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1.  Role of AMP-Activated Protein Kinase on Steroid Hormone Biosynthesis in Adrenal NCI-H295R Cells 
PLoS ONE  2012;7(1):e30956.
Regulation of human androgen biosynthesis is poorly understood. However, detailed knowledge is needed to eventually solve disorders with androgen dysbalance. We showed that starvation growth conditions shift steroidogenesis of human adrenal NCI-H295R cells towards androgen production attributable to decreased HSD3B2 expression and activity and increased CYP17A1 phosphorylation and 17,20-lyase activity. Generally, starvation induces stress and energy deprivation that need to be counteracted to maintain proper cell functions. AMP-activated protein kinase (AMPK) is a master energy sensor that regulates cellular energy balance. AMPK regulates steroidogenesis in the gonad. Therefore, we investigated whether AMPK is also a regulator of adrenal steroidogenesis. We hypothesized that starvation uses AMPK signaling to enhance androgen production in NCI-H295R cells. We found that AMPK subunits are expressed in NCI-H295 cells, normal adrenal tissue and human as well as pig ovary cells. Starvation growth conditions decreased phosphorylation, but not activity of AMPK in NCI-H295 cells. In contrast, the AMPK activator 5-aminoimidazole-4-carboxamide (AICAR) increased AMPKα phosphorylation and increased CYP17A1-17,20 lyase activity. Compound C (an AMPK inhibitor), directly inhibited CYP17A1 activities and can therefore not be used for AMPK signaling studies in steroidogenesis. HSD3B2 activity was neither altered by AICAR nor compound C. Starvation did not affect mitochondrial respiratory chain function in NCI-H295R cells suggesting that there is no indirect energy effect on AMPK through this avenue. In summary, starvation-mediated increase of androgen production in NCI-H295 cells does not seem to be mediated by AMPK signaling. But AMPK activation can enhance androgen production through a specific increase in CYP17A1-17,20 lyase activity.
doi:10.1371/journal.pone.0030956
PMCID: PMC3266282  PMID: 22295121
2.  THE NATURE AND SIGNIFICANCE OF CHANGES IN ADRENAL CYTOLOGY, WEIGHT, AND CORTICAL/MEDULLARY RATIO IN EXPERIMENTAL RENAL HYPERTENSION AND CLINICAL HYPERTENSION 
There is a direct proportionality between the degree of adrenal and that of cardiac enlargement in experimental renal hypertension. This is evidence for the participation of the adrenal to an extent dependent on the severity of the hypertension as reflected in the degree of cardiac hypertrophy. The greater part of the weight increase of the adrenal is due to growth of the cortex. However, the relative degree of medullary growth exceeds that of cortical growth. There is evidence of medullary hyperplasia, but the cortical growth may be due to cell hypertrophy alone. In view of the known relationship between prolonged skeletal muscle work and the size of the adrenals, in which there is likewise a relatively greater growth of the medulla, the possibility that adrenal growth in experimental renal hypertension is a consequence of the metabolic demand of increased heart muscle work must be considered. The hyperplastic, hypertrophic medulla of the renal hypertensive rat is presumed to be producing increased amounts of a hormone whose action is not known. The adrenal medulla is not necessary for the development of moderate renal hypertension though this does not exclude the possibility that it may be involved somehow in the maintainance of the hypertensive state. Large, periodic-Schiff-positive, hyaline droplets are found in the cytoplasm of adrenal cortical cells with nuclear evidence of active function. There is some evidence that these indicate hypophyseal stimulation. Similar particles are found in the medulla, suggesting an interrelationship between the two parts of the adrenal. The close resemblance of changes in adrenal weight, nuclear/cytoplasmic ratio, and nuclear and cytoplasmic structure, indicates that similar physiological and morphological controlling mechanisms are involved in the pathogenesis and maintainance of experimental renal hypertension and clinical essential hypertension.
PMCID: PMC2136066  PMID: 14832403
3.  ADRENIC ACID METABOLITES AS ENDOGENOUS ENDOTHELIUM- AND ZONA GLOMERULOSA-DERIVED HYPERPOLARIZING FACTORS 
Hypertension  2009;55(2):547.
Adrenic acid (docosatetraenoic acid), an abundant fatty acid in the adrenal gland, is identical to arachidonic acid except for two additional carbons on the carboxyl end. Adrenic acid is metabolized by cycloxygenases, cytochrome P450s, and lipoxygenases; however, little is known regarding the role of adrenic acid and its metabolites in vascular tone. Due to its abundance in the adrenal gland, we investigated the role of adrenic acid in vascular tone of bovine adrenal cortical arteries and its metabolism by bovine adrenal zona glomerulosa cells. In adrenal cortical arteries, adrenic acid caused concentration-dependent relaxations, which were inhibited by the epoxyeicosatrienoic acid antagonist 14,15-epoxyeicosa-5(Z)-enoic acid and the cytochrome 450 inhibitor SKF-525A. The large-conductance calcium-activated potassium channel channel blocker iberiotoxin or removal of the endothelium abolished these relaxations. Reverse-phase high-pressure liquid chromatography and liquid chromatography/mass spectrometry isolated and identified numerous adrenic acid metabolites from zona glomerulosa cells including dihomo-epoxyeicosatrienoic acids and dihomo-prostaglandins. In denuded adrenal cortical arteries, adrenic acid caused concentration-dependent relaxations in the presence of zona glomerulosa cells but not in their absence. These relaxations were inhibited by SKF-525A, 14,15-epoxyeicosa-5(Z)-enoic acid, and iberiotoxin. Dihomo-16,17-epoxyeicosatrienoic acid caused concentration-dependent relaxations of adrenal cortical arteries, which were inhibited by 14,15-epoxyeicosa-5(Z)-enoic acid and high potassium. Our results suggest that adrenic acid relaxations of bovine adrenal cortical arteries are mediated by endothelial and zona glomerulosa cell cytochrome P450 metabolites. Thus, adrenic acid metabolites could function as endogenous endothelium- and zona glomerulosa-derived hyperpolarizing factors in the adrenal cortex and contribute to the regulation of adrenal blood flow.
