Corticotrophic Hormone Research Articles

8133 Spatial Transcriptomic Profiling of Pituitary Corticotroph Carcinoma: Uncovering Architectural Complexity

Abstract Disclosure: D. Zhang: None. M. Bergsneider: None. M.B. Wang: None. W. Kim: None. H. Vinters: None. A.P. Heaney: None. Most pituitary corticotroph adenomas are benign but ∼15% are refractory to conventional surgical, medical and even radiotherapeutic management. This tumor subset invade sellar adjacent structures, and in rare cases metastasize locally within the central nervous system or to neck lymph nodes (LN) or more distant organs such as the liver. To better understand the potential interactions between tumor cells and neighboring tissues during these progressive stages, we used spatial transcriptomics (ST, Visium, 10x Genomics) to profile the genetic composition and native architecture of 4 surgically resected corticotroph tumor paraffin-embedded samples collected from the same patient over several years. Samples 1& 2 invaded the sino-nasal mucosa, sample 3 the parietal dura, sample 4 the clival bone, and sample 5 had metastasized locally to a neck LN. Quality of the 4 samples was confirmed by DV200 score (51 ± 7%). An average of 2,473 tissue spots per tissue sample were obtained after sequencing with a median of 4,893 genes detected per spot. We then used the Seurat analytic pipeline to reconstitute spatial transcriptional distribution that authentically mirrored histologically verifiable structures. These included the main tumor area itself, it’s invading tumor edge, adjacent normal epithelium, dura, and LN tissue. Further deconvolution analysis revealed a distinct cellular composition at the invading tumor edge which was tissue context specific. For instance, a proliferative cell population was noted between the central tumor area and it’s invasive margin, B cell and fibroblast cell enrichment was prominent at sino-nasal mucosal invasive margins, whereas endothelial and pericyte cells were prominent along the tumor/ normal pituitary border. . As expected, the central tumor area expressed genes associated with corticotroph hormone production including POMC, NNAT, GAL and GNAS, genes associated with mitochondrial energy metabolism such as ATP5F1E, NDUFA8 and COX7B as well as transcripts related to lipid kinase activity (GKG, CERKL, PIK3C2G, DGKK). Most intriguingly, tumor cells at the fore-front of the invading edge expressed high level of cyclin-dependent kinases, potentially reflecting higher proliferative rates of these invasive margin cells. Additional studies to validate and define the role of theses invasive margin transcripts are now warranted to translate our profiling findings into potential drug targets. In summary, this is the first use of spatial transcriptomics to delineate the evolving transcriptomic features in a series of surgically resected pituitary corticotroph tumors from the same patient that progressed over time to a locally metastatic corticotroph carcinoma. It provides unparalleled insights into the differential transcriptional topography of corticotroph tumor tissue and most importantly, its invading edge and may identify novel therapeutic targets. Presentation: 6/3/2024

Relative Adrenal Insufficiency in Patients with Alcoholic Hepatitis

Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with high morbidity and mortality. Treatment with steroids is known to decrease short-term mortality in severe AH patients. Hence, we hypothesize that adrenal insufficiency can be associated with severe AH and affects prognosis. The aim of this study was (1) to evaluate relative adrenal insufficiency (RAI) in patients with AH and (2) to Compare RAI with the severity of AH. Newly diagnosed cases of AH hospitalized in SMS Medical College and Hospital, Department of Gastroenterology were, enrolled. All patients of AH were classified as mild and severe AH on the basis of Maddrey discriminant function (DF). After baseline serum cortisol, 25 IU ACTH (Adreno Corticotrophic Hormone) was injected intramuscularly and blood sample was collected after 1 h and assessed for serum cortisol. RAI was defined as <7 μg increase in the cortisol level from baseline. RAI was compared with severity of AH. Of 120 patients of AH, 58 patients fulfilled the inclusion criteria, in which 48 patients were diagnosed as severe AH and 10 patients were diagnosed as mild AH. In patients with severe AH, the baseline mean serum cortisol level was significantly high as compared with mild AH; 26 patients (54.16 %) of 48 patients with severe AH showed RAI (P≤0.001).Whereas in patients with mild AH, none of patients showed RAI. RAI also showed negative correlation with DF. There was no difference in RAI with respect to acute kidney injury (AKI). RAI is a common entity in patients with severe AH, and it is related with the severity of disease.

