the hypertensive group. A transient kaliuresis and a continuous fall in serum K+ were observed in all patients. ACTH induced sodium retention and weight gain. The observed increase in systolic blood pressure correlated significantly with the cumulative sodium retention in the normotensive and the hypertensive groups. No correlation between sodium retention and diastolic pressure was found. ACTH on a low salt diet (10 meq/24 h) produced a blood pressure rise which was smaller than that on regular salt. The blood pressure rise did not correlate with any of the hormones measured. This study provides evidence for an unidentified ACTH-stimulable adrenal factor capable of raising blood pressure in normotensive children and patients with juvenile hypertension. The ACTH-induced blood pressure rise is only partly salt dependent and the mechanism of the rise remains unclear.