doi:10.1161/HYPERTENSIONAHA.109.144147
PMCID: PMC2819927  PMID: 20038752
endothelium-dependent relaxation; cytochrome P450; epoxygenase; cyclooxygenase; potassium channels; endothelium-derived hyperpolarizing factor; adrenal cortex
4.  EXPERIMENTAL IMMUNOLOGIC ADRENAL INJURY  
Twenty-three unilaterally adrenalectomized guinea pigs were injected with autologous and homologous adrenal tissue homogenates respectively, in Freund's adjuvant. Widespread adrenal lesions were found in 10 of 12 animals receiving auto-antigen and to a lesser extent in 6 of 11 animals injected with homologous pooled antigen. Widespread systemic lesions were present in both these and in control animals receiving Freund's adjuvant alone. These latter animals showed no adrenal involvement. The early changes within the adrenal consisted of perisinusoidal cellular proliferations in the deeper layers of the cortex. Focal granulomata developing at a later stage tended to become confluent and to displace cortical cells. Some loss of these cells was attributable to ischemic injury. The localization in the deep fasciculata and reticularis was thought to depend (a) on the varying antigenicity of adrenal cortical components, (b) the possible inhibitory effect of antiphlogistic adrenal cortical hormones on the development of lesions in the outer cortex, and (c) the presence of littoral cells in the deep cortex. These cells are thought to be involved in the mediation of the stimulus initiating differentiation of primitive mesenchymal cells in response to a circulating auto-antigen. The medullary lesions may be related to the presence of ectopic reticularis cells in this location. It was suggested that the cellular response in the target organ to injections of adrenal homogenates may denote a specific "organ-self" recognition mechanism involving an immune (i.e. defensive) reaction. It was postulated that this may be an accentuation of the physiological function of immunologically competent cells. Their proliferation, under normal circumstances, would prevent by means of production of "binding" globulins, the escape and dissemination of endogenous freed adrenal antigens into the circulation. Although the experimental stimulus arose from without the gland, by virtue of the presence of a circulating adjuvant-bound antigen, the adrenal reaction followed the same pattern as would obtain if the antigen was liberated within the suprarenal cortex.
PMCID: PMC2137215  PMID: 19867172
5.  Steroid hormone receptors ERα and PR characterised by immunohistochemistry in the mare adrenal gland 
Background
Sex steroid hormone receptors have been identified in the adrenal gland of rat, sheep and rhesus monkey, indicating a direct effect of sex steroids on adrenal gland function.
Methods
In the present study, immunohistochemistry using two different mouse monoclonal antibodies was employed to determine the presence of oestrogen receptor alpha (ERalpha) and progesterone receptor (PR) in the mare adrenal gland. Adrenal glands from intact (n = 5) and ovariectomised (OVX) (n = 5) mares, as well as uterine tissue (n = 9), were collected after euthanasia. Three of the OVX mares were treated with a single intramuscular injection of oestradiol benzoate (2.5 mg) 18 – 22 hours prior to euthanasia and tissue collection (OVX+Oe). Uterine tissue was used as a positive control and showed positive staining for both ERalpha and PR.
Results
ERalpha staining was detected in the adrenal zona glomerulosa, fasciculata and reticularis of all mare groups. Ovariectomy increased cortical ERalpha staining intensity. In OVX mares and one intact mare, positive ERalpha staining was also detected in adrenal medullary cells. PR staining of weak intensity was present in a low proportion of cells in the zona fasciculata and reticularis of all mare groups. Weak PR staining was also found in a high proportion of adrenal medullary cells. In contrast to staining in the adrenal cortex, which was always located within the cell nuclei, medullary staining for both ERalpha and PR was observed only in the cell cytoplasm.
Conclusion
The present results show the presence of ERalpha in the adrenal cortex, indicating oestradiol may have a direct effect on mare adrenal function. However, further studies are needed to confirm the presence of PR as staining in the present study was only weak and/or minor. Also, any possible effect of oestradiol treatment on the levels of steroid receptors cannot be determined by the present study, as treatment time was of a too short duration.
doi:10.1186/1751-0147-51-31
PMCID: PMC2727514  PMID: 19624811
6.  Urinary Concentrating Defect of Adrenal Insufficiency 
Journal of Clinical Investigation  1980;66(2):234-242.
Mineralo- and glucocorticoid-deficient states, such as Addison's disease, are partly characterized by an inability to generate a maximally concentrated urine. The purpose of the present study was to develop a model of adrenal insufficiency and to determine whether changes in the intrinsic function of the collecting duct could partly account for this concentrating defect. Two kinds of experiments were performed: an assessment of the in vivo ability of adrenal-ectomized rabbits to concentrate their urine, and an examination of the intrinsic hydroosmotic responsiveness of in vitro perfused collecting ducts isolated from normal and adrenalectomized rabbits. The present study demonstrates that adrenalectomized rabbits are unable to concentrate their urine maximally, and that the in vivo administration of either deoxycorticosterone, 250 μg/kg, or dexamethasone, 50 μg/kg, restored to or toward normal their concentrating ability. When cortical collecting tubules from adrenalectomized rabbits were perfused in vitro, they demonstrated a markedly blunted hydroosmotic response to antidiuretic hormone (ADH), which was corrected by the in vitro addition of either aldosterone (50 pM) or dexamethasone (50 pM), but not progesterone (50 pM). The steroids by themselves, in the absence of ADH, had no intrinsic effect on the water permeability of the collecting duct. The blunted hydroosmotic response across cortical collecting tubules from adrenal-ectomized rabbits was corrected by the addition of either 8-bromo cyclic AMP or a potent phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine. The present studies show that the cortical collecting tubules obtained from adrenalectomized rabbits do not respond normally to ADH. The poor hydroosmotic response to ADH was corrected by exogenous aldosterone, dexamethasone, an analog of cyclic AMP, or a phosphodiesterase inhibitor. In conclusion, the present studies are consistent with the view that the concentrating defect seen in adrenal insufficiency is at least partly the result of the absence of the permissive effect that adrenal steroids exert on the ADH-induced reabsorption of water across the collecting duct. The absence of adrenal steroids results in a diminished rate of cyclic AMP accumulation in the cells of the collecting duct, either as a result of an augmented activity of cyclic AMP phosphodiesterase or a diminished rate of cyclic AMP generation.