Clinical use of pasireotide for Cushing&amp;#39;s disease in&amp;nbsp;adults

Cushing’s diseaseExcessive corticotroph hormone levels sustained by an adrenocorticotropic hormone-secreting pituitary adenoma lead to a severe clinical condition caused by excess cortisol secretion, called Cushing’s disease (CD). Neurosurgery and radiotherapy are used to treat the pituitary adenoma directly, but new medical treatments targeting the corticotroph cells have recently become available.PasireotideThis is a novel multireceptor ligand somatostatin (SST) analog with a high binding affinity for SST receptor 5, the predominant receptor in human corticotroph adenomas that is not downregulated by high cortisol levels (as SST receptor 2 is). Pasireotide has been recently approved by the European Medical Agency and the US Food and Drug Administration for treating adults with CD with recurrent hypercortisolism after surgery, or for whom surgery is not an option. A dose of 600–1,200 μg twice a day can normalize urinary free cortisol levels after 3 months of treatment in up to 28% of patients, reducing their blood pressure and improving their weight, lipid profile, and quality of life. Combining pasireotide with cabergoline to achieve a greater hormone response can normalize cortisol secretion in 50% of patients, and adding ketoconazole induces biochemical control in most patients with CD.Safety and hyperglycemiaThe adverse effects of pasireotide are similar to those of other SST analogs, including diarrhea, nausea, and biliary sludge or gallstones. Hyperglycemia is common during pasireotide treatment, which affects the secretion of pancreatic insulin and intestinal glucagon-like peptide 1. Self-monitoring is essential to achieve good metabolic control, and endocrinologists should first administer metformin if insulin resistance is evident and then add dipeptidyl peptidase 4 inhibitors/glucagon-like peptide 1 receptor agonists or insulin.ConclusionIn recent years, medical treatment with pasireotide has been proposed as monotherapy for adults with CD characterized by mild to moderate hypercortisolemia, as well as in combination with other available therapies. It is generally well-tolerated, but endocrinologists need to monitor glucose levels to ensure prompt treatment.

Screening for autoimmune diseases in type 1 diabetes: Low incidence of adrenal insufficiency

Abstract Objectives Primary Adrenocortical insufficiency (Addison's disease) is a potentially fatal condition that often develops incidentally and can be easily overlooked. Although rare in the general population, it is more common in patients with type 1 diabetes mellitus (T1D). In this study, we reviewed our experience with the occurrence of associated adrenal insufficiency (AI) in children with T1D over 15 year's period at King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia Methods This is a retrospective hospital based study, included children and adolescents with T1D at KKUH in the period January 1995–December 2012. All patients were serologically screened for Celiac and thyroid diseases. Adrenal function was assessed at the time of diagnosis, and annually thereafter by measuring serum cortisol and adrenal corticotrophic hormone (ACTH) using the available commercial kit. Adrenal cortex antibodies (AAA) test was done by Bioscientia laboratory, Germany, in one patient. Results In a cohort of 305 children and adolescents with T1D at KKUH, only one patient was found to have AI as a part of autoimmune polyendocrine syndrome type 1. Thyroid functions were abnormal in 65 (21.3%) patients. Of these, 26 (8.5%) patients have evidence of overt hypothyroidism and 39 (12.8%) patients had subclinical hypothyroidism. In twenty-six patients (8.5%), the intestinal biopsy results were positive for CD. Conclusion There is no international consensus on the issue of screening for AI in children with T1D. In our experience, we do not favour screening for AI in children with T1D unless there is a clear risk factor.

