The role of the hypothalamus in pituitary neoplasia.

Although the role of the hypothalamus in the genesis of pituitary tumours has emerged to be one of promotion rather than of initiation, it remains of utmost clinical importance. The epidemiological finding that occult pituitary tumours are very frequent, but only very seldom progress towards clinical evidence and exceptionally to malignancy suggests that their aggressive potential is kept under control by a host of factors and that only the disruption of this complex mechanism can allow occult tumours to grow. Most of these factors are hypothalamic in origin, although the stimulatory action of releasing hormones can be enhanced and the inhibitory action of inhibiting hormones reduced by receptor/post-receptor alterations occurring in pituitary tumours. If in the case of oncogenic mutations the clone expansion might be sustained only by the constitutive activation of proliferative signals and not require the intervention of other promoting factors, in other circumstances promoting factors (such as an excess of stimulatory or lack of inhibitory factors) may be necessary for the expansion of the tumoral clone. The development of pituitary somatotrophinomas or corticotrophinomas in patients with GHRH or CRH hyperproduction, respectively, gives clinical evidence to the role of releasing hormones. The shrinking effect of dopamine or SRIH agonists on the tumour mass of prolactinomas and somatotrophinomas, respectively, and, conversely, the rapid tumour expansion of corticotrophinomas after the removal of the cortisol negative feedback by bilateral adrenalectomy are clinical proofs of the importance of inhibitory signals on tumour growth.

Abnormalities of endocrine function in patients with clinically "silent" adrenal masses.

Because, in recent years, patients with incidentally discovered adrenal masses have been encountered increasingly, their endocrine function was investigated in basal conditions and after dynamic tests. Thirty-two patients (23 women and 9 men, aged 28-74 years) were studied. Lesion diameter, as documented by computed tomography and/or nuclear magnetic resonance imaging, ranged between 5 and 65 mm; the tumors were localized on the right in 22 patients, on the left in 5 and bilaterally in 5 cases. In basal conditions, urinary free cortisol (UFC) excretion, plasma adrenocorticotropin (ACTH) and cortisol levels were normal, except for 4 patients who showed high UFC and ACTH levels in the low-normal range. Ovine corticotropin-releasing hormone (CRH, 1 microgram/kg iv) was given to 18 patients, inducing normal ACTH and cortisol responses in 12, blunted responses in 4 and no response in 2 cases. No reduction in ACTH and cortisol levels after suppression tests was observed in 4 of 29 patients after dexamethasone (1 mg overnight) or in 6 of 29 after loperamide. The 4 patients who were unresponsive to both tests did not show any further inhibition after high-dose dexamethasone administration, had low plasma ACTH levels and showed impaired or absent responses to the CRH test: they were diagnosed as affected with preclinical Cushing's syndrome. An exogenous ACTH test performed in 30 patients caused a normal cortisol rise. Basal mean 17-hydroxy-progesterone (17-OHP) levels were not different from those in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular alterations in pituitary tumors.

In the last few years, molecular studies on pituitary adenomas have yielded evidence supporting a primary pituitary origin of these tumors. Although the existence of genomic alterations in tumoral cells is strongly suggested by the fact that almost all pituitary adenomas are monoclonal in origin, structural genetic abnormalities such as rearrangement, deletion or mutation, which could result in transcriptional activation, have been identified in a minority of tumors. As far as the possible loss of anti-oncogenes in pituitary tumors is concerned, gene alterations have not been found in the p53 nor in the retinoblastoma gene, while loss of chromosome 11q13 sequences, which contain the deduced location of the yet uncloned MEN-1 gene, has been reported in a subset of GH-secreting adenomas. With regard to the activation of dominant oncogenes in the process of tumor formation, activating mutations of either the Gs alpha-subunit or the ras gene have been identified in a large proportion of GH-secreting adenomas and in individual particularly invasive tumours, respectively. Promoting agents such as hypothalamic neurohormones and growth factors may be required for the selective growth of genetically altered cells. In this respect, it is worth noting that receptor/postreceptor alterations occurring in pituitary tumors may cause an increased action of stimulatory neurohormones with growth promoting properties as well as defective action of inhibitory inputs.

