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PubMed1988

Inhibition by prednisone of growth hormone (GH) response to GH-releasing hormone in normal men.

Glucocorticoids increase GHRH-stimulated GH secretion when added in vitro to cultured monkey, rat, and human pituitary cells and when injected in vivo into anesthetized rats. Yet, in man glucocorticoids inhibit linear growth and GH secretion. To clarify this apparent disparity and to determine if glucocorticoid stimulation can augment GH release in man after direct pituitary stimulation with GHRH, we administered 1 microgram/kg GHRH dosage to seven normal men before and after a 4-day course of prednisone (20 mg, orally, three times daily). The second GHRH test was done 12 h after the last dose of prednisone was given. Prednisone significantly inhibited the mean maximal increase in serum GH after GHRH treatment [20.7 +/- 4.5 (+/- SE) vs. 6.3 +/- 2.4 micrograms/L; P less than 0.01] as well as the GH value obtained by summing and averaging the individual means of the 15, 30, 45, 60, 75, and 90 min serum GH concentrations (11.1 +/- 1.2 vs. 4.3 +/- 0.9 micrograms/L; P less than 0.05). The mean serum insulin-like growth factor I and plasma glucose concentrations were not significantly altered by prednisone administration. These results together with previous in vitro findings imply that glucocorticoid-induced inhibition of GH secretion in man does not occur at the level of the pituitary gland, but, rather, at the hypothalamus or above.

Adrenocortical Hyperfunction↗
PubMed1991

Routine inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing's syndrome: early recognition of the occult ectopic ACTH syndrome.

The clinical, biochemical, and radiographic features of ectopic ACTH-dependent Cushing's syndrome are often indistinguishable from those of pituitary ACTH-dependent hypercortisolism (Cushing's disease). We prospectively evaluated 29 patients with ACTH-dependent hypercortisolism by means of bilateral inferior petrosal sinus ACTH sampling with ovine CRH (oCRH) stimulation. Patients with Cushing's disease (n = 20), had a maximal basal inferior petrosal sinus to peripheral ACTH ratio (IPS:P-ACTH) of 11.7 +/- 4.4 (+/- SE) from the dominant IPS, which increased to 50.8 +/- 18.3 after oCRH administration. Bilateral IPS sampling was necessary to correctly identify patients with Cushing's disease, since the maximal basal nondominant IPS:P-ACTH was less than 2.0 in over 50% of the patients and remained less than 2.0 after oCRH administration in one third. In contrast, patients with occult ectopic ACTH-secreting neoplasms (n = 9) had maximal basal IPS:P-ACTH of 1.2 +/- 0.1 that did not change after oCRH administration. Occult ectopic ACTH-secreting neoplasms were found in 7 of 9 patients from 0.4-14 yr after the recognition of Cushing's syndrome, and 4 of these patients had intermittent hypercortisolism with prolonged periods of remission. Selective endobronchial lavage for ACTH correctly localized a radiologically occult ACTH-secreting bronchial carcinoid in 1 patient, and magnetic resonance imaging identified a similar neoplasm in a patient with a normal chest computed tomographic scan. Basal ACTH and urinary free cortisol excretion were significantly higher in patients with ectopic ACTH than in those with Cushing's disease, but overlap existed between groups. High dose dexamethasone suppression testing inaccurately classified 24% of patients, and radiological imaging of the pituitary and adrenal glands was misleading. The occult ectopic ACTH syndrome is a common form of ACTH-dependent hypercortisolism that cannot be distinguished from Cushing's disease with routine clinical studies. The accurate differential diagnosis of ACTH-dependent Cushing's syndrome requires bilateral inferior petrosal sinus ACTH sampling with oCRH stimulation.

Adrenocortical Hyperfunction↗
PubMed1992

Natural history of premature pubarche: an auxological study.

