pituitrin and Hyperplasia

AIMAH is a clinical condition characterized by the presence of adrenal macronodules even in the absence of ACTH. Usually the clinical overt syndrome only becomes apparent after several decades of life; this is probably due to the low steroidogenic enzyme capacity of the hyperplastic tissue. However, in asymptomatic individuals in whom the AIMAH was incidentally discovered, the HHA axis is usually disrupted. In the great majority of AIMAH cases, cortisol secretion is aberrantly regulated by hormones such as GIP, AVP, beta-adrenergic agonists, LH/hCG and in some cases by serotonin, acting through their specific receptors. The molecular mechanisms responsible by ectopic expression of such hormone receptors and/or their aberrant coupling to steroidogenesis are still largely unknown. Although this aberrant expression may have an important role in the augmented cell proliferation initiation, as well as in the steroidogenesis, it is probable that additional genetic events involving cell cycle regulation, adhesion and transcription occur. In rare cases GNAS1 mutations not related to McCune-Albright syndrome may be found in this condition. In some patients, the presence of aberrant hormone receptors creates the possibility of specific pharmacological treatment, isolated or associated with unilateral adrenalectomy.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Chromogranins; Cushing Syndrome; GTP-Binding Protein alpha Subunits, Gs; Humans; Hyperplasia; Mutation; Signal Transduction; Vasopressins

Topics: Addison Disease; Adrenocorticotropic Hormone; Biological Assay; Blood Chemical Analysis; Circadian Rhythm; Cushing Syndrome; Hormones, Ectopic; Humans; Hyperplasia; Hypopituitarism; Insulin; Lysine; Metyrapone; Pituitary Neoplasms; Pyrogens; Radioimmunoassay; Vasopressins

The participation of aberrant receptors and intra-adrenal ACTH in hyperplastic tissue are considered mechanisms that regulate hypercortisolism in PMAH. Additionally, germline ARMC5 mutations have been described as the most frequent genetic abnormality found in patients diagnosed with PMAH. Previous functional studies analyzed ARMC5 role using H295R cells. Therefore, we investigated the role of ARMC5 in cell cultures obtained from PMAH nodules containing steroidogenic cells, aberrant receptors and intra-adrenal ACTH. ARMC5 silencing in non-mutated PMAH cell cultures decreased steroidogenesis-related genes and increased CCNE1 mRNA expression and proliferative capacity without affecting cell viability. Additionally, ARMC5 overexpression induced cell death in PMAH mutated cell cultures, thereby decreasing cell viability. We confirmed the role of ARMC5 as an important pro-apoptotic protein involved in PMAH-related steroidogenesis. We also report for the first time the involvement of ARMC5 in controlling proliferation and regulating cell cycle in PMAH cell cultures; these effects need to be explored further.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Aged; Armadillo Domain Proteins; Cells, Cultured; Female; Gene Expression Regulation; Gene Silencing; Humans; Hyperplasia; Lipid Droplets; Male; Middle Aged; Mutation; Pro-Opiomelanocortin; Progesterone Reductase; Receptor, Melanocortin, Type 2; Receptors, G-Protein-Coupled; Sequence Analysis, DNA; Staining and Labeling; Steroid 17-alpha-Hydroxylase; Tumor Suppressor Proteins; Vasopressins

Adaptation to stress is a basic phenomenon in mammalian life that is mandatorily associated with the activity of the hypothalamic-pituitary-adrenal (HPA) axis. An increased resting activity of the HPA axis can be measured during pregnancy and lactation, suggesting that these reproductive states lead to chronic load in females. In this study, we examined the consequences of the congenital lack of vasopressin on the activity of the HPA axis during lactation using vasopressin-deficient Brattleboro rats. Virgin and lactating, homozygous vasopressin-deficient rats were compared with control, heterozygous rats. In control dams compared with virgins, physiological changes similar to those observed in a chronic stress state (thymus involution, adrenal gland hyperplasia, elevation of proopiomelanocortin mRNA levels in the adenohypophysis, and resting plasma corticosterone levels) were observed. In vasopressin-deficient dams, adrenal gland hyperplasia and resting corticosterone level elevations were not observed. Corticotropin-releasing hormone (Crh) mRNA levels in the hypothalamic paraventricular nucleus were elevated in only the control dams, while oxytocin (OT) mRNA levels were higher in vasopressin-deficient virgins and lactation induced a further increase in both the genotypes. Suckling-induced ACTH and corticosterone level elevations were blunted in vasopressin-deficient dams. Anaphylactoid reaction (i.v. egg white) and insulin-induced hypoglycemia stimulated the HPA axis, which were blunted in lactating rats compared with the virgins and in vasopressin-deficient rats compared with the controls without interaction of the two factors. Vasopressin seems to contribute to the physiological changes observed during lactation mimicking a chronic stress state, but its role in acute HPA axis regulation during lactation seems to be similar to that observed in virgins. If vasopressin is congenitally absent, OT, but not the CRH, compensates for the missing vasopressin; however, the functional restitution remains incomplete.