G-proteins and hormonal signalling in human pituitary tumors: genetic mutations and functional alterations.

In the last few years, molecular studies on pituitary adenomas have yielded several lines of evidence supporting a primary pituitary origin for these tumors. In fact, analyses of x-chromosomal inactivation show that the great majority of pituitary tumors are monoclonal in origin, suggesting that one or more mutations are responsible for the selective expansion of a single cell clone. Mutations constitutively activating GTP-binding proteins have been identified in subsets of pituitary adenomas. Single amino acid substitutions replacing Arg 201 with either Cys, His, or Gln 227 with either Arg or Leu of the alpha-subunit of the Gs gene were identified in one third of growth hormone (GH)-secreting adenomas. Both mutations stabilize alpha s in its active conformation by inhibiting GTPase activity, thus mimicking the effect of specific extracellular growth factors, such as growth hormone releasing hormone (GHRH). Since several lines of evidence suggest that cAMP is involved in somatotrope replication, it has been proposed that the alpha s gene can be converted into an oncogene, designated gsp (for Gs protein). Recently, the ras oncogene has been identified in one prolactinoma characterized by unusual invasiveness. Although these data seem to negate a primary role for hypothalamic neurohormones in adenoma formation, it is conceivable that the hormones may exert a role in the sequence of events leading to clonal expansion of a transformed cell. Moreover, alterations in receptor and/or postreceptor events triggered by hypothalamic neurohormones may result in amplification of stimulatory inputs and impairment of inhibitory ones.

Effect of two consecutive administrations of GHRH in children with constitutional growth delay.

It has been suggested that children with constitutional growth delay might have a transient immaturity of the neurotransmitter pathways necessary for the control of growth hormone releasing hormone (GHRH) secretion. In this study we evaluated the effects of two consecutive GHRH boluses (1 microgram/kg, i.v.) in nine prepubertal boys with constitutional growth delay. Growth hormone (GH) responses to GHRH administration were similar to that observed in normal children (first GHRH bolus, GH net incremental area under the curve (nAUC) +/- SE: 788 +/- 244 vs 984 +/- 242 ng/ml per hour; second bolus, GHnAUC: 657 +/- 122 vs 541 +/- 129 ng/ml per hour, respectively). These data suggest that no relevant abnormalities in the mechanisms determining the somatotroph sensitivity to GHRH are present in children with constitutional growth delay.

Mineralocorticoid hypertension due to a nasal spray containing 9 alpha-fluoroprednisolone.

The finding of hypokalemia and of low plasma renin activity (PRA) in a hypertensive patient suggests a diagnosis of primary hypermineralocorticoidism. Medications containing compounds with mineralocorticoid-like activity (licorice, carbenexolone) may also cause the same syndrome. Recently, we carried out detailed studies on 10 patients with severe hypertension and hypokalemic alkalosis, suppressed PRA and low aldosterone levels. Plasma levels of cortisol and ACTH were suppressed in most of the cases. Measurement of deoxycorticosterone and corticosterone (and in some patient of 18-hydroxydeoxycorticosterone and 18-hydroxycorticosterone) was not significantly higher than normal. Therapeutic trials of dexamethasone and aminoglutethimide were ineffective. In contrast, spironolactone and amiloride treatment resulted in substantial but incomplete amelioration of both hypertension and hypokalemia. All of the patients share a common history of chronic rhinitis and habitual use of large doses of nasal spray containing 9 alpha-fluoroprednisolone and vasoconstrictor agents. Withdrawal resulted in a complete remission of hypokalemia in one to two weeks in all patients. The hypertension and depressed levels of PRA, aldosterone and cortisol took longer to return to normal, varying from case to case; in all but one patient, the values returned to normal within two months. This report reveals another cause of factitious mineralocorticoid excess which may be considered in the differential diagnosis of hypokalemic hypertensive syndromes.

Thyrotropin secretion in patients with central hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin.

