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In more than 95% of cases acromegaly is due to GH hypersecretion by a pituitary adenoma. GHRH hypersecretion accounts for about 0.5% of cases of acromegaly. Intracranial GHRH-secreting tumors are extremely rare and only a few well-documented cases have been reported. The clinical features of acromegaly due to intracranial GHRH-secreting tumor are indistinguishable from those of other patients with "classical acromegaly". In cases of intrasellar gangliocytomas, not even radiological findings help to make the correct diagnosis, which can only be made with the hystological study. We present the case of a woman with acromegaly; the magnetic resonance demonstrated a 2x1.8x1.2 cm mass in the jugum sphenoidalis region, associated with a partial empty sella. There was a partial response to high-dose lanreotide therapy, so surgical treatment was decided, although only part of the tumor could be removed. Histopathological diagnosis was consistent with gangliocytoma, and immunostaining in the ganglionic cells was positive for GHRH. After surgery, hormone hypersecretion persisted, so medical treatment was reintroduced. In summary, we report a well-documented case of an intracranial GHRH-secreting gangliocytoma, an exceedingly rare cause of acromegaly. Clinical and biochemical data did not allow to make the correct diagnosis, which was only made on the pathological study. This case underscores that acromegaly can be due to causes other than a GH-secreting adenoma, and underlines that finding an image not typical of a pituitary adenoma should raise the suspicion that an unusual cause subsides the acromegaly.

Isolated TSH deficiency is rare. The diagnosis is based on (i) symptoms and signs of thyroid hormone deficiency, (ii) demonstration of an absent or impaired TSH response to TRH and (iii) other pituitary hormones remaining intact. We report a 60-year-old female in whom isolated TSH deficiency was found, with a free thyroxine - 7.0 pmol/L (11-20), total triiodothyronine level - 1.5 nmol/L (1.1-2.6) and thyroid stimulating hormone - 0.87 mU/L (0.38-4.3). A TRH test on two separate occasions demonstrated an inappropriately low TSH response. Computed assisted tomography revealed a partially empty sella and other pituitary hormones were demonstrated to be intact. We were unable to detect pituitary antibodies using indirect immunofluorescence on sections of monkey pituitary. Treatment with thyroxine improved this patient's symptoms and suppressed the TSH further.

Some evidence suggests that late stage autoimmune hypophysitