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PubMed1987

The synthesis and processing of pro-ACTH/endorphin in the developing rat pituitary.

In many aspects of pro-ACTH/endorphin processing, newborn melanocytes are mature by birth. The newborn melanocytes correctly process precursor to many of the expected products including alpha MSH and beta-endorphin, the melanocytes perform tissue-specific modifications such as alpha-N-acetylation and additional proteolytic steps and they respond to dopaminergic agents but not to physiological levels of CRF or glucocorticoids. These features are retained in serum-free cultures of newborn intermediate pituitary cells. Thus, the major developmental alterations in the intermediate pituitary melanotropes involve the net 150-fold rise in pro-ACTH/endorphin synthetic rate, from birth to adulthood. In contrast, processing of pro-ACTH/endorphin in the newborn anterior lobe is not mature by birth. Both in vivo and in vitro newborn anterior pituitary corticotropes contain a large pool of pro-ACTH/endorphin, and a substantial amount of ACTH(1-39) is cleaved to ACTH(1-13)NH2 and CLIP. Surprisingly, the amount of ACTH(1-13)NH2 and beta-endorphin rises with increasing time in culture, but alpha-N-acetylation of ACTH(1-13)NH2 or beta-endorphin is not seen in the corticotropes. As in the adult, the synthesis of pro-ACTH/endorphin in newborn corticotropes is subject to regulation by CRF and glucocorticoids. In addition, glucocorticoid treatment of newborn corticotropes acts to suppress the cleavage of ACTH(1-39) to ACTH(1-13)NH2 and of beta-LPH to beta-endorphin, rendering the treated corticotropes more like the adult corticotropes. This plasticity in processing observed in the newborn corticotropes is not seen in the adult. It will be important to examine whether peptide processing patterns which are changed during this period of plasticity are permanently altered, and then what the consequences of those altered processing patterns might be.

Aging↗

PubMed1984

Interaction between stimulus intensity and corticosteroid feedback in control of ACTH.

These studies were performed to examine the relationship between stimulus intensity and corticosteroid feedback on ACTH secretion. We have measured the ACTH responses in five dogs to each of three levels of hypoglycemia induced by injection of three doses of insulin after production of each of four levels of corticosteroid feedback induced by the infusion of saline or three rates of ACTH. Both the peak and integrated ACTH responses were related to the degree of hypoglycemia in saline-infused dogs (P less than 0.01). ACTH infusions did not affect the hypoglycemia induced by insulin; however, the lower two infusion rates (20 and 50 ng/min for 40 min) inhibited the peak ACTH responses to hypoglycemia by mean values of 45 and 75%, respectively, and the integrated ACTH responses by about 60 and 90%, respectively. The high infusion rate of ACTH (500 ng/min for 40 min) abolished the subsequent ACTH responses to hypoglycemia (103% inhibition). Therefore, the degree (%) of inhibition was the same for a given prior corticosteroid level at all intensities of hypoglycemia. The plasma ACTH response was a function of both stimulus intensity and prior corticosteroid levels and was proportional to the stimulus intensity divided by the feedback dose. Thus, corticosteroids exert a modulatory rather than a simple subtractive effect on the secretion of ACTH.

Adrenal Cortex Hormones↗

PubMed1994

Ultrasensitive assay for measuring the intact (1-39) ACTH molecule: an asset in depression research.

This study investigates the utility for depression research of an assay for intact (1-39) adrenocorticotropic hormone (ACTH) versus that of a previously employed (i.e., 1-17, 1-24 sequences) ACTH assay. ACTH plasma levels were measured using two different ACTH assays (labeled as intact versus nonintact) in 10 minor and 27 major depressed subjects undergoing the combined dexamethasone suppression (DST) and corticotropin-releasing hormone (CRH) test. Intact--but not nonintact--ACTH values were significantly correlated with the severity of illness. Major depressed subjects exhibited significantly higher post-DST+CRH intact ACTH values than minor depressives, whereas nonintact ACTH values were not significantly different between these groups. Post-DST+CRH intact ACTH values were significantly more closely related to post-DST+CRH cortisol than nonintact ACTH values. It is concluded that the assay of the intact ACTH molecule is an asset in depression research and should replace the previous less specific and sensitive ACTH assays.

Adrenocorticotropic Hormone↗

PubMed1985

A detailed examination of the in vivo and in vitro effects of ACTH on gonadotropin secretion in the adult rat.

These studies were designed to: (1) determine the effects of continuous infusion of synthetic ACTH(1-24) on postcastration changes in serum and pituitary LH, FSH and prolactin in the male rat; (2) assess the effects of adrenalectomy on the gonadotropin and prolactin response to ACTH, and (3) test the hypothesis that ACTH may directly (not via adrenal factors) alter gonadotropin secretion at the brain and/or pituitary level. Adult male rats were either orchidectomized (ORX) or orchidectomized-adrenalectomized (ORX-ADX), and were treated continuously for 6 days with ACTH(1-24) (10 micrograms/day) or saline using an osmotic minipump. Animals were killed on day 6 following castration. ACTH treatment reduced serum LH and prolactin levels in ORX rats to mean values +/- SE of 204 +/- 25 and 37 +/- 3 ng/ml respectively, compared to 366 +/- 72 and 62 +/- 7 ng/ml in saline-treated ORX animals. Serum FSH concentrations were not altered by ACTH administration. Pituitary concentrations of LH and FSH, but not prolactin were enhanced by ACTH treatment. Adrenalectomy had no effect on serum and pituitary gonadotropin and prolactin levels, but abolished the effects of ACTH on these parameters. Central (intracerebroventricular) infusion of ACTH(1-24) (6 micrograms/day X 4 days) failed to alter the rise in serum LH in male rats following orchidectomy. Acute treatment with large doses of ACTH of perifused anterior pituitary glands from male rats and chronic treatment with ACTH of enzymatically dispersed anterior pituitary cells from female rats did not influence basal or GnRH-stimulated LH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1990

Ontogeny of plasma, CSF and brainstem ACTH in piglets: effects of hypoxia and anesthesia.

This study was designed to assess the postnatal maturation of adrenocorticotropin (ACTH) levels in piglets under basal conditions and in response to single, acute stressors. ACTH levels were measured by radioimmunoassay in plasma, cerebrospinal fluid (CSF) and in a dorsal medullary slice containing the nucleus tractus solitarii (dmscNTS) of young and older piglets (1.5-6 and 35-43 days old, respectively) under the following experimental conditions: (1) normoxia (both groups); (2) hypoxia, 10% O2/N2 for greater than or equal to 30 min (both groups); (3) sham anesthesia, i.p. saline in normoxia (young group); (4) anesthesia, 25 mg/kg i.p. pentobarbital in normoxia (young group), and (5) anesthesia combined with hypoxia (young group). During normoxia, ACTH levels in young, as compared to older piglets, were higher in CSF (p less than 0.01) and plasma (0.05 less than p less than 0.10) and not different in dmscNTS. Hypoxia produced no ACTH changes in CSF, increased ACTH in plasma of young (p = 0.03) and older piglets (p = 0.09), and decreased ACTH in dmscNTS of older (p = 0.01) and young piglets (p = 0.07). As compared to sham anesthesia, anesthesia did not alter any ACTH levels. Combined hypoxia and anesthesia increased ACTH levels in plasma when compared to normoxia (p less than 0.05), sham anesthesia (p less than 0.05) or anesthesia alone (p less than 0.05), but not when compared to hypoxia alone. We conclude that neonatal swine have high basal ACTH levels and mount significant plasma ACTH responses to a single, acute hypoxic stressor. The presence of ACTH in the region of the NTS supports its possible role as a neuromodulator in the brain.

Adrenocorticotropic Hormone↗

PubMed1992

Pulsatile ACTH and cortisol in goats: effects of insulin-induced hypoglycemia and dexamethasone.

Insulin-induced hypoglycemia is a metabolic stress that stimulates secretion of adrenocorticotropic hormone (ACTH) and cortisol in a number of animal species. Dexamethasone is a potent synthetic glucocorticoid that suppresses the secretion of ACTH and cortisol. Both ACTH and cortisol exhibit complex secretory patterns demonstrating ultradian and circadian rhythms. This work investigated the pattern of ACTH and cortisol response to hypoglycemia in goats and the effect of dexamethasone on this response. Five goats were pretreated with dexamethasone (0.1 mg/kg) and 5 with saline. Blood samples were taken every 2 min for 60 min before and 60 min after administration of insulin (2.5 IU/kg, i.v.). Immunoreactive ACTH and cortisol were measured in all samples and glucose in selected samples. Data sets were analyzed for significant pulses with the Cluster Analysis program. Complete data sets were compared as well as those for each 30-min interval. Plasma glucose was lower than preinsulin levels at 10 min, declined rapidly between 10 and 30 min, and remained low 30-60 min after insulin injection in both treatment groups. Controls showed a rapid rise in ACTH and cortisol beginning 30 +/- 10 min postinsulin. The increase in mean plasma hormone levels during hypoglycemia was predominantly due to an increase in amplitude of secretory pulses for ACTH and cortisol compared with the 30 min before insulin. Dexamethasone significantly lowered mean ACTH and cortisol levels and prevented alteration in plasma ACTH and cortisol secretion during hypoglycemia but did not totally ablate pulsatile activity of either hormone. The amplitude of ACTH and cortisol pulses was significantly decreased by dexamethasone treatment. The frequency of cortisol but not ACTH pulses was also significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1968

Radioimmunoassay of ACTH in plasma.

Techniques are described in detail for a radioimmunoassay of plasma adrenocorticotropin (ACTH) that is capable of detecting hormone in unextracted normal human plasma at 1:5 dilution under the conditions described. The sensitivity of the assay is at the level of 1 mumug/ml (equivalent to 0.014 mU/100 ml). In normal subjects ACTH concentrations averaged 22 mumug/ml (equivalent to 0.308 mU/100 ml) plasma at 8-10 a.m. In a smaller group the concentrations averaged 9.6 mumug/ml (equivalent to 0.134 mU/100 ml) at 10-11 p.m. Although a circadian rhythm in normal subjects was not always well marked throughout the daytime hours, plasma ACTH usually fell to its lowest value in the late evening. In hospital patients who were not acutely ill, concentrations were infrequently above 100 mumug/ml in the morning and usually fell to significantly lower levels in the late evening. Severely ill hospital patients occasionally exhibited a.m. concentrations above 200 mumug/ml. In a group of subjects showing frequent spiking of plasma 17-OHCS concentrations throughout the day parallel spiking of plasma ACTH as well was generally observed.Metyrapone produced marked increases in plasma ACTH within 24 hr in all cases and generally within 3-6 hr except when started late in the day. Dexamethasone brought about a persistent reduction in plasma ACTH in a patient under continued treatment with metyrapone.Hypoglycemia, electroshock, surgery under general anesthesia, histalog and vasopressin administration were usually followed by significant increases in plasma ACTH concentration. Prior administration of dexamethasone blocked the response to hypoglycemia. Marked elevations in plasma ACTH were observed in patients with adrenal insufficiency off steroid therapy, in Cushing's disease after adrenalectomy even in the presence of persistent hypercortisolemia, and in some untreated patients with Cushing's disease. Umbilical cord blood contained higher plasma ACTH concentrations than maternal blood at delivery in seven of eight cases. After suppression of ACTH secretion by dexamethasone or cortisol. ACTH disappeared from plasma with half-times ranging from 22 min to 30 min in three cases studied.

17-Hydroxycorticosteroids↗

PubMed1975

Characterization of mouse ACTH in plasma and in extracts of pituitary and of adrenotropic pituitary tumor.

The predominant component of immunoreactive ACTH in the plasma of adrenalectomized normal mice and of mice bearing the adrenotropic mouse pituitary tumor, AtT-20, and in extracts of the normal mouse pituitary and pituitary tumor, has an elution volume on Sephadex G-50 gel filtration approximately midway between the void volume and the elution volume of human ACTH (1-39 peptide). The tumor extracts are shown to contain, in addition to this intermediate ACTH, 2 other components of immunoreactive ACTH, one which coelutes with 131I-labeled albumin (big ACTH) and the other with [125I]hACTH (little ACTH). Big and intermediate ACTH are urea-stable. Controlled tryptic digestion of mouse-tumor big ACTH results within 10 seconds in conversion to an intermediate component followed by continued loss of immunoreactivity. Under the same conditions of tryptic digestion of intermediate ACTH, there is only continuous loss of immuno-reactivity with no change of hormonal form. These findings strengthen the hypothesis that mouse intermediate ACTH is not a precursor for little ACTH.

Adrenal Glands↗

PubMed2002

Low-dose ACTH therapy for West syndrome: initial effects and long-term outcome.

BACKGROUND: Most Japanese pediatric neurologists attempt other treatments before using adrenocorticotropic hormone (ACTH) therapy for West syndrome (WS), and even then, they use only a low-dose synthetic ACTH to avoid serious adverse effects. In this multi-institutional study, the authors analyzed the initial effects, adverse effects, and long-term outcome in patients treated with low-dose synthetic ACTH in Japan. METHODS: The medical records of 138 patients with WS, who were treated with low-dose synthetic ACTH therapy for the first time at the authors' institutions between 1989 and 1998, were analyzed. RESULTS: At the end of ACTH therapy, excellent effect on seizures was noted in 106 of 138 (76%) patients, good effect in 23 (17%), and poor effect in 9 (7%). Initial effects on EEG were excellent in 53 of 138 (38%) patients, good in 76 (55%), and poor in 9 (7%). As for seizure prognosis at the time of follow-up, 51 of 99 (52%) patients were seizure-free, whereas 48 (48%) patients had seizures. Mental outcome was normal in 6 of 98 (6%) patients, mild mental retardation in 16 (16%), moderate mental retardation in 26 (27%), and severe mental retardation in 50 (51%). The initial effects of ACTH on seizures and long-term outcome were not dose dependent (daily dosage 0.005 to 0.032 mg/kg, 0.2 to 1.28 IU/kg; total dosage 0.1 to 0.87 mg/kg, 4 to 34.8 IU/kg). The severity of adverse effects correlated with total dosage of ACTH, and the severity of brain volume loss due to ACTH correlated well with the daily dosage and total dosage of ACTH. CONCLUSION: Low-dose synthetic ACTH therapy is as effective for the treatment of WS as the higher doses used in previous studies. The dosage of synthetic ACTH used in the treatment of WS can be decreased as much as possible to avoid serious adverse effects.

Brain↗

PubMed2005

Alteration of reproductive hormone levels in pregnant sows induced by repeated ACTH application and its possible influence on pre- and post-natal hormone secretion of piglets.

Prenatal stress has been seen as a reason for reproductive failures in pig offspring mostly originated or mediated by changed maternal functions. Experiments were conducted in pregnant gilts (n=32) to characterize effects of elevated maternal glucocorticoids on the secretion of reproductive hormones (LH, progesterone) during the 1st (EXP 1), 2nd (EXP 2) and 3rd (EXP 3) trimester of pregnancy (TP). Transiently elevated cortisol release was repeatedly achieved by application of 100 IU adenocorticotropic hormone (ACTH) (Synacthen Depot) six times every second day beginning either on day 28 (EXP 1), day 49 (EXP 2) or day 75 of pregnancy (EXP 3). Glucocorticoid concentrations were examined in umbilical blood vessels of fetuses which mothers were subjected to ACTH at 2nd and 3rd TP (EXP 4). Furthermore, the pituitary function of newborn piglets of EXP 2 was checked by a LH-RH challenge test. In sows, LH concentrations were at low basal level (0.1-0.2 ng/ml) but with pulsatory release pattern during each TP. The number of LH pulses/6 h (LSM +/- SE) of saline treated Controls increased with ongoing pregnancy and decreased to the 3rd TP (1.3 +/- 0.2 in EXP 1 vs. 2.0 +/- 0.1 in EXP 2 vs. 1.4 +/- 0.1 in EXP 3, p<0.05). After ACTH treatment the number of LH pulses left unchanged in Experiments 1 and 2 (1.3 +/- 0.2 and 1.5 +/- 0.1) and decreased in EXP 3 (0.8 +/- 0.2, p<0.05). Differences (p<0.05) were obtained comparing the LH pulse number of ACTH and saline treated sows at the 2nd and 3rd TP. Moreover, areas under the curve (AUC) of each LH pulse and of LH over baseline were significantly reduced by treatment. Levels of progesterone increased (p<0.05) for 150 to 170 min after each ACTH application both in EXP 1 and EXP 2, but not in EXP 3. The mean progesterone concentration was different between trimesters, and ACTH and Controls (1st TP: 30.0 +/- 0.9 and 24.4 +/- 0.7 ng/ml; 2nd TP: 35.5 +/- 0.9 and 29.1 +/- 1.0 ng/ml; 3rd TP: 13.6 +/- 0.2 and 13.1 +/- 0.1 ng/ml; p<0.05). In fetuses (n=87) recovered 3 h after ACTH or saline (EXP 4), the plasma cortisol concentrations were significantly increased in umbilical vein (93.7 +/- 5.5 vs. 47.0 +/- 5.3 nmol/l) and artery (95.7 +/- 5.4 vs. 66.4 +/- 5.4 nmol/l), and in periphery (46.8 +/- 5.3 vs. 27.1 +/- 5.3 nmol/l) compared to controls. Plasma ACTH concentrations, however, did not differ in fetuses of both treatment groups. Postnatal LH-RH challenge tests (1st and 28th day post partum) induced LH surges in female piglets (n=67) both of ACTH and saline treated sows, but did not differ between groups (1st day: 7.2 +/- 0.8 vs. 8.1 +/- 0.7 ng/ml; 28th day: 10.5 +/- 1.7 vs. 13.6 +/- 2.2 ng/ml). However, basal LH of piglets whose mothers were submitted to ACTH during 2nd TP was lower on 1st day (1.7 +/- 0.2 vs. 2.3 +/- 0.2 ng/ml, p<0.05) but not on 28th day (1.0 +/- 0.2 vs. 1.1 +/- 0.2 ng/ml). However in both groups, the basal LH was always higher on 1st as on 28th day (p<0.05). Thus, chronic intermittent ACTH administration is able to influence the release pattern of maternal reproductive hormones. However, these findings demonstrate that these effects are dependent on the stage of pregnancy. Furthermore, it was shown that maternal cortisol can cross the placenta during gestation and thus may affect maternal-fetal interactions and, as a result, reproductive function of offspring.

Adrenocorticotropic Hormone↗

PubMed2006

Diversity of ACTH-immunoreactive cells in the human adenohypophysis: an immunohistochemical study with special reference to cluster formation and follicular cell association.

Horvath et al. called relatively small ACTH-immunoreactive (ACTH-IR) cells observed in basophil invasion "proopiomelanocortin (POMC) cells," and these cells were supposed to be different from larger ACTH-IR cells in human adenohypophysis. To clarify the existence of "anterior POMC cells," we examined 21 autopsy cases taking note of follicular cells (FCs). We found that smaller ACTH-IR cells were clustered forming small areas without FC association, clustered small cell island (CSCI). CSCI was found in all the specimens we examined using immunohistochemical staining for ACTH and cytokeratin (AE1/AE3) in serial sections. ACTH-IR cells outside CSCI were of various sizes, mainly consisting of larger ACTH-IR cells that were diffusely scattered among other hormone-secreting cells and closely associated with FCs. By immunohistochemistry, ACTH-IR cells within CSCI and basophil invasion showed uniformly weak reactivity and common patterns for cytokeratins (CAM5.2 and 35 beta H11), carboxypeptidase D, and LeuM1, whereas those outside CSCI showed a great variety of immunoreactivity. The similarity in the immunoreactivity of ACTH-IR cells between CSCI and basophil invasion suggests that ACTH-IR cells in these two areas have common characteristics and ACTH-IR cells in CSCI are most likely "POMC cells." The clustered "anterior POMC cells" may be distinguishable by light microscopic immunohistochemistry.

Adrenocorticotropic Hormone↗

PubMed1985

[The role of Ca ions and cAMP in ACTH lipolysis].