TSH concentration was measured in plasma before and after TRH administration (200 micrograms, iv) in 89 patients with documented hypothyroidism consequent to various hypothalamic-pituitary disorders. Basal plasma TSH was less than 1.0 microI/ml in 34.8%, between 1.0-3.6 microU/ml in 40.5% and slightly elevated (3.7-9.7 microU/ml) in 24.7% of the cases. The plasma TSH response to TRH was absent in 13.5%, impaired in 16.8%, normal in 47.2%, and exaggerated in 22.5% of the cases, with delayed and/or prolonged pattern of response in 65% of the cases. The dilution curves of several plasmas drawn before and after TRH were parallel to those obtained with TSH standard preparation. After gel filtration, the elution pattern of TRH-stimulated plasmas from 4 patients did not show any major difference from that of pooled plasmas from normal subjects given TRH or from that of patients with primary hypothyroidism. Plasma TSH values determined by cytochemical bioassay on both basal and TRH-stimulated samples of 5 patients were markedly lower than those obtained by RIA. The serum T3 response to TRH was absent or low in 40 out of 53 patients in whom it was evaluated. The administration of T3 (100 micrograms/day for 3 days) or dexamethasone (3 mg/day for 5 days) respectively suppressed or reduced both basal and TRH-induced plasma TSH levels. Two patients became hypothyroid shortly after pituitary surgery in spite of basal and TRH-induced plasma TSH levels similar to or higher than those before surgery. Though thyroid atrophy due to chronic understimulation could explain the low T3 response to TRH in secondary hypothyroidism, it is difficult to reconcile thyroid understimulation with normal or increased plasma TSH unless the immunoreactive material has low biological activity. Present data suggest that several patients with hypothyroidism consequent to hypothalamic-pituitary diseases secrete a material which is immunologically similar to pituitary standard TSH and responds to stimulatory and suppressive agents in a manner similar to normal TSH but has low or absent biological activity. Thus, hypothyroidism due to insufficient TSH stimulation can be termed central hypothyroidism and can be due 1) to pituitary insufficiency (secondary hypothyroidism), 2) to a hypothalamic defect (tertiary hypothyroidism), or 3) to the secretion of biologically inactive TSH.

Some aspects of hypothalamic-pituitary function in patients with anorexia nervosa.

The secretion of lutenizing hormone (LH), follicle-stimulating hormone (FSH), thyrotrophin (TSH) and prolactin (PRL, was studied in 17 women suffering from anorexia nervosa. The mean basal serum LH was reduced (8.4 +/- 0.8 SE mIU/ml; P less than 0.001 vs normal controls), while LH increase after gonadotrophin-releasing hormone (LH-RH) appeared to be normal in 9 cases and impaired in 6 cases. The mean basal FSH did not significantly differ from normal subjects (3.9 +/- 0.5 mIU/ml), while LH-RH administration elicited an exaggerated increase in 7 cases and a normal increase in 8 cases: the mean FSH response was significantly higher than in controls (P less than 0.02). Plasma oestradiol-17beta was reduced (20.4 +/- 0.4 pg/ml; P less than 0.001) while the serum testosterone levels were normal (0.73 +/- 0.09 ng/ml). Clomiphene administration induced an increase in gonadotrophins in only 1 out of 7 patients. The mean serum TSH concentration was normal (2.3 +/- 0.4 muU/ml), while serum thyroxine and triiodothyronine and free thyroxine index, thought generally in the normal range, were significantly lower than values obtained in a control group (6.1 +/- 0.4 mug/100 ml, P less than 0.005; 102.3 +/- 7.7 ng/100 ml, P less than 0.005; 3.8 +/- 0.3, P less than 0.05). Though the mean serum TSH increase after thyrotrophin-releasing hormone (TRH) was normal (12.0 +/- 2.3 muU/ml), there were 4 impaired and 1 exaggerated increases, and 8 patients showed a delayed and frequently prolonged response. The increase in serum T3 after TRH appeared lower than in normal subjects (36.3 +/- 1.8 ng/100 ml, P less than 0.001). Serum PRL levels in basal conditions were higher than in the controls (19.4 +/- 4.1 ng/ml, P less than 0.001) while the increase in PRL after TRH was exaggerated in only 2 patients. The present data suggest that the primary failure in gonadotrophin secretion in anorexia nervosa occurs at hypothalamic level; moreover the data on TSH and PRL secretion also point to the existence of a hypothalamic disorder in this disease.