PMCID: PMC371703  PMID: 6156951
7.  SERIAL RENAL CLEARANCES IN DOGS WITH NEPHROGENIC AND SPONTANEOUS HYPERTENSION 
Evidence is presented on the occurrence of spontaneous hypertension in dogs. All dogs with spontaneous hypertension exhibited normal renal plasma flow and glomerular filtration rate. Clearances on nephrogenic hypertensive dogs revealed that some exhibited normal kidney function, while others had significant depression of renal plasma flow and glomerular filtration rate. In the latter, the filtration fraction may or may not be elevated. Serial renal clearances were done at intervals on 3 dogs with spontaneous hypertension during their 3rd year of known hypertension. They exhibited no tendency to develop impaired renal function in the face of prolonged benign hypertension. Serial renal clearances on nephrogenic hypertensive dogs revealed no tendency for kidney function to become progressively impaired. This was true, whether the immediate postoperative clearance values were normal or depressed. It was also true regardless of the duration of the hypertension. It is suggested that mechanisms other than elevated blood pressure per se operate to produce progressive kidney damage and impairment of renal function. No tendency was revealed over the course of a year or more for the kidney function to improve in Goldblatt dogs exhibiting depressed clearances immediately postoperatively. This is interpreted as evidence against the postoperative development in persistently hypertensive Goldblatt dogs of a renal collateral circulation sufficient to augment significantly effective renal blood flow. Pathological studies on 2 dogs with spontaneous hypertension revealed slight to moderate chronic focal lesions in the kidneys, and bilateral adrenal cortical adenomatous hyperplasia. Both lesions may have no pathogenetic significance. In accord with previous observations, autopsies on 3 Goldblatt dogs revealed minimal renal changes in one, and unilateral kidney atrophy with contralateral hypertrophy in the 2 others. The adrenals were normal. In general, data on renal clearances showed correlation with postmortem kidney findings. However, normal renal clearances are found in the presence of anatomically abnormal kidneys. The findings in canine spontaneous and nephrogenic hypertension are compared and contrasted with data obtained in human essential hypertension. Pathogenetic relationships are discussed.
PMCID: PMC2135930  PMID: 15394070
8.  A rare cavernous hemangioma of the adrenal gland☆ 
INTRODUCTION
Cavernous hemangiomas of the adrenal gland are rare. We report a case of a cavernous hemangioma of the adrenal gland presenting as an adrenal incidentaloma suspicious for adrenal cortical carcinoma (ACC).
PRESENTATION OF CASE
A 78 year old woman was admitted after a fall. Abdominal computed tomography revealed a large right adrenal lesion with features suspicious for adrenal cortical carcinoma (5.4 cm × 3.3 cm, unilateral, tumor calcifications, average Hounsfield units 55). The tumor was removed intact by a laparoscopic approach and pathology revealed a cavernous hemangioma of the adrenal gland.
DISCUSSION
Adrenal incidentalomas are found in up to 10% of patients undergoing abdominal imaging. Differential diagnosis includes both benign and malignant lesions. Guidelines for removal of adrenal incidentalomas recommend surgery based on functional status, size, and presence of concerning features on diagnostic imaging. Cavernous hemangiomas are rare, benign vascular malformations which can be challenging to distinguish pre-operatively from malignant lesions such as ACC.
CONCLUSION
Cavernous hemangiomas of the adrenal gland are exceedingly rare. These benign tumors have imaging features which may be suggestive of adrenal cortical carcinoma. The treatment of choice is surgical excision due the difficulty of excluding malignancy.
doi:10.1016/j.ijscr.2013.11.003
PMCID: PMC3921650  PMID: 24441435
Adrenal; Cavernous hemangioma; Adrenal cortical carcinoma
9.  The Perilipin Homologue, Lipid Storage Droplet 2, Regulates Sleep Homeostasis and Prevents Learning Impairments Following Sleep Loss 
PLoS Biology  2010;8(8):e1000466.
Starvation, which is common in the wild, appears to initiate a genetic program that allows fruitflies to remain awake without the sleepiness and cognitive impairments that typically follow sleep deprivation.
Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. Recently, two genes, brummer (bmm) and Lipid storage droplet 2 (Lsd2), have been shown to modulate the response to starvation. bmm mutants have excess fat and are resistant to starvation, whereas Lsd2 mutants are lean and sensitive to starvation. Thus, we hypothesized that bmm and Lsd2 may play a role in sleep regulation. Indeed, bmm mutant flies display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking.
Author Summary
It is well established in humans that sleep deficits lead to adverse outcomes, including cognitive impairments and an increased risk for obesity. Given the relationship between sleep and lipid stores, we hypothesized that metabolic pathways play a role in sleep regulation and contribute to deficits induced by sleep loss. Since starvation has a large impact on metabolic pathways and is an environmental condition that is encountered by animals living in the wild, we examined its effects on sleep in the fruit fly Drosophila melanogaster. Interestingly, when flies are starved they display an immediate increase in waking. However, in contrast to sleep deprivation, waking induced by starvation does not result in increased sleepiness or impairments in short-term memory. To identify the mechanisms underlying these processes, we evaluated mutants for genes that have been shown to alter an animal's response to starvation. Interestingly, brummer mutants, which are fat, show an exaggerated response to sleep loss. In contrast, mutants for Lipid storage droplet 2 are lean and are able to stay awake without becoming sleepy or showing signs of cognitive impairment. These results indicate that while sleep loss can alter lipids, lipid enzymes may, in turn, play a role in regulating sleep and influence the response to sleep deprivation.
doi:10.1371/journal.pbio.1000466
PMCID: PMC2930866  PMID: 20824166
10.  OPERATIVE AND POSTOPERATIVE EMERGENCY USE OF HYDROCORTISONE DERIVATIVES AND CORTICOTROPIN 
California Medicine  1957;86(6):374-377.
Impairment of adrenal function is a great hazard to patients undergoing major operation. The most important adrenal steroids are glucocorticoids (hydrocortisone), 17-ketosteroids, mineralo-corticoids (aldosterone), and small amounts of estrogen and progesterone. Urinary output of 17-hydroxycorticoids reflects overall adrenal cortical activity. Under severe stress this output increases greatly.
Adrenal replacement therapy is facilitated by the advent of more powerful and more soluble adrenal hormone derivatives. Hydrocortisone hemisuccinate sodium is the agent of choice in surgical emergencies and for management of bilateral adrenalectomy. Fatal adrenal crisis may develop during operation in patients receiving hydrocortisone for long periods of time. Hydrocortisone may be of help in unresponsive shock not due to loss of blood. The usual side effects of the corticoids can be controlled easily.
PMCID: PMC1511944  PMID: 13426811
11.  THE INFLUENCE OF THE ADRENAL GLANDS ON RESISTANCE  
1. The majority of rats (Mus norvegicus), because of accessory cortical tissue, will survive double adrenalectomy indefinitely under optimum conditions. 2. Resistance to morphine is greatly diminished in healthy adrenalectomized rats tested before hypertrophy of the accessories occurs. 3. This greater sensitiveness seems to be due to some fundamental alteration in metabolism dependent on a partial adrenal insufficiency. Protocol 1.—Rat 13; brown and white, male. Sept. 15, 1922. In stock. Sept. 18. Active, vigorous, and very vicious. Weight 281 gm. Operation, double adrenalectomy. Prompt recovery. Sept. 21. Very active and vicious. Sept. 22. Jumps viciously this morning on opening the cage. This afternoon, quiet and marked diarrhea. Transferred to individual cage. Eating nothing. Sept. 23, Diarrhea. Quiet, Sept. 24. Diarrhea diminished, more active, but is not vicious. Appetite poor, ate 5 gm, Sept. 25. Diarrhea, ate nothing. Sept. 26. Diarrhea still marked, ate nothing. Died this afternoon. Autopsy.—Weight 215 gm. Thyroid, heart, and lungs normal. Abdomen: intra-abdominal fat almost completely gone. Adrenals absent. Stomach: definite multiple minute hemorrhages in the mucous membrane throughout the pyloric part. Intestines: several loops of small gut deep red in color. Liver: nutmeg color. Protocol 2— Rat 43; white, male. Oct. 20, Active. Weight, 236 gm. Operation, excision of right adrenal and excision of piece of pancreas near left adrenal. Moderate bleeding. Oct. 22. Has not eaten since operation. Oct. 23. Active, beginning to eat. Oct. 27. Active,, eating well now. Slight diarrhea. Weight, 222 gm. At 11:10 a.m. injected subcutaneously with 1.78 cc. of 1 per cent morphine sulfate solution ( = 80 mg. per kg.). 1:30 p.m., quiet. 6 p.m., recovering. Oct. 28. Active, eating well. Nov. 10. In good condition. Sacrificed Jan. 8. Right adrenal absent, left adrenal intact. Protocol 3.— Rat 42; white, male. Oct. 20, Active. Weight, 320 gm. Operation, excision of both adrenals, much abdominal fat. Oct. 21. Ate 10 gm. of food. Oct. 22. Active, ate all of food (15 gm.). Oct. 27. Active. Weight, 310 gm. At II a.m. injected subcutaneously 0.62 cc. of 1 per cent morphine sulfate solution (= 20 mg. per kg.). 1:30 p.m., marked pilomotor effect. Did not move. 6 p.m., very quiet. Oct. 28. Very quiet, not eating. Oct. 29. Quiet. Ate a little today. Oct. 30. Very dull, not eating. 5 p.m., comatose. 9:30 p.m., found dead. Autopsy.—Weight 277 gm. Diarrhea. Thyroid large and dark red. Heart and lungs normal. Abdomen: scant fat. Both adrenals absent. No accessories seen. Right testicle congested. Liver and spleen normal. Stomach: one hemorrhage beneath mucosa near fundus. Prolocol4.—Rat 21;white and brown,male. Sept-27. Active. Weight345gm. Operation, excision of left adrenal, easy operation. Oct. 4. Active, eating well. Weight 333 gm. At 10:48 a.m. injected 0.75 cc. of 2 per cent morphine sulfate intravenously ( = 45 mg. per kg.). 10:50 a.m. respirations imperceptible. Board-like rigidity. 11:10 a.m. respirations very shallow. Complete coma. 1 p.m. condition gradually improving. Oct. 5. Alert and active, eating well. Oct. 11. Active, eating well (15 gm. per day). Weight 335 gm. Operation, excision of right adrenal. Easy operation, no hemorrhage. Moderate fat. Oct. 18. Excellent condition, active, good appetite. Weight 321 gm. At 3:50 p.m. injected 0.74 cc. of 1 per cent morphine sulfate intravenously ( = 23 mg. per kg.). 3:52 p.m. respirations imperceptible for a minute, and rat is stiff. 3:57 p.m. voluntary movement. Oct. 19. 9 a.m. very quiet. Marked ruffling of fur. Not eating. 6 p.m. very quiet and dopey. Oct. 20. Found dead this morning. Autopsy.—Well preserved fat. Diarrhea. Thyroid rather large and red. Heart and lungs normal. Abdomen: both adrenals absent. No accessories seen. Stomach: five distinct hemorrhages into mucous membrane, one is 3 x 4 mm. Protocols 5.—Rat 24; white and gray, male. Sept. 27. Active. Weight 320 gm. Operation: double adrenalectomy. Easy operation. Sept. 29. Eating well, alert. Oct. 2. Active, ate 12 gm. Weight 318 gm. Oct. 3. Ate 10 gm. Oct. 4. Active. Weight 311 gm. Ate 12 gm. At 10:30 a.m. injected 0.28 cc. of 1 per cent morphine sulfate intravenously (= 9 mg. per kg.). Became quiet but did not stop breathing. 5 p.m. quiet and fur ruffled. Oct. 5, very quiet. Eyes closed most of time. Hunched up, fur ruffled. Drinks with eyes closed. Not eating. Oct. 6. Head between front paws most of time. Pilomotor reaction marked. Oct. 7. Condition about the same. Has eaten nothing since operation. Oct. 8. Seems slightly more active, not eating. Oct. 9. Ate 5 gm. of food, first since injection. Oct. 10. Very drowsy. Stools firm and white. Not eating. Oct. 14. Very weak. Has not eaten 10 gm. since injection. Oct. 15. Found dead this morning. Autopsy.—Weight 240 gm. Thyroid moderate size. Heart in systole. Lungs normal. Abdomen: adrenals absent. No accessories seen. Left testis converted into a sack filled with dark red grumous material. Right testis atrophied. Stomach: postmortem change.
PMCID: PMC2128485  PMID: 19868809
12.  RESULTS OF LONG-CONTINUED CORTISONE ADMINISTRATION IN RHEUMATOID ARTHRITIS 
California Medicine  1951;74(6):416-423.
The administration of cortisone acetate to patients with rheumatoid arthritis usually produces prompt and often dramatic suppression of the disease manifestations. The effects of the hormone are not lasting, however, and after withdrawal relapse ensues. For sustained improvement in a chronic disease such as rheumatoid arthritis, it appears that cortisone must be given more or less continuously. This raises the question whether administration may be continued effectively and safely for long periods.
Seventy-six patients with rheumatoid arthritis were given cortisone in the hope that treatment could be continued uninterruptedly for extended periods. For various clinical reasons it was necessary to discontinue treatment in 16 of these before six months, but the remaining 60 patients received the hormone uninterruptedly for six to 15 months. By using initial large suppressive amounts, then gradually reducing the dosage, and finally employing smaller maintenance doses, adequate degrees of rheumatic control were maintained in approximately two-thirds of the original 76 patients. The ability to sustain satisfactory improvement varied indirectly, in general, with the severity of the rheumatoid arthritis. The chief detriment to better results in the more severe cases was the intervention of adverse hormonal side effects which developed frequently when large or relatively large maintenance doses were required to support satisfactory improvement.