The natural history of girls with premature pubarche is reported to be normal, but the effects on puberty and on final height are not well documented. We assessed the outcome of a group of girls with premature pubarche from two Latin populations in whom 21-hydroxylase deficiency had been ruled out by an ACTH test. Patients comprised 127 girls (70 Northern-Italian and 57 Northern-Spanish), of whom 69 had entered puberty and 38 had attained adult height. Height, bone age, onset and progression of puberty, height prognosis, adult height, and baseline plasma androgen levels were evaluated. Advanced skeletal maturation and tall stature were constant features during the first years of follow-up and subsequently declined. Puberty began at 9.7 +/- 0.9 yr, and age at menarche (12.0 +/- 1.0 yr) was comparable to maternal and population menarcheal ages. The appearance and chronology of pubertal milestones in both populations were very similar. Adult heights correlated with the height prognosis at diagnosis and at onset of puberty, and were above midparental heights. Premature pubarche produces a transient acceleration in growth and bone maturation with no negative effects on the onset and progression of puberty and final height.

Adolescent↗
PubMed1992

Fertility in women with late-onset adrenal hyperplasia due to 21-hydroxylase deficiency.

Fertility was evaluated in 53 female patients with late-onset adrenal hyperplasia (LAH) due to 21-hydroxylase deficiency. The majority of patients (n = 33) were seen for isolated postpubertal hirsutism, 9 patients consulted for sterility, and 11 for irregular menstrual cycles. At the time of diagnosis, the ages of patients ranged from 15-40 yr (mean +/- SD, 24.6 +/- 5.2). No patient had major signs of virilization. The plasma 17-hydroxyprogesterone level was higher than normal in all patients (26.8 +/- 18.9 nmol/L; range, 3.4-139.4) and dramatically increased to 140.1 +/- 80.6 nmol/L (range, 35.2-324.2) after ACTH treatment. Plasma androgen levels were high (testosterone, 3.25 +/- 2.03 nmol/L; delta 4-androstenedione, 13.65 +/- 5.60 nmol/L). Plasma basal and LHRH-stimulated values were normal for FSH and high for LH. Basal and TRH-stimulated plasma PRL levels were normal. Among these 53 LAH patients, only 20 desired a pregnancy. These had a total of 38 pregnancies. Ten patients became pregnant before the diagnosis of LAH and without any treatment; they had a total of 18 pregnancies, 12 of which were successful. Moreover, 19 normal pregnancies without any spontaneous abortion were carried to term by 14 of 16 hydrocortisone-treated patients. One patient needed the association of one cure of clomiphene citrate. Hypofertility in LAH patients seems, therefore, to be relative. Its mechanism is hormonal, with anovulation or dysovulation, due to the continuous steroid feedback of adrenal origin on the hypothalamo-pituitary axis. Hydrocortisone is the appropriate treatment in most cases, reducing adrenal androgen overproduction and relieving hypothalamic-pituitary gonadotropin function, thereby making possible cyclic ovarian activity and ovulations.

17-alpha-Hydroxyprogesterone↗
PubMed1993

The limited ability of inferior petrosal sinus sampling with corticotropin-releasing hormone to distinguish Cushing's disease from pseudo-Cushing states or normal physiology.

To determine whether petrosal sinus sampling is useful to distinguish patients with mild or intermittent Cushing's disease from normal subjects and individuals with pseudo-Cushing states, we performed bilateral inferior petrosal sinus sampling for ACTH before and after the administration of CRH in 7 eucortisolemic volunteers, 8 hypercortisolemic patients with pseudo-Cushing states, and 40 patients with ACTH-dependent Cushing's disease whose urinary free cortisol excretion was within the range found in patients with, pseudo-Cushing states (< 1000 nmol/day; < 360 micrograms/day). The ACTH level, the ratio of the inferior petrosal sinus ACTH to the peripheral venous ACTH concentration (the IPS:P ratio), and the greater ratio of right to left or left to right petrosal sinuses (the R:L ratio) were compared in patients with and without Cushing's disease. Maximal petrosal ACTH values were significantly elevated in patients with Cushing's disease compared to patients with pseudo-Cushing states before CRH administration (P < 0.001), but not after CRH. Maximal petrosal plasma ACTH values after the administration of CRH as high as 808 pmol/L (3670 pg/mL) and 469 pmol/L (2130 pg/mL) were found in patients with pseudo-Cushing states and in normal volunteers, respectively, whereas maximal petrosal ACTH levels as low as 10 pmol/L (46 pg/mL) were observed in patients with surgically proven Cushing's disease. Maximal and minimal IPS:P ratios were significantly greater in patients with Cushing's disease than in subjects without Cushing's disease before, but not after, CRH treatment. R:L ratios did not differ among groups either before or after CRH. All of the subjects without Cushing's disease showed large R:L gradients, consistent with the notion of one dominant petrosal sinus containing a greater percentage of pituitary effluent. The ACTH concentrations, IPS:P ratios, and R:L ratios exhibited great overlap between those with and without Cushing's disease, which resulted in a diagnostic accuracy of 81% at best for the diagnosis of Cushing's disease. We conclude that petrosal sinus sampling is of limited usefulness in distinguishing either normal individuals or patients with pseudo-Cushing states from those with mild Cushing's disease. This limited usefulness must be recognized when interpreting the results of petrosal sinus sampling in patients with mild or intermittent hypercortisolism who may have a pseudo-Cushing state. Because of these limitations, petrosal sinus sampling should be reserved for patients with clear clinical and biochemical evidence of Cushing's syndrome.

Adrenocortical Hyperfunction↗
PubMed1995

Lysine vasopressin stimulation of cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia.

We present two patients with Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia who showed marked plasma cortisol response to lysine-8-vasopressin (LVP) injection (from 930 and 731 pmol/L to 2177 and 1920 pmol/L, respectively), while plasma ACTH levels remained undetectable. The ACTH independence of cortisol secretion in the two patients was determined from the following endocrinological findings. Plasma cortisol levels were not increased by corticotropin-releasing hormone injections and were not suppressed by high dose (16 mg) dexamethasone administrations. The plasma ACTH levels, measured by two independent sensitive immunoassays, were persistently undetectable even after corticotropin-releasing hormone injection, metyrapone administration, and bilateral adrenalectomy. The particular pathological finding of the two cases, atrophic lesions in nonnodular parts of the adrenal cortexes, also indicated ACTH independence of the macronodular hyperplasia. In vitro examination revealed a direct effect of LVP on cortisol secretion from the adrenal cells of the macronodules. We also examined seven patients with Cushing's syndrome caused by adrenal adenoma and found a statistically significant plasma cortisol response to LVP injection. The direct effect of LVP was also demonstrated in cultured adenoma cells. In conclusion, we discovered a direct adrenal effect of LVP on cortisol secretion in patients with ACTH-independent macronodular hyperplasia and, to a lesser extent, in patients with cortisol-producing adrenal adenoma. The cortisol response to LVP may serve to facilitate their diagnosis and choice of therapy.

17-Hydroxycorticosteroids↗
PubMed1996

Apparent cortisone reductase deficiency: a unique form of hypercortisolism.

We describe two female siblings who had production of cortisol (F; as determined from excretion of urinary metabolites) high enough to give rise to Cushing's disease, but who had no clinical indications of the condition. The teenage patients were hirsute as a result of adrenal hyperandrogenism. A notable feature of the condition was the elevated excretion of corticosteroid metabolites with 11-carbonyl groups and very low excretion of 11 beta-hydroxylated steroids. We termed this disorder apparent cortisone (E) reductase disorder. The steroid metabolite phenotype appeared to be the opposite of that seen in the apparent mineralocorticoid excess syndrome, in which the excretion of 11-keto compounds is attenuated. As an example, the tetrahydrocortisol plus 5 alpha-tetrahydrocortisol/tetrahydrocortisone ratio was about 0.04 compared to normal values of about 1.0 and apparent mineralocorticoid excess syndrome values of 5.0-50.0. Paradoxically, among the F metabolites that had not undergone A-ring reduction, 11 beta-hydroxylated steroids dominated over 11-carbonyl compounds. The F/E ratio was about 1.8 compared to an average normal value of 0.54. Neither the father nor the mother of the patient had abnormal F metabolite/E metabolite ratios, although the father did excrete highly elevated free E and F, possibly an unrelated condition. A conclusion was not reached regarding the basis of the disorder. We considered that the most likely causes were 1) defective hepatic 11 beta-hydroxysteroid dehydrogenase-1, 2) failure to develop the adult form of F metabolism, or 3) excessive activity of A ring reduction enzymes acting on E.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2001

Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency.

Cytochrome P450scc, the mitochondrial cholesterol side chain cleavage enzyme, is the only enzyme that catalyzes the conversion of cholesterol to pregnenolone and, thus, is required for the biosynthesis of all steroid hormones. Congenital lipoid adrenal hyperplasia is a severe disorder of steroidogenesis in which cholesterol accumulates within steroidogenic cells and the synthesis of all adrenal and gonadal steroids is impaired, hormonally suggesting a disorder in P450scc. However, congenital lipoid adrenal hyperplasia is caused by mutations in the steroidogenic acute regulatory protein StAR; it has been thought that P450scc mutations are incompatible with human term gestation, because P450scc is needed for placental biosynthesis of progesterone, which is required to maintain pregnancy. In studying patients with congenital lipoid adrenal hyperplasia, we identified an individual with normal StAR and SF-1 genes and a heterozygous mutation in P450scc. The mutation was found in multiple cell types, but neither parent carried the mutation, suggesting it arose de novo during meiosis, before fertilization. The patient was atypical for congenital lipoid adrenal hyperplasia, having survived for 4 yr without hormonal replacement before experiencing life-threatening adrenal insufficiency. The P450scc mutation, an in-frame insertion of Gly and Asp between Asp271 and Val272, was inserted into a catalytically active fusion protein of the P450scc system (H2N-P450scc-Adrenodoxin Reductase-Adrenodoxin-COOH), completely inactivating enzymatic activity. Cotransfection of wild-type and mutant vectors showed that the mutation did not exert a dominant negative effect. Because P450scc is normally a slow and inefficient enzyme, we propose that P450scc haploinsufficiency results in subnormal responses to ACTH, so that recurrent ACTH stimulation leads to a slow accumulation of adrenal cholesterol, eventually causing cellular damage. Thus, although homozygous absence of P450scc should be incompatible with term gestation, haploinsufficiency of P450scc causes a late-onset form of congenital lipoid adrenal hyperplasia that can be explained by the same two-hit model that has been validated for congenital lipoid adrenal hyperplasia caused by StAR deficiency.

17-alpha-Hydroxyprogesterone↗
PubMed2002

Development of pituitary-adrenal endocrine function in the marmoset monkey: infant hypercortisolism is the norm.

Early life stress, involving activation of the hypothalamic-pituitary-adrenal (HPA) system, is associated with altered functioning of stress-related systems in adulthood. In the rat, postnatal development is characterized by low basal HPA activity and stress hyporesponsiveness, and infant exposure to atypical glucocorticoid levels leads to chronic alteration of HPA function and HPA-dependent peripheral and central processes. There have been few studies of primate HPA ontogeny, and here we report a study of changes in pituitary-adrenal function between birth and adulthood in the common marmoset monkey. In this simian primate, basal plasma ACTH and cortisol levels were actually elevated in neonates (ACTH, 141 +/- 28 pg/ml; cortisol, 1903 +/- 326 microg/dl) and wk 4 infants (ACTH, 114 +/- 9 pg/ml; cortisol, 290 +/- 8 microg/dl) relative to month 2 infants, juveniles (month 6), subadults (month 12), and adults (>2 yr; ACTH, 37 +/- 4 to 61 +/- 8 pg/ml; cortisol, 101 +/- 2 to 195 +/- 4 microg/dl). In contrast to older life stages, neonates lacked circadian change in their plasma cortisol levels, and this state of consistently high cortisol was associated with large adrenal glands in addition to high ACTH levels. Cerebrospinal fluid cortisol levels were, in accord with plasma levels, higher in wk 4 infants than in juveniles and subadults. In terms of stress response, month 2 infants demonstrated ACTH and cortisol peak stress responses similar to those at older life stages (infant stress cortisol, 185 +/- 36% of basal; subadult stress cortisol, 174 +/- 6% of basal); whereas infant ACTH recovery was also similar to that in older subjects, their cortisol poststress recovery was retarded. This primate, it is proposed, provides an excellent complementary model in which to test hypotheses derived from the rat model relating to HPA system ontogeny and the chronic effects and biomedical implications of hypercorticoidism during early life.

Adrenal Glands↗
PubMed1992

Pituitary dependent hyperadrenocorticism in a cat.

A cat that was suspected some insulin resistance was diagnosed as pituitary dependent hyperadrenocorticism from an adrenocorticotropic hormone (ACTH) stimulation test, dexamethasone suppression test and measure of endogenous plasma ACTH concentration. Histopathological examination revealed chromophobe adenoma in pituitary gland and hyperplasia in adrenal cortex.

Adenoma, Chromophobe↗