Topics: Adrenal Glands; Animals; Corticosterone; Female; Hyperplasia; Hypothalamo-Hypophyseal System; Lactation; Models, Animal; Oxytocin; Pituitary-Adrenal System; Rats; Rats, Brattleboro; Stress, Physiological; Vasopressins

Mesangial cell growth is a key feature of several glomerular diseases. Vascular endothelial growth factor (VEGF) is a potent mitogen of vascular endothelial cells and promoter of vascular permeability. Here, we examined the ability of vasopressin (AVP), which causes mesangial cell proliferation and hypertrophy, to stimulate VEGF secretion from cultured rat mesangial cells. AVP potently induced a time- and concentration-dependent increase in VEGF secretion in these cells, which was then inhibited by a V(1A) receptor-selective antagonist, confirming this is a V(1A) receptor-mediated event. VEGF also induced hyperplasia and hypertrophy in mesangial cells, which was completely abolished by an anti-VEGF antibody. In addition, AVP-induced hyperplasia and hypertrophy were completely inhibited by the V(1A) receptor-selective antagonist and partially abolished by the anti-VEGF antibody. These results indicate that AVP increases VEGF secretion in rat mesangial cells via V(1A) receptors and modulates mesangial cell growth not only by direct action but also through stimulation of VEGF secretion. This autocrine mechanism might contribute to glomerulosclerosis in renal diseases such as diabetic nephropathy.

Topics: Animals; Antibodies; Antidiuretic Hormone Receptor Antagonists; Autocrine Communication; Benzazepines; Cell Proliferation; Cells, Cultured; Collagen Type IV; Hyperplasia; Hypertrophy; Male; Mesangial Cells; Piperidines; Rats; Rats, Wistar; Receptors, Vasopressin; Vascular Endothelial Growth Factor A; Vasopressins

Bilateral adrenalectomy is the standard treatment for Cushing's syndrome (CS) related to ACTH-independent bilateral macronodular hyperplasia (AIMAH), although it imposes life-long adrenal insufficiency. This study reports a clinical case in order to discuss the clinical interest of pharmacological beta-blockade of illegitimate membrane receptors and unilateral adrenalectomy as alternatives to bilateral adrenalectomy for treatment of CS due to AIMAH. Evidence for cortisol stimulation by upright posture and insulin-induced hypoglycemia in a patient with CS related to AIMAH led us to try beta-blockers as a therapeutic test and then as a first line treatment. Thus, a 3-day beta-blocker test (320 mg/d propranolol) induced normalization of cortisol secretion, with return of hypercortisolism at the end of the test. A long term treatment with 320 mg/d propranolol allowed sustained normalization of cortisol secretion and progressive disappearance of Cushingoid features but after 8 months the patient complained of Raynaud's syndrome and fatigue. Lowering propranolol dosage or switching to atenolol was less efficient to reduce cortisol levels. Unilateral adrenalectomy was then performed as a second line treatment, leading to normalisation of the 24h urinary cortisol without adrenal insufficiency. Long term control of blood pressure and glycemia were observed during a 7-year follow-up without beta-blocker. In conclusion, a 3-day propranolol test may identify patients with AIMAH who can benefit from a long term beta-blocker treatment. In case of intolerance to beta-blocking agents, unilateral adrenalectomy may allow for long term control of Cushing's syndrome related to AIMAH without adrenal insufficiency.

Topics: Adrenal Glands; Adrenalectomy; Adrenergic beta-Antagonists; Atenolol; Cushing Syndrome; Female; Humans; Hydrocortisone; Hyperplasia; Middle Aged; Posture; Propranolol; Treatment Outcome; Vasopressins

A 38-year-old woman was admitted with severe thirst and polyuria at 31 weeks' gestation. The plasma concentration of vasopressin (AVP) was very low (0.73 pg/ml) under conditions of high plasma osmolality (316 mOsm/ kg). T1-weighted magnetic resonance (MR) images revealed enlargement of the pituitary posterior lobe with absence of the hyperintense signal. After delivery, restoration of the hyperintense signal was demonstrated. This depletion-repletion process, which reflects the decrease and increase in amount of neurosecretory granules, is recognized in the case of transient central diabetes insipidus during pregnancy. We consider that an increase in cystine-aminopeptidase (CAP) activity is implicated in the pathogenesis.