Unwanted signs of hormonal excess developed in 40 per cent of cases at some time during the course of treatment. Most of them were mild or transient and disappeared or lessened when the dose of cortisone was reduced, but when the dose was reduced the degree of improvement often declined also.
During prolonged cortisone therapy evidence of functional suppression of the adrenal cortices, as indicated by a decreased response of circulating eosinophils to exogenous ACTH, was present. The depression of cortical function was temporary, however. Whether irreversible damage may result when the drug is employed for longer periods cannot yet be answered.
PMCID: PMC1520676  PMID: 14848703
13.  Control and localization of rat adrenal cyclic guanosine 3', 5'-monophosphate. Comparison with adrenal cyclic adenosine 3', 5'-monophosphate. 
Journal of Clinical Investigation  1975;56(1):146-154.
Cyclic AMP and cyclic GMP were measured in rat adrenal glands after either hypophysectomy alone or after hypophysectomy and treatment with ACTH. Adrenal cyclic GMP levels rise in acutely hypophysectomized rats to a maximum at 1 h of approximately 200% of control levels; there is a return to base line at 4-12 h after hypophysectomy. In contrast, adrenal cyclic AMP falls immediately to about 50% of control levels after hypophysectomy and remains at approximately 1 pmol per mg tissue. Doses of ACTH beyond the physiological range markedly suppress adrenal cyclic GMP while producing a 50-fold or greater rise in cyclic AMP in hypophysectomized rats. This pattern of adrenal cyclic GMP rise was unchanged in acutely hypophysectomized animals treated with desamethasone. N-6-2'-0 dibutyryl cyclic AMP acted similarly to the effect of ACTH in bringing about a suppression of adrenal cyclic GMP levels. Physiological i.v. pulse doses of ACTH produced a rapid dose related increase in adrenal cyclic GMP. In vitro incubation of quartered adrenal pairs with 500 mU ACTH produced elevated cyclic AMP levels and suppression of cyclic GMP. Whereas adrenal cyclic AMP fell rapidly to 50% of control levels after hypophysectomy and remained at about 1 pmol per mg tissue for 7 days, adrenal cyclic GMP showed a biphasic rhythm in long-term hypophysectomized animals. After an initial peak at 1 h after hypophysectomy, adrenal cyclic GMP declined to baseline at 4-12 h but thereafter progressively rose with time, eventually reaching levels over 1 pmol per mg tissue. Fluorescent immunocytochemical staining of rat adrenal zona fasciculata showed cyclic AMP largely confined to cytoplasmic elements with little fluorescence contained in nuclei. In constant, cyclic GMP was found discretely positioned in nuclei with prominent fluorescence in nucleoli in addition to cytoplasmic localization. It is concluded that in hypophysectomized rats ACTH, either directly or in conjunction with altertion of adrenal cyclic AMP, appears to be one factor which regulates adrenal cyclic GMP. The direction of cyclic GMP change and the different subcellular localization of the nucleotides suggest divergent roles for cyclic AMP and cyclic GMP in adrenocortical function. Furthermore, our observations suggest a role for adrenal cyclic GMP in nuclear directed events.
Images
PMCID: PMC436565  PMID: 167054
14.  Investigating the Role of Adrenal Cortex in Organization and Differentiation of the Adrenal Medulla in Mice 
Molecular and cellular endocrinology  2012;361(1-2):165-171.
Functions of adrenal medulla, particularly synthesis of catecholamine, are under the control of glucocorticoids. To further investigate whether development/differentiation of the adrenal medulla is associated with proper organization of the adrenal cortex, we examined development of the medulla in four different mouse models with various defects in the adrenal cortex. By using the Sf1/Cre mouse line that inactivates/activates genes in Steroidogenic factor 1 (SF1)-positive cells of the fetal adrenal cortex, we produced mice that exhibit either 1) cortex hypoplasia, 2) progressive degeneration of fetal adrenal cortex, 3) cortex dysgenesis, or 4) cortex-medulla disorganization. The formation of phenylethanolamine N-methyltransferase (PNMT)-positive medulla in all models indicating that differentiation of adrenal medulla is independent of the growth of adrenal cortex. However, the misplaced/dysgenic medulla which is outside of adrenal proper, indicating that the beta-catenin pathway in the adrenal cortical cells plays an indirect role in controlling proper organization of the adrenal medulla.
doi:10.1016/j.mce.2012.04.004
PMCID: PMC3409340  PMID: 22580128
adrenal cortex; adrenal medulla; beta-catenin; Sonic hedgehog; Dicer1
15.  THE EFFECTS OF CORTISONE AND ADRENOCORTICOTROPIC HORMONE (ACTH) ON CERTAIN RHEUMATIC DISEASES 
California Medicine  1950;72(6):405-414.
The adrenal cortical hormone, cortisone, and the pituitary adrenocorticotropic hormone (ACTH) possess potent antirheumatic properties. Their administration produces strikingly beneficial effects on a number of rheumatic diseases including rheumatoid arthritis, rheumatoid (ankylosing) spondylitis, acute rheumatic fever, disseminated lupus erythematosus, periarteritis nodosa, psoriatic arthritis, dermatomyositis, and gout. In general the effects of these substances are temporary and they cause suppression rather than cure of the disease processes. Improvement is maintained usually only by continuing administration, and on hormonal withdrawal prompt or fairly prompt relapse of the disease manifestations ensues. In addition to their antirheumatic effects cortisone and ACTH influence a wide variety of physiologic functions. Administration of them therefore may produce a number of metabolic and clinical changes, some of which are not advantageous from a therapeutic standpoint. Adverse side-reactions are more liable to occur when large doses of the hormones are given for prolonged periods; such reactions appear to be reversible and disappear when administration of the hormones is stopped. With cortisone, comparatively few untoward signs develop when smaller amounts are administered continuously even for periods of months.
Greater clinical experience is needed before optimal doses and schedules of administration are finally determined. It appears that some severe cases, many moderately severe cases, and most moderate and mild cases of rheumatoid arthritis may be adequately controlled with smaller “maintenance” doses of cortisone ranging from 32 to 65 mg. a day, providing larger doses to suppress the disease manifestations are employed initially.
Neither cortisone nor ACTH should be considered as a therapeutic agent for general use until more information regarding their physiologic activities and the consequences of prolonged or repeated administration of them are available. Until the potential dangers of these hormones can be determined precisely, the use of them should be considered as an investigative procedure.