Ca ions and cAMP are known to be involved in the action of hormones. In this study, the actions of Ca ions and cAMP in ACTH lipolysis were investigated by comparing ACTH1-24, ACTH1-10 and ACTH11-24 with regard to: lipolytic activity, binding affinity to the fat cell membrane, changes in Ca ion binding to the fat cell membrane and cAMP formation. Rat adipocytes were used. Lipolytic activity was measured in terms of the amount of FFA released from fat cells into the medium after incubation with the ACTH analogs at 37 degrees C for 30 minutes. Binding affinity to the fat cell membrane was expressed as competitive binding affinity, determined by simultaneously incubating fat cell ghosts with 125I-ACTH1-24 and unlabelled ACTH analogs at 4 degrees for 40 minutes. Changes in Ca ion binding to the fat cell membrane was expressed as Ca binding capacity, measured by simultaneously incubating fat cell ghosts with 45Ca and ACTH analogs at 24 degrees C for 20 minutes. CAMP formation was measured by RIA as the amount of cAMP formed in fat cells incubated with 10(-6)M ACTH analogs at 37 degrees C for 0, 3, 5 and 10 minutes. FFA release after incubation with each of the ACTH analogs at 10(-6) M was 1.17 mEq/L/tube for ACTH1-24, 0.26 mEq/L/tube for ACTH1-10 and 0.25 mEq/L/tube for ACTH11-24, showing a high value only for ACTH1-24. The binding affinity to the fat cell membrane (high affinity constant) was 4.4 X 10(-8) M for ACTH1-24, 4.6 X 10(-8) M for ACTH1-10 and 4.6 X 10(-8) M for ACTH11-24. There were no significant differences among the binding affinities of these ACTH analogs. The binding capacity of 45Ca++ to the fat cell membrane (high affinity constant) was 3.64 X 10(-6) M for ACTH1-24, 4.49 X 10(-6) M for ACTH1-10 and 5.46 X 10(-6) M for ACTH11-24. There were no significant differences among these ACTH analogs. The increase in cAMP formation during the first 3 minutes of incubation was 35.5 fmol/mg dry weight of fat cells for ACTH1-24, 2.2 fmol/mg for ACTH1-10 and 1.8 fmol/mg for ACTH11-24. An increase was only observed for ACTH1-24. The fact that FFA release and cAMP formation were high only with ACTH1-24 among the ACTH analogs tested indicates that cAMP formation plays an important role in the lipolytic activity of ACTH in fat cells and that the three-dimensional structure of ACTH is important for cAMP formation.

Adipose Tissue↗

PubMed2001

Adrenal insufficiency after incomplete resection of pituitary macrocorticotropinoma of Cushing's disease: role of high molecular weight ACTH.

A 15-year-old girl with Cushing's disease exhibited adrenal insufficiency following incomplete trans-sphenoidal resection of a large pituitary corticotropinoma, approximately 35 mm in diameter. Within two weeks following surgery, her plasma ACTH level decreased from 42 to 13 pmol/l, while, her plasma cortisol levels and urinary excretion of free cortisol decreased from 607 nmol/l and 1112 nmol/day to 94 nmol/l and 55 nmol/day, respectively. Immunoreactive ACTH was characterized in plasma using Sephadex G-75 column chromatography and measuring ACTH with immunoradiometric assay (IRMA) and radioimmunoassay (RIA) to determine additional peaks, other than the one demonstrated for 1-39 ACTH. In particular, when measured with RIA, a broad peak including the high molecular weight ACTH was detected as well as 1-39 ACTH. The bioactivity of the high molecular weight ACTH in patient plasma was lower than the reference range of 1-39 ACTH, which is determined by the ability of dispersed rat adrenocortical cells to secrete corticosterone. The large pituitary corticotropinoma found in this patient secreted not only 1-39 ACTH but also high molecular weight proopiomelanocortin (POMC)-derived peptides, which could be detected by measuring with IRMA and RIA for ACTH. Based on the results of biological activity and molecular ratios, no positive evidence could be found to support the hypothesis that the high molecular weight ACTH induced any postoperative adrenal insufficiency in this patient. However, based on this study, the possibility of adrenal insufficiency should be carefully monitored, even when post-operative remnant tumor tissue is clearly present in patients with Cushing's disease, accompanied by macrocorticotropinoma.