Topics: Adult; Diabetes Insipidus, Neurogenic; Female; Follow-Up Studies; Humans; Hyperplasia; Magnetic Resonance Imaging; Pituitary Gland, Posterior; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, Third; Remission, Spontaneous; Risk Assessment; Vasopressins

We investigated the effects of YM087, a potent nonpeptide V1A and V2 vasopressin (AVP)-receptor antagonist, in binding and functional studies on rat vascular smooth-muscle cells (VSMCs). V1A AVP receptors on VSMCs were characterized by using the radioligand [3H]AVP. Specific binding of [3H]AVP was time dependent, reversible, and saturable. A single class of high-affinity binding sites with the expected V1A profile was identified. YM087 showed high affinity for V1A receptors with an inhibitory dissociation constant (Ki) value of 0.24 nM. In addition, YM087 potently and concentration-dependently inhibited AVP-induced increase in intracellular free calcium concentration and activation of mitogen-activated protein kinase. When added to growth-arrested VSMCs, AVP concentration-dependently induced hyperplasia and hypertrophy. YM087 prevented AVP-induced hyperplasia and hypertrophy of these cells in a concentration-dependent manner. YM087 had no agonistic activity in any biological assays used. These results suggest that YM087 displays high affinity for V1A receptors on VSMCs and high potency in inhibiting the AVP-induced physiological response. YM087 is a potent pharmacologic probe for investigating the physiologic and pathophysiologic roles of AVP in several diseases.

Topics: Animals; Benzazepines; Binding, Competitive; Calcium; Calcium-Calmodulin-Dependent Protein Kinases; Cell Culture Techniques; DNA; Enzyme Activation; Hyperplasia; Hypertrophy; Muscle, Smooth, Vascular; Protein Biosynthesis; Rats; Receptors, Vasopressin; Vasopressins

Insulin-like growth factor I (IGF-I) and IGF binding protein 1 (IGFBP-1) mRNAs are colocalized in the medullary thick ascending limb (MTAL) of the rat nephron, a segment that undergoes selective growth in response to elevated dietary protein. In the present study, rats were fed isocaloric diets containing variable protein content (6-40%) for 1-7 days, and changes in fractional renal weight, MTAL length, and regional DNA synthesis were assayed and compared with local changes in IGF-I/IGFBP-1 mRNAs, as determined by quantitative in situ hybridization. Rats switched to high-protein diets demonstrated increased IGF-I and decreased IGFBP-1 mRNA levels in MTALs, whereas those switched to low protein showed inverse changes. The increase in renal IGF-I mRNA was maximal at 2 days and was closely paralleled by significant increases in fractional renal weight, DNA synthesis, and MTAL length. Similar changes were seen in vasopressin-deficient Brattleboro and growth hormone (GH)-deficient dwarf rats in response to high-protein diets, suggesting that the effects of dietary protein in this model are not mediated by vasopressin or GH. The close spatial and temporal correlation between changes in renal IGF-I expression and changes in regional growth parameters strongly supports a role for locally produced IGF-I in the induction of protein-induced renal growth.

Topics: Animals; Body Weight; Carrier Proteins; Dietary Proteins; Gene Expression; Growth Hormone; Hyperplasia; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Kidney; Organ Size; Rats; Rats, Brattleboro; Rats, Mutant Strains; Rats, Sprague-Dawley; RNA, Messenger; Somatomedins; Vasopressins

Plasma ACTH (normal value: 0.16 plus or minus mU/100 ml) was measured in 116 patients with Cushing's syndrome, using a bioassay including dynamic tests and sequential determinations. In 10 patients with adrenal tumors ACTH levels were nondetectable (ND) or low, and usually nonstimulatable. In 10 patients with ectopic ACTH secretion high levels (0.42 plus or minus 0.07 mU/100 ml) were measured. The extracts of 6 tumors yielded an ACTH-like substance. Forty-three patients with Cushing's disease (without pituitary tumor) had, before treatment, a mean ACTH level of 0.18 plus or minus 0.01 mU/100 ml, accompanied by high levels of plasma cortisol (32.1 plus or minus 1.9 mug/100 ml). Irregular nycthemeral variations occurred. ACTH rose to 0.30 mU/100 ml after incomplete adrenalectomy (20 patients) and to 1.14 mU/100 ml after total adrenalectomy (21 patients). Dexamethasone (8 mg per day) suppressed ACTH levels. Metyrapone induced a normal ACTH rise, but at abnormal times. Lysine-vasopressin (LVP) induced an ACTH mean relative increase of 120% before, and of 140% after adrenalectomy (i.e., within the normal range). Six nonadrenalectomized patients with pituitary tumors showed similar abnormalities of ACTH regulation. However, the ACTH rise after LVP was above 500%. When pituitary tumors occurred after adrenalectomy (12 patients) the mean basal ACTH level was 18 mU/100 ml. Dexamethasone induced a 90% decrease, and LVP a 416% increase in ACTH levels. In 6 patients with nodular adrenal hyperplasia, ACTH was undetectable before treatment. After adrenalectomy, ACTH rose to 0.4 mU/100 ml (11 patients) and the increase after LVP was 90%. Five additional patients developed pituitary tumors. These data confirm the abnormalities of ACTH feedback regulation in Cushing's disease. However, even when pituitary tumors occur, ACTH levels can be altered by metyrapone, dexamethasone and LVP. This last test is of particular interest for the detection of pituitary tumors. The follow-up pattern of treated nodular adrenal hyperplasia appears to be very similar to that of Cushing's disease.