PMCID: PMC1520365  PMID: 15414440
16.  Adrenal imaging (Part 1): Imaging techniques and primary cortical lesions 
Adrenal glands can be affected by a variety of lesions. Adrenal lesions can either be primary, of adrenal origin, or secondary to other pathologies. Primary adrenal lesions can further be either of cortical or medullary origin. Functioning adrenal lesions can also give clues to the histologic diagnosis and direct workup. Over the years, various imaging techniques have been developed that have increased diagnostic accuracy and helped in better characterization of adrenal lesions non-invasively. In the first part of the two part series, we review adrenal imaging techniques and adrenal cortical tumors such as adenomas, adrenocortical tumors, adrenal hyperplasia and oncocytomas.
doi:10.4103/2230-8210.146858
PMCID: PMC4287786  PMID: 25593820
Adrenal adenoma; adrenal cancer; adrenal imaging; adrenocortical carcinoma
17.  Quantitative Relations of Fetal and Maternal Pitiutary - Adrenal Systems I. EFFECTS OF MATERNAL HYPOPHYSECTOMY 
Journal of Clinical Investigation  1973;52(12):3154-3160.
Even though certain aspects of the fetal pituitary-adrenal system have been extensively studied, much remains to be learned of its basic development and function. In the present work, the effect of maternal hypophysectomy upon quantitative pituitary-adrenal relations in mother and fetus was investigated in pregnant beagle dogs. At 57 days gestation in each of seven normal animals and seven animals 3 wk posthypophysectomy, a cannula for collection of adrenal effluent was placed in a single fetus in utero under halothane anesthesia. A timed fetal adrenal sample was obtained; ACTH (10 mU) was injected into the fetus; 3 min thereafter a second fetal adrenal sample was collected and fetal and maternal peripheral arterial samples were drawn. All fetuses and their adrenal glands were weighed. Concentrations of cortisol and corticosterone were determined by a modification of the double-isotope dilution derivative method of Kliman and Peterson.
Mean peripheral cortisol concentrations in mother and fetus were 92 and 94 ng/ml, respectively (ratio 1.0), in normal pregnancies and 11 and 54 ng/ml, respectively (ratio 0.2), in maternal hypophysectomy pregnancies. Weights of fetal adrenal gland pairs of 32 and 44 mg, respectively, in normal and hypophysectomy pregnancies indicate increased fetal ACTH secretion in response to lowered circulating cortisol in the fetus secondary to maternal hypophysectomy. These data demonstrate the presence of an active pituitary-adrenal feedback mechanism in the dog fetus which is partly influenced by maternal pituitary-adrenal function. The shift in the maternal-fetal ratio of peripheral cortisol concentrations from 1.0 to 0.2 occasioned by maternal hypophysectomy neither supports nor rules out the presence of specific placental mechanisms affecting relative concentrations of cortisol in mother and fetus. It does suggest, however, that the relative steroid input into maternal and fetal compartments is one of the factors which influences such concentration ratios. Concentrations of cortisol were significantly higher in fetal adrenal effluent (pre-ACTH) than in fetal peripheral plasma in normal pregnancies, which demonstrates secretion of cortisol by the fetus and shows that corticosteroid of maternal origin does not lead to complete suppression of fetal pituitary-adrenal function. Cortisol secretion rates in response to exogenous ACTH were essentially the same in fetuses in normal and hypophysectomy pregnancies (132 and 128 ng/min, respectively). Thus, fetal adrenal responsiveness to ACTH, i.e., maximum secretory capacity, is not enhanced by increased ACTH stimulation sufficient to induce adrenal hypertrophy in the same fetuses.
Images
PMCID: PMC302591  PMID: 4356264
18.  Immunohistochemical staining of normal, hyperplastic, and neoplastic adrenal cortex with a monoclonal antibody against alpha inhibin. 
Journal of Clinical Pathology  1998;51(2):114-116.
AIMS: To investigate the immunohisto-chemical staining of normal, hyperplastic, and neoplastic adrenal cortex with a monoclonal antibody against alpha inhibin. Also, to determine whether immunostaining with this antibody is useful in differentiating between adrenal cortical neoplasms and other tumours involving the adrenal gland that might mimic them. METHODS: Normal adrenal tissue (n = 20) and specimens from cases of adrenal hyperplasia (n = 13), adrenal cortical adenoma (n = 15), adrenal cortical carcinoma (n = 4), phaeochromocytoma (n = 8), and adrenal metastatic tumour (n = 7) were stained with a monoclonal antibody against the alpha subunit of human inhibin. RESULTS: Positive staining with the anti-alpha inhibin monoclonal antibody was seen in all normal adrenal glands. Immunoreactivity was largely confined to the inner cell layers of the adrenal cortex, with no staining of the adrenal medulla. All hyperplastic adrenal glands and adrenal cortical adenomas and carcinomas were also immunoreactive. The other tumours studied were negative. CONCLUSIONS: There is consistent immunoreactivity with the anti-alpha inhibin monoclonal antibody in normal adrenal cortex and in hyperplastic and neoplastic adrenal cortical lesions. In the normal adrenal cortex, positive staining is mainly confined to the zona reticularis. Other neoplasms involving the adrenal gland are negative. Immunohistochemical staining with anti-alpha inhibin monoclonal antibody, performed as part of a panel, may prove to be of value in the distinction between adrenal cortical carcinoma and phaeochromocytoma or metastatic tumour.
Images
PMCID: PMC500504  PMID: 9602683
19.  Peripheral administration of the N-terminal POMC fragment 1-28 to Pomc−/− mice reduces food intake and weight but does not affect adrenal growth or corticosterone production 
The Journal of endocrinology  2006;190(2):515-525.
Pro-opiomelanocortin (POMC) is a polypeptide precursor that undergoes extensive processing to yield a range of peptides with biologically diverse functions. POMC-derived ACTH is vital for normal adrenal function and the melanocortin α-MSH plays a key role in appetite control and energy homeostasis. However, the roles of peptide fragments derived from the highly conserved N-terminal region of POMC are less well characterised. We have used mice with a null mutation in the Pomc gene (Pomc−/−) to determine the in vivo effects of synthetic N-terminal 1-28 POMC, which has been shown previously to possess adrenal mitogenic activity.
1-28 POMC (20 μg) given subcutaneously for ten days had no effect on the adrenal cortex of Pomc−/− mice with resultant cortical morphology and plasma corticosterone levels indistinguishable from sham treatment. Concurrent administration of 1-28 POMC and 1-24 ACTH (30μg per day) resulted in changes identical to 1-24 ACTH treatment alone, which consisted of upregulation of steroidogenic enzymes, elevation of corticosterone levels, hypertrophy of the zona fasciculata and regression of the X-zone.