Receptor activity modifying proteins (RAMPs) interact with the VPAC2 receptor and CRF1 receptors and modulate their function

Although it is established that the receptor activity modifying proteins (RAMPs) can interact with a number of GPCRs, little is known about the consequences of these interactions. Here the interaction of RAMPs with the glucagon-like peptide 1 receptor (GLP-1 receptor), the human vasoactive intestinal polypeptide/pituitary AC-activating peptide 2 receptor (VPAC(2)) and the type 1 corticotrophin releasing factor receptor (CRF(1)) has been examined. GPCRs were co-transfected with RAMPs in HEK 293S and CHO-K1 cells. Cell surface expression of RAMPs and GPCRs was examined by ELISA. Where there was evidence for interactions, agonist-stimulated cAMP production, Ca(2+) mobilization and GTPγS binding to G(s), G(i), G(12) and G(q) were examined. The ability of CRF to stimulate adrenal corticotrophic hormone release in Ramp2(+/-) mice was assessed. The GLP-1 receptor failed to enhance the cell surface expression of any RAMP. VPAC(2) enhanced the cell surface expression of all three RAMPs. CRF(1) enhanced the cell surface expression of RAMP2; the cell surface expression of CRF(1) was also increased. There was no effect on agonist-stimulated cAMP production. However, there was enhanced G-protein coupling in a receptor and agonist-dependent manner. The CRF(1) : RAMP2 complex resulted in enhanced elevation of intracellular calcium to CRF and urocortin 1 but not sauvagine. In Ramp2(+/-) mice, there was a loss of responsiveness to CRF. The VPAC(2) and CRF(1) receptors interact with RAMPs. This modulates G-protein coupling in an agonist-specific manner. For CRF(1), coupling to RAMP2 may be of physiological significance.

Peri-conceptual cytokine environment and consequences for human pregnancy

Growth hormone, prolactin and placental lactogen are known as the growth- and lactogenic hormone (GLH; e.g., GH, PRL, and PL) family, which maintain adaptive immunity, including cell-mediated immunity, antibody, and autoimmune reactions, as well as maintain thymus and bone marrow functions. Insulin-like growth factor-1 participates in the regulatory action of growth hormone and prolactin. GLH shares signal transduction pathways with type I (γ-c) cytokines. This indicates a functional overlap. Dopamine is the hypothalamic regulator of PRL and GH secretion and the HPA axis. This action regulates healing and recovery from a disease. During acute illness, corticotrophic hormone (CRH) stimulates the HPA axis and vasopressin (VP) helps to maintain acute illness. The pituitary gland secretes adrenal cortex-stimulating hormone (ACTH) and the adrenal gland secretes glucocorticoids (GC) and catecholamines (CAT). When the disease subsides, VP not CRH will regulate chronic inflammation and recovery. VP also maintains adaptive immunocompetence during homeostasis because it stimulates the HPA axis and also prolactin. Oxytocin is immunoregulatory. Thyroidectomy in rats suppresses immune function and thyroxin releases growth hormone and prolactin from transplanted pituitary grafts in rats and also restores immune function. This indicates that thyroxin is an important immunoregulator. The growth hormone secretagogue, ghrelin, is immunoregulatory.

Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects

Subclinical hypercortisolism (SH) has been associated with increased prevalence of hypertension, type 2 diabetes mellitus, dyslipidaemia, central obesity, osteoporosis and vertebral fractures. We aimed to investigate the accuracy of different SH diagnostic criteria in predicting the presence of complications. This was a retrospective study. We evaluated data from 231 patients (120 women and 111 men) affected with adrenal incidentalomas (AI). We studied the accuracy of different SH diagnostic criteria (cortisol after 1 mg overnight dexamethasone suppression test - 1mg-DST - at different cut-off such as 49.7, 82.8, 137.9 nmol/l, elevated urinary free cortisol, reduced adrenal corticotroph hormone (ACTH) levels alone or various combination of these parameters) in predicting the concomitant presence of the following three complications: hypertension, type 2 diabetes and vertebral fractures. The criterion characterized by the presence of two of 1mg-DST >82.8 nmol/l, elevated UFC and reduced ACTH struck the best balance between sensitivity and specificity, reaching a good accuracy in predicting the cluster of complications (61.9%; 77.1% and 75.8%, respectively). The presence of this cluster was associated with this criterion (OR 4.75, 95%CI 1.8-12.7, P = 0.002) regardless of gonadal status, body mass index (BMI) and age. The SH criterion characterized by the presence of two of 1mg-DST >82.8 nmol/l, elevated UFC and reduced ACTH seems the best in predicting the presence of chronic manifestations of subtle cortisol excess.

Immune challenge induces differential corticosterone and interleukin-6 responsiveness in rats bred for extremes in anxiety-related behavior

Disturbances in mood such as anxiety and depression are often associated with altered hypothalamo-pituitary–adrenal (HPA) axis reactivity, but also with changes in cytokine production, such as interleukin-6 (IL-6), an essential immune factor produced by macrophages and lymphocytes during inflammatory processes. The reciprocal relationship between the HPA axis and the immune system is now well established. In order to understand better the endocrine reactivity of anxious individuals faced with an immune challenge, a model of innate anxiety-related behavior, HAB and LAB rats (HABs, high and LABs, low anxiety–related behavior) was used in this study. We sought to determine whether injection of lipopolysaccharide (LPS) induced a differential HPA axis reactivity and plasma IL-6 release in HABs and LABs. After LPS injection, the plasma adrenal corticotrophic hormone increase did not differ between HABs and LABs, whereas a larger increase in plasma corticosterone levels occurred in HABs than in LABs at 2 h after injection. Moreover, basal IL-6 levels were lower in HABs than in LABs, leading to a higher IL-6 2 h/basal ratio in HABs. In conclusion, we propose for the first time a link between the endocrine and immune systems of HABs and LABs and suggest that IL-6 could be a neuroendocrine correlate of trait anxiety in HABs.

Destruction of serotonergic nerve terminals prevents fluoxetine-induced desensitization of hypothalamic 5-HT(1A) receptors.

Selective serotonin (5-HT, 5-hydroxytryptamine) reuptake inhibitors (SSRIs) such as fluoxetine produce a gradual desensitization of hypothalamic post-synaptic 5-HT(1A) receptor systems. It is assumed that the effects of SSRIs on post-synaptic 5-HT(1A) receptors are mediated by 5-HT reuptake inhibition, leading to an increase of 5-HT in the synapse. However, there is no direct evidence to support this hypothesis. The present study determined whether 5-HT(1A) receptor desensitization was mediated by fluoxetine's effects on serotonergic nerve terminals. Serotonergic nerve terminals were destroyed by intracerebroventricular (i.c.v.) injection of the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) combined with injection of the norepinephrine/dopamine reuptake inhibitor nomifensine. 5,7-DHT-induced loss of serotonergic terminals was confirmed by a 95% reduction in the density of [(3)H]paroxetine-labeled 5-HT transporters in the hypothalamus and a 97% reduction in the levels of 5-HT and 5-hydroxyindoleacetic acid in the cortex. Two weeks after the 5,7-DHT injections, rats were injected daily with fluoxetine (5 mg/kg or 10 mg/kg, i.p.) or saline for 14 days. Injections of 10 mg/kg fluoxetine produced a significant decrease in body weight gain. Destruction of serotonergic nerve terminals reduced body weight and potentiated the ability of fluoxetine to further inhibit body weight gain. Increases in plasma levels of adrenal corticotrophic hormone (ACTH, corticotropin), corticosterone, and oxytocin after injection of the 5-HT(1A) agonist 8-hydroxy-2-dipropylaminotetralin [(+/-)8-OH-DPAT] were used as peripheral markers of 5-HT(1A) receptor function in the hypothalamus. In vehicle-pretreated rats, fluoxetine produced a dose-dependent reduction in the (+/-)8-OH-DPAT-induced increase in plasma ACTH and oxytocin levels. Destruction of serotonergic nerve terminals blocked the ability of fluoxetine to produce a desensitization in the ACTH, corticosterone, and oxytocin responses to (+/-)8-OH-DPAT. The ability of fluoxetine to induce a desensitization of hypothalamic post-synaptic 5-HT(1A) receptor systems is dependent on the integrity of serotonergic nerve terminals in the hypothalamus, while its effect on body weight is not mediated by serotonergic nerve terminals in the hypothalamus.