Topics: Adrenal Gland Diseases; Adrenalectomy; Adrenocorticotropic Hormone; Animals; Biological Assay; Cushing Syndrome; Dexamethasone; Hormones, Ectopic; Humans; Hydrocortisone; Hyperplasia; Metyrapone; Pituitary Function Tests; Pituitary Gland; Pituitary Gland, Anterior; Pituitary Neoplasms; Rats; Vasopressins

Topics: Aldosterone; Alkalosis; Angiotensin II; Biopsy; Blood Pressure; Child, Preschool; Diet Therapy; Female; Follow-Up Studies; Growth Disorders; Humans; Hyperaldosteronism; Hyperplasia; Hypertrophy; Hypokalemia; Juxtaglomerular Apparatus; Kidney Concentrating Ability; Kidney Diseases; Norepinephrine; Potassium; Renin; Secretory Rate; Sodium Chloride; Spironolactone; Syndrome; Vasopressins

Topics: 17-Hydroxycorticosteroids; Adenoma; Adrenal Gland Neoplasms; Adrenal Glands; Adrenocortical Hyperfunction; Adult; Depression, Chemical; Dexamethasone; Diagnosis, Differential; Humans; Hydrocortisone; Hyperplasia; Male; Methods; Metyrapone; Phlebography; Stimulation, Chemical; Vasopressins

Topics: Adrenal Gland Diseases; Endocrine System Diseases; Erythrocytes; Female; Gastrins; Gynecomastia; Hormones, Ectopic; Humans; Hypercalcemia; Hyperplasia; Hyperthyroidism; Hypoglycemia; Male; Malignant Carcinoid Syndrome; Metabolic Diseases; Neoplasms; Neurologic Manifestations; Polycythemia; Prognosis; Puberty, Precocious; Vasopressins

Topics: Addison Disease; Adolescent; Adrenal Gland Diseases; Adrenal Glands; Adrenalectomy; Adrenocorticotropic Hormone; Adult; Aged; Child; Cushing Syndrome; Dexamethasone; Female; Fluorometry; Humans; Hydrocortisone; Hyperplasia; Hypopituitarism; Hypothalamo-Hypophyseal System; Injections, Intramuscular; Lysine; Male; Metyrapone; Middle Aged; Pituitary Neoplasms; Pituitary-Adrenal Function Tests; Vasopressins

Topics: 17-Hydroxycorticosteroids; Adrenal Gland Diseases; Adrenocorticotropic Hormone; Circadian Rhythm; Cushing Syndrome; Dexamethasone; Humans; Hydrocortisone; Hyperplasia; Insulin; Metyrapone; Pituitary-Adrenal Function Tests; Pyrogens; Vasopressins

Topics: 17-Hydroxycorticosteroids; Adenoma; Adolescent; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Adult; Circadian Rhythm; Cushing Syndrome; Dexamethasone; Diagnosis, Differential; Female; Humans; Hydrocortisone; Hyperplasia; Hypoglycemia; Hypothalamo-Hypophyseal System; Male; Metyrapone; Middle Aged; Pituitary-Adrenal Function Tests; Pituitary-Adrenal System; Secretory Rate; Vasopressins

Topics: Animals; Arteries; Cytoplasmic Granules; Hyperplasia; Hypertrophy; Juxtaglomerular Apparatus; Male; Rats; Vasopressins

Topics: Adolescent; Adult; Aminohippuric Acids; Contrast Media; Creatinine; Diuresis; Humans; Hyperplasia; Hypertension, Renal; Kidney Function Tests; Methods; Middle Aged; Renal Artery Obstruction; Sodium; Sodium Chloride; Urea; Urinary Catheterization; Urography; Vasopressins