However, treatment of corticosterone-deplete Pomc−/− mice with 1-28 POMC reduced cumulative food intake and total body weight. These anorexigenic effects were ameliorated when the peptide was administered to Pomc−/− mice with circulating corticosterone restored either to a low physiological level by corticosterone-supplemented drinking water (CORT) or to a supraphysiological level by concurrent 1-24 ACTH administration. Further, icv administration of 1-28 POMC to CORT-treated Pomc−/− mice had no effect on food intake or body weight. In wild type mice the effects of 1-28 POMC upon food intake and body weight were identical to sham but 1-28 POMC was able to ameliorate the hyperphagia induced by concurrent 1-24 ACTH treatment.
In a mouse model which lacks all endogenous POMC peptides, subcutaneous treatment with synthetic 1-28 POMC alone can reduce food intake and body weight but has no impact upon adrenal growth or steroidogenesis.
doi:10.1677/joe.1.06749
PMCID: PMC2638022  PMID: 16899584
adrenal; POMC; steroidogenesis; ACTH; hypertrophy; hyperplasia; X-zone
20.  Noradrenergic Pharmacotherapy, Intracerebral Infusion and Adrenal Transplantation Promote Functional Recovery After Cortical Damage 
The research described in this review briefly summarizes evidence that short term pharmacological enhancement of noradrenergic (NA) synaptic activity, combined with symptom relevant experience (SRE), promotes functional recovery of some symptoms of cortical damage in rat, cat and human beings even when treatment is initiated from days to weeks after injury. A summary is provided of the numerous drugs tested in rodent cortical injury models which have been proven useful for predicting beneficial or harmful effects on behavioral outcome in human stroke. The pattern of drug effects indicates a central role for NA in functional recovery. Additionally, studies of the effects of direct intraventricular infusion of monoamine neurotransmitters are reviewed and further support the hypothesized role of NA in recovery from some symptoms of cortical injury. The site of NA/SRE interaction to promote recovery from hemiplegia apparently involves the cerebellar hemisphere contralateral to the cortical injury. Microinfusions of NA into the contra- but not ipsilaterai cerebellar hemisphere dramatically enhance recovery. Furthermore, like its systemic action, microinfusion of the α1- NA receptor antagonist, phenoxybenzamine, reinstates hemiplegia. A “permanent” symptom of motor cortex injury in the cat is the complete loss of tactile placing contralateral to the injury which does not spontaneously recover for as long as seven years after ablation. This posturai reflex is temporarily restored for 8-12 hours following amphetamine administration. However, this permanently lost reflex can be enduringly restored by transplanting catecholamine secreting adrenal tissue into the wound cavity. The experiment is reviewed in detail and involves chromaffin cell autografts into the frontal cortex ablation wound cavity producing a restoration of tactile placing for the 7-10 month duration of the study. This enduring restoration of tactile placing is considered a result of the release of catecholamines into the CNS from the grafted chromaffin cells found, by histochemical methods, surviving 7-10 months after transplant. Lastly, we attribute these delayed treatment effects to an attenuation of a diaschisis, or remote functional depression, in morphologically intact areas anatomically connected to the area of injury. The widespread reduction of glycolytic and oxidative metabolism, produced by focal cortical injury, is normalized by the same treatment which alleviates symptoms and is worsened by drugs which exacerbate deficits. These data support the hypothesis that providing SRE during a period of enhanced NA synaptic activity produces an enduring functional recovery after cortical injury by attenuating remote functional depression. This treatment for enhancing recovery is especially attractive since it is effective even when begun weeks after cortical damage.
doi:10.1155/NP.1993.199
PMCID: PMC2565261  PMID: 8018752
21.  Angiotensin II Relaxations of Bovine Adrenal Cortical Arteries: Role of Angiotensin II Metabolites and Endothelial NO 
Hypertension  2008;52(1):150-155.
Angiotensin II (Ang II) regulates adrenal steroidogenesis and adrenal cortical arterial tone. Vascular metabolism could decrease Ang II concentrations and produce metabolites with vascular activity. Our goal was to study adrenal artery Ang II metabolism and to characterize metabolite vascular activity. Bovine adrenal cortical arteries were incubated with Ang II (100 nmol/L) for 10 and 30 min. Metabolites were analyzed by mass spectrometry. Ang (1-7), Ang III and Ang IV concentrations were 146±21, 173±42 and 58±11 pg/mg at 10 min and 845±163, 70±14 and 31±3 pg/mg at 30 min, respectively. Concentration-related relaxations of U46619-preconstricted cortical arteries to Ang II (maximum relaxation=29±3%, EC50=3.4 pmol/L) were eliminated by endothelium removal and inhibited by the NO synthase inhibitor, nitro-l-arginine (L-NA, 30 μmol/L, maximum relaxation=14±7%). Ang II relaxations were enhanced by the angiotensin type-1 receptor antagonist, losartan (1 μmol/L, maximum relaxation=41±3%, EC50=11 pmol/L). Losartan-enhanced Ang II relaxations were inhibited by L-NA (maximum relaxation=18±5%) and the angiotensin type-2 receptor antagonist PD123319 (10 μmol/L, maximum relaxation=27±5%). Ang (1-7) and Ang III caused concentration-related relaxations with less potency (EC50= 43 and 24 nmol/L, respectively) but similar efficacy (maximum relaxations=39±3%, 48±5%, respectively) as losartan-enhanced Ang II relaxations. Ang (1-7) relaxations were inhibited by L-NA (maximum relaxation=16±4%) and the Ang (1-7) receptor antagonist, 7D-Ala-Ang (1-7) (1 μmol/L, maximum relaxation=10±3%) and eliminated by endothelium removal. Thus, Ang II metabolism by adrenal cortical arteries to metabolites with decreased vascular activity represents an inactivation pathway possibly decreasing Ang II presentation to adrenal steroidogenic cells and limits Ang II vascular effects.