Effects of vasoconstriction on the acute anterior pituitary hormonal response to head injury

Since cerebral vasoconstriction alone may impair the hypothalamic and pituitary circulation, we planned to investigate whether the hormonal response to the vasoconstriction that may be induced by the head injury is a significant component of the general acute hormonal response to head injury. Although diffuse adrenocorticotropic hormone immunohistochemical staining of the adenohypophysis of rabbits was observed in the head trauma administered group, only mild positive staining was present in the Endothelin-1 administered group. However, decreased prolactin staining was found in both of the groups. It is postulated that trauma induced vasoconstriction may not be an important manipulating factor in the corticotrophic hormone response to injury, while it may be responsible for the decreased prolactin response.

Proopiomelanocortin (POMC) products in the central regulation of sympathetic and cardiovascular dynamics: studies on melanocortin and opioid interactions

The proopiomelanocortin (POMC)-derived peptides are important regulators in a number of central nervous system pathways especially as they relate to food intake as well as metabolic and autonomic responses. In this study, we investigated the sympathetic nervous and cardiovascular responses to intracerebroventricular (i.c.v.) administration of alpha melanocyte stimulating hormone (αMSH), β-endorphin (β-END) and adrenal corticotrophic hormone (ACTH) alone or in the presence of a melanocortin antagonist, or an opioid antagonist, in normal animals. The i.c.v. administration of αMSH and ACTH resulted in a significant increase in the lumbar sympathetic nerve activity (LSNA) that was accompanied by an increase in mean arterial pressure (MAP). On the other hand i.c.v. administration of β-END decreased the LSNA and MAP. The pretreatment of animals with the melanocortin-4 (MC-4) receptor antagonist, agouti protein, significantly antagonized the response to αMSH and also, paradoxically, not only antagonized the response to β-END but converted its inhibitory responses on both the LSNA and MAP to a sympathetic activated and pressor response. Pretreatment with the opioid antagonist, naloxone, significantly antagonized the sympathetic nervous and cardiovascular response to β-END. It partially but significantly antagonized the MAP response to αMSH, but the sympathetic response was unaffected. Neither agouti protein nor naloxone altered the sympathetic nervous and cardiovascular response to ACTH. From these studies, we conclude that i.c.v. administration of αMSH and ACTH increases the LSNA and cardiovascular dynamics, whereas β-END decreases it. And, the MC-4 receptor antagonist reverses the endorphin response and the opioid antagonist attenuates the αMSH response suggesting possible receptor or central neural pathway interactions between MC-4 and the opioid receptor mediated effects.

Docosahexaenoic Acid Increases Thyroid-Stimulating Hormone Concentration in Male and Adrenal Corticotrophic Hormone Concentration in Female Weanling Rats