Adenoma↗

PubMed1976

Effects of ACTH on plasma levels of adrenal steroids in essential hypertension.

Plasma concentrations of progesterone (P), deoxycorticosterone (DOC), 17-hydroxyprogesterone (17-OH P), corticosterone (B), deoxycortisol (S), cortisol (F) and aldosterone (A) in 8 control subjects (mean age: 40.5 years) and 10 patients with essential hypertension (EH) (mean age: 48.5 years) were determined before, 4 and 8 hours after an infusion of ACTH at a rate of 25 units per 8 hours. Secretion rates (SR) of 18-hydroxy-11-deoxycorticosterone (18-OH DOC) were measured 24 hours before and again on the day of ACTH infusion. All subjects were studied on the fourth day of a diet containing 135 mEq of sodium and 90 mEq of potassium. There was no statistically significant difference between 8 control subjects and 10 patients with EH in the 7 plasma steroid levels and the SR of 18-OH DOC before ACTH infusion. The mean plasma P response to ACTH was slightly lower in controls than in patients with EH, while that of 17-OH P (in male subjects) was slightly higher. The mean plasma B response was significantly lower after 4 hours of ACTH infusion (p less than 0.01), while that of DOC was significantly higher after 8 hours of ACTH infusion (p less than 0.05) in patients with EH. The mean plasma S rose significantly more in patients with EH (p less than 0.025) at 4 and 8 hours after ACTH infusion. The mean plasma F response to ACTH infusion was slightly lower in patients with EH than in controls. The mean response of 18-OH DOC SR to ACTH infusion was slightly higher in patients with EH than in controls. The mean plasma A response was significantly higher in patients with EH than in controls 4 (p less than 0.05) and 8 hour (p less than 0.001) after an ACTH infusion. These results could be explained in part by abnormalities in the 17- and 11-hydroxylase systems, and that the abnormality in 11-hydroxylation was more pronounced than that in the 17-position. Furthermore, we suspect that the sensitivity of adrenal aldosterone to ACTH might be increased or another accelerated pathway to aldosterone biosynthesis might exist in patients with EH.

Adrenal Cortex Hormones↗

PubMed1978

Clinical studies of "big ACTH": its physico-chemical characteristics.

The big ACTH fractions available from human plasma and pituitary glands and from porcine pituitary glands were physico-chemically characterized by gel filtration, disc electrophoresis and isoelectric separation. In the case of healthy human subjects, big ACTH fractions were isolated by gel filtration from plasma samples taken during states of acute ACTH hypersecretion such as the lysine-8-vasopressin, insulin or metopyrone tests though none of these fractions were isolated from plasma sampled under normal conditions. Even with no stimulation of ACTH secretion, patients with Cushing's disease gave plasma samples that contained an isolable big ACTH fraction, but such a fraction was hardly isolated from plasma taken from patient with Addison's disease. Both human pituitaries and porcine pituitaries contained an isolable big ACTH fraction. By a gel filtration analysis the molecular weight of the big ACTH was estimated to be higher than 20 000. Disc electrophoresis with an acrylamide gel indicated that big ACTH is strongly basic while small ACTH is more acidic than pH 8.3. Isoelectric separation revealed that the isoelectric point of human big ACTH is higher than pH 10.0 while that of small ACTH is about pH 6.8.

Addison Disease↗

PubMed1984

Influence of anti-oestrogens on gonadotrophin secretion in control and ACTH-infused immature rats.

The objective of this study was to determine whether anti-oestrogens (nafoxidine, MER-25) would block the suppressive effects of ACTH on gonadotrophin secretion in immature rats. Female rats were castrated at 25-26 days of age, and an Alzet osmotic minipump containing ACTH (1-24) or saline was implanted in each animal. ACTH was administered at a rate of 1 IU/day by constant infusion. Beginning on the day of surgery, animals were injected daily for 5 days with 0.25, 5 or 25 micrograms/100 g body weight of nafoxidine or 5 mg MER-25 and sacrificed on the sixth day following castration. ACTH lowered serum LH concentrations and increased pituitary LH levels. Serum androstenedione concentrations were more than two times greater in ACTH-infused than in control rats, but serum oestrone levels were not affected. Serum testosterone and oestradiol concentrations in ACTH-infused rats remained below levels of detection. Administration of 0.25 micrograms of nafoxidine prevented the suppressive effects of ACTH on serum LH. Serum levels of LH in these animals were comparable to saline-treated controls (418 +/- 94 vs 443 +/- 73 ng/ml). The two higher doses of nafoxidine and MER-25 were ineffective in suppressing the actions of ACTH on serum LH. MER-25 reduced serum LH values in both controls and ACTH-infused rats. Serum FSH concentrations were not altered by ACTH or nafoxidine treatment. MER-25 elevated pituitary FSH concentrations in both control and ACTH-infused rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1984

Effect of ACTH on endogenous steroid biosynthesis in long-term primary cultures from newborn rat adrenal cells.

Normal newborn rat adrenal cells kept in primary culture up to 2 1/2 months respond to ACTH stimulation and produced corticosteroid hormones and smaller amounts of 20 alpha-reduced progesterone metabolites. Cholesterol from the serum complemented culture medium serves as precursor without further addition of exogenous steroid substrates. A long-term qualitative and quantitative study of individual steroid production under the influence of ACTH was performed. ACTH treatment produced a triphasic effect on steroid production: an induction period (up to 3 days), an acute maximum production period (3rd to 6th day) and a chronic production period (to the end of the treatment). The increase in total steroid production resulted from the increase in the production of corticosteroids only. This indicated an increase of cholesterol side-chain cleavage and of the 21- and 11 beta/18-steroid hydroxylations. Removal of ACTH led to a reversible drop in total steroid production. The response to ACTH was dose dependent, so that a 2.2 mU/ml dose elicited lower steroid production than the 6.6 or 22 mU/ml doses. Increasing the lower dose after a week of treatment to a higher dose brought total steroid production and 11 beta/18-steroid hydroxylation up to the corresponding chronic production levels. The 20 alpha-steroid reduction system was not affected by ACTH. ACTH changes the importance of the two main steroidogenic pathways. With no ACTH there is approximately a 1:1 ratio between corticosteroid synthesis and progesterone reductive metabolism; a low dose of ACTH increases the total steroid production, but since corticosteroid production and 20 alpha-reduced metabolites both increase, the ratio changes little; a high dose of ACTH increases the ratio to more than 30:1. Refractoriness or desensitization to ACTH is postulated to occur through the control of cholesterol availability inside the cell possibly combined with a control of its utilization for steroidogenesis.

Adrenal Cortex Hormones↗

PubMed1986

Plasma ACTH in diagnosis and control of adrenal disorders.

Unstimulated plasma ACTH concentrations remain at or below the detection limit of conventional immunoassays. Grossly elevated ACTH concentrations are diagnostic in suspected adrenal insufficiency, remain elevated well above 200 ng/l during substitution therapy and obviate the need of further tests. For the diagnosis of secondary adrenal failure, plasma ACTH, cortisol and 11-desoxycortisol response to a single midnight dose of metyrapone (1.2 g/m2 = 30 mg/kg) discriminates between a normal (morning ACTH above 100 ng/l), diminished (morning ACTH detectable, but below 100 ng/l), and an absent (ACTH below 20 - 40 ng/l) ACTH reserve. In congenital adrenal hyperplasia, plasma ACTH concentrations mirror, together with 17-alpha-hydroxyprogesterone, the extent of ACTH suppression. Elevated ACTH concentrations were suppressed by prednisolone (25%), dexamethasone (2% of the hydrocortisone dose) or by addition of cyproterone acetate (100 mg/m2/day). Using selective venous catheterisation in clinically and biochemically proven Cushing's syndromes, a pituitary adenoma could be identified and localized in 6 of 8 patients by measuring ACTH concentrations in the left and right petrosal sinus before and after stimulation with corticotrophin releasing hormone.

17-alpha-Hydroxyprogesterone↗