doi:10.1161/HYPERTENSIONAHA.107.104158
PMCID: PMC3202425  PMID: 18490519
Angiotensin (1-7); angiotensin III; angiotensin IV; mass spectrometry
22.  ADRENERGIC RESPONSES TO STRESS: TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL CHANGES 
Stress effects on adrenergic responses in rats were examined in adrenal medulla, the primary source of circulating epinephrine (Epi). Irrespective of duration, immobilization (IMMO) increased adrenal corticosterone to the same extent. In contrast, epinephrine changed little, suggesting that Epi synthesis replenishes adrenal pools and sustains circulating levels for the heightened alertness and physiological changes required of the "flight or fight" response. IMMO also induced the epinephrine-synthesizing enzyme, phenylethanolamine N-methyltransferase (PNMT). The rise in its mRNA and protein was preceded by increases in Egr-1 and Sp1 mRNA, protein and protein-DNA binding complex formation. With repeated and prolonged stress, PNMT protein did not reflect the magnitude of change in mRNA. The latter suggests that post-transcriptional, in addition to transcriptional mechanisms, regulate PNMT responses to stress. To further reveal molecular mechanisms underlying stress-induced changes in adrenergic function, the effects of hypoxia on PNMT promoter-driven gene expression are being examined in adrenal medulla-derived PC12 cells. Hypoxia activates the PNMT promoter to increase PNMT promoter-driven luciferase reporter gene expression and endogenous PNMT in PC12 cells. Induction of both appear mediated via activation of multiple signaling pathways and downstream activation of hypoxia inducible factor (HIF) and PNMT transcriptional activators, Egr-1 and Sp1. Hypoxia generates both partially and fully processed forms of PNMT mRNA. The former reportedly is translated into a truncated, non-functional protein and the latter into enzymatically active PNMT. Together, findings suggest that stress does increase PNMT gene transcriptional activity but post-transcriptional regulatory mechanisms limit the biological end-point of functional PNMT enzyme and thereby, Epi.
doi:10.1196/annals.1410.048
PMCID: PMC2722431  PMID: 19120117
phenylethanolamine N-methyltransferase (PNMT); stress; gene regulation; transcription factors; post-transcriptional control
23.  Pituitary and adrenal involvement in diffuse large B-cell lymphoma, with recovery of their function after chemotherapy 
Background
Diffuse large B-cell lymphoma sometimes involves the endocrine organs, but involvement of both the pituitary and adrenal glands is extremely rare. Involvement of these structures can lead to hypopituitarism and adrenal insufficiency, and subsequent recovery of their function is rarely seen. The present report describes an extremely rare case of pituitary and adrenal diffuse large B-cell lymphoma presenting with hypopituitarism and adrenal insufficiency with subsequent recovery of pituitary and adrenal function after successful treatment of the lymphoma.
Case presentation
A 63-year-old Japanese man was referred to our hospital due to miosis, ptosis, hypohidrosis of his left face, polydipsia and polyuria. 18F-fluorodeoxy glucose positron emission tomography / computed tomography revealed hotspots in the pituitary gland, bilateral adrenal glands and the apex of his left lung. Surgical biopsy from the pituitary lesion confirmed the diagnosis of diffuse large B-cell lymphoma, with lymphoma cells replacing normal pituitary tissue. Endocrine function tests revealed adrenal insufficiency and panhypopituitarism, including a possible affection of the posterior pituitary. Hormone replacement therapy with desmopressin and hydrocortisone was started. Chemotherapy consisted of six courses of R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone) and two courses of high-dose methotrexate followed by autologous hematopoietic stem cell transplantation. Subsequently, his pituitary and bilateral adrenal lesions resolved, and serial endocrine function tests showed gradual improvement in pituitary and adrenal function.
Conclusions
The present report describes an extremely rare case of diffuse large B-cell lymphoma with involvement of both the pituitary and bilateral adrenal glands. R-CHOP and high-dose methotrexate therapy followed by autologous hematopoietic stem cell transplantation was quite effective, and panhypopituitarism and adrenal insufficiency improved to almost normal values after successful treatment of the lymphoma with chemotherapy.
doi:10.1186/1472-6823-13-45
PMCID: PMC3851926  PMID: 24106823
Pituitary lymphoma; Adrenal lymphoma; Diffuse large B-cell lymphoma; Panhypopituitarism; Autologous hematopoietic stem cell transplantation; Recovery of pituitary and adrenal function
24.  Basic Fibroblast Growth Factor Delivery Enhances Adrenal Cortical Cellular Regeneration 
Tissue Engineering. Part A  2009;15(8):2093-2101.
The effective delivery of angiogenic factors is a useful strategy for the engineering of vascularized tissues. When adrenal cortical cells were implanted in mice under the renal capsule, the size of the implant was reduced to about 100 μm in thickness after 8 weeks. Either low (∼2 μg) levels of basic fibroblast growth factor (bFGF ) or high (∼12 μg) levels of bFGF were encapsulated into poly-lactic-co-glycolic acid microspheres, and these bFGF-encapsulated microspheres were coimplanted with adrenal cortical cells. After 56 days, the implants with low and high levels of bFGF weighed five and eight times more, respectively, than the implants without bFGF delivery. The implants with bFGF-encapsulated microspheres also contained significantly more cells than the implants without bFGF delivery. The levels of adrenal cortical gene expression were not significantly changed with bFGF delivery. The implants with high levels of bFGF also had a more uniform distribution of anti-CD31 immunofluorescence. Based on the increased number of cells that expressed adrenal cortical genes, the delivery of bFGF enhanced adrenal cortical cellular regeneration, possibly through an angiogenic response.
doi:10.1089/ten.tea.2008.0305
PMCID: PMC2792105  PMID: 19196135
25.  Macrophage migration inhibitory factor plays a permissive role in the maintenance of cardiac contractile function under starvation through regulation of autophagy 
Cardiovascular Research  2013;99(3):412-421.
Aims
The cytokine macrophage migration inhibitory factor (MIF) protects the heart through AMPK activation. Autophagy, a conserved pathway for bulk degradation of intracellular proteins and organelles, helps preserve and recycle energy and nutrients for cells to survive under starvation. This study was designed to examine the role of MIF in cardiac homeostasis and autophagy regulation following an acute starvation challenge.
Methods and results
Wild-type (WT) and MIF knockout mice were starved for 48 h. Echocardiographic data revealed little effect of starvation on cardiac geometry, contractile and intracellular Ca2+ properties. MIF deficiency unmasked an increase in left ventricular end-systolic diameter, a drop in fractional shortening associated with cardiomyocyte contractile and intracellular Ca2+ anomalies following starvation. Interestingly, the unfavourable effect of MIF deficiency was associated with interruption of starvation-induced autophagy. Furthermore, restoration of autophagy using rapamycin partially protected against starvation-induced cardiomyocyte contractile defects. In our in vitro model of starvation, neonatal mouse cardiomyocytes from WT and MIF−/− mice and H9C2 cells were treated with serum free-glucose free DMEM for 2 h. MIF depletion dramatically attenuated starvation-induced autophagic vacuole formation in neonatal mouse cardiomyocytes and exacerbated starvation-induced cell death in H9C2 cells.
Conclusion
In summary, these results indicate that MIF plays a permissive role in the maintenance of cardiac contractile function under starvation by regulation of autophagy.
doi:10.1093/cvr/cvt116
PMCID: PMC3732061  PMID: 23674514
Starvation; MIF; Autophagy; AMPK; Rapamycin

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