Circulating levels of thyroid-stimulating hormone (TSH), growth hormone (GH), adrenal corticotrophic hormone (ACTH) and prolactin (PRL) were assessed in suckling rats in the postweaning period after rats were fed diets that reflect the fat composition of a current infant formula with or without the addition of 1.2 g/100 g fatty acid arachidonic acid [20:4(n-6)] and 0.7 g/100 g fatty acid docosahexaenoic acid [22:6(n-3)] or both 20:4(n-6) and 22:6(n-3). At 2 wk of age, no effect of diet on circulating levels of TSH, ACTH, GH or PRL was apparent. By 6 wk of age (3 wk postweaning), male rats consuming the diet containing 22:6(n-3) had significantly elevated levels of TSH, and females had significantly higher ACTH concentrations than males. No effect of diet was observed on circulating GH or PRL levels. Male pups had higher levels of TSH than females (P < 0.0001), whereas female pups from the 22:6(n-3) diet treatment exhibited much higher levels of ACTH than all male pups from any of the other diet treatments. These results suggest that metabolic controls, functioning through endocrine mechanisms, can be altered by changing the 20:4(n-6) to 22:6(n-3) balance in the diet.

Quantitative morphological analysis of the pituitary gland in protein‐calorie malnourished rats

A quantitative analysis of the pituitary gland was conducted to ascertain the effects of protein-calorie malnutrition on the morphology of the somatotrophs, gonadotrophs, thyrotrophs, and corticotrophs. Male rats were fed a low, 8% protein diet from 20 to 50 days of age, while their age-matched controls were given a diet containing 27% protein. The hypophyses were then processed for light microscopic immunocytochemical staining using antibodies to growth hormone, the beta subunits of luteinizing hormone and thyroid stimulating hormone, and adrenal corticotrophic hormone. The number of each cell type along with an evaluation of the cell, cytoplasmic, and nuclear areas was conducted using a computerized image analyzer. All of these parameters were reduced significantly in the somatotrophs as a result of the low protein diet, while in the gonadotrophs, the cell, cytoplasmic, and nuclear areas were similarly affected. Smaller cell number, cell area, and nuclear area were noted in the corticotrophs of the malnourished animals, while in the thyrotrophs, only the cell and nuclear areas were reduced. The data demonstrate that each pituitary cell type responds in a unique manner to undernutrition.

Visual function before and after ACTH therapy for vision loss in multiple sclerosis

The visual function of a patient with multiple sclerosis (MS) was evaluated by visually evoked cortical potentials (VEPs) and the contrast sensitivity function (CSF) before and after adrenal corticotrophic hormone (ACTH) therapy for an acute exacerbation of the condition. Although Snellen visual acuity returned to normal in each eye, steady-state pattern reversal VEP waveforms remained degraded long after therapy and monocular CSFs were reduced unequally 18 days after therapy, and even three years later. On the other hand, flash VEPs, recorded within three weeks of ACTH therapy, showed an improvement that parallelled the patient's overall improvement which appeared to be associated with the ACTH therapy. These observations indicate that MS can affect spatial and temporal channels differentially, reinforce the previously reported clinical utility of VEPs for the diagnosis of MS, and suggest that they may be simple, clinically useful, objective indices of the effectiveness of any interventive medical management of the disease. Language: en

Dopaminergic Supersensitivity Factors in Tourette's Syndrome: A Hypothesis

Alterations in striatal dopamine receptor functions are thought to underlie the major symptoms of Tourette's syndrome (TS). In this communication, evidence is presented to suggest that the striatal dopamine receptor supersensitivity in TS may be mediated by alterations in the release and function of dopamine supersensitive factors including prolactin, estrogens, beta-endorphin, melanocyte stimulating hormone (MSH), and adrenal corticotrophic hormone (ACTH). It is suggested that treatment of TS should be directed towards rectifying these endocrine and neuropeptide imbalances.

Pro-opiomelanocortin peptides in the human fetal pituitary

Levels of immunoreactive pro-opiomelanocortin (POMC) peptides (N- and C-terminal ACTH, N- and C-terminal LPH and α-MSH) have been measured in pituitary extracts from human fetuses of 12–22 weeks gestation. The levels of ACTH were 30–200 times higher than α-MSH in all fetuses studied. Sephadex G-75 and G-25 chromatography of 8 extracts showed peaks of 34 kilodaltons (K) POMC, 22K ACTH, β-LPH, γ-LPH, β-endorphin, approximately 8K ACTH, 1–39 ACTH, α-MSH and CLIP. The 8K and 22K forms of ACTH are both partly glycosylated. In vitro culture of pituitaries from 2 fetuses (22 and 26 weeks gestation) gave a detectable basal output of ACTH but not of α-MSH. Stimulation of these pituitary cells with human fetal and rat hypothalamic extracts and with synthetic ovine CRF-41 produced a significant increase in ACTH release, and either small or undetectable amounts of α-MSH. These results demonstrate the presence of POMC-related peptides in early gestation human fetal pituitaries and suggest that ACTH, and not α-MSH, is the major corticotrophic hormone at this stage of gestation.

Basosquamous (transitional cloacogenic) carcinoma of the sigmoid colon

A case of basosquamous or so-called transitional cloacogenic carcinoma of the sigmoid colon, which arose above the pelvic brim at the peritoneal reflection, is reported. We were not able to find a report of this histologic type of tumor arising this far from the pectinate line of the anus, which is the most common primary site of this neoplasm. Possibilities as to the histogenesis of this tumor at this site are stated. The neoplasm also produced parathyroid hormone (PTH) and also possibly adrenal corticotrophic hormone (ACTH), which had not been previously reported for this specific neoplasm.

Histochemical and ultrastructural changes in rat muscle. Occurrence following adrenal corticotrophic hormone, glucocorticoids, and starvation.

THE SPECIFIC effects of glucocorticoids on muscle histology have attracted much attention since the recognition that these compounds could induce muscle weakness. Although there have been numerous reports of the light microscopic and ultrastructural changes in muscle under these circumstances, 1-10 they have not been correlated with the histochemical alterations. 11 Furthermore, the type of muscle fiber most severely affected has not been clarified, with considerable variation in these observations amongst various reports. 6,11,12 Part of this inconsistency can be attributed to the species variation of muscle, as measured by the morphological differences and by the pathological response to glucocorticoids. In this report, the enzyme histochemical and ultrastructural changes in rat muscle following adrenal corticotrophic hormone (ACTH), glucocorticoids, and starvation will be described, in addition to changes in average muscle fiber diameters. Materials and Methods Forty-eight Osborn-Mendel rats, weighing 237 to 494 gm, were used. The food containers and

Effects of calcium on ACTH stimulation of the adrenal: separation of hormone binding from adenyl cyclase activation.

CALCIUM is thought to be required for the binding of adrenal corticotrophic hormone (ACTH) to its cellular receptor1–5: in its absence, ACTH fails to stimulate steroidogenesis in the adrenal or lipolysis in adipose tissue1,2,6,7. The actions of other lipolytic hormones such as adrenaline and glucagon do not require calcium1–3. On the other hand, high calcium concentrations (>1 mM) inhibit the activation of adenyl cyclase by ACTH in subcellular particles from adipose and adrenal tissue8,9. The sites of these effects of calcium have not been unequivocally located.

Effect of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and adrenal corticotrophic hormone (ACTH) on steroidogenesis by intact and sectioned rat adrenals

When using a “closed system” of incubation the addition of NADP plus glucose-6-phosphate (G-6-P) to the incubation media increased the formation of corticosterone by quartered rat adrenals — 2-fold from 4- 14C-progesterone and 6-fold from endogenous precursors, but did not affect the production of corticosterone by whole glands. Similarly, in a continuous flow incubation the addition of NADP plus G-6-P increased the formation of corticosterone from quartered glands only, but not from intact glands, whereas the addition of ACTH stimulated corticosterone production by both the quartered and the whole adrenals. These observations are interpreted as indicating that the steroidogenic effect of NADP plus G-6-P on adrenal sections is limited to activation of enzymes in the incubation medium and stimulation of enzyme systems in damaged cells, whereas that of ACTH is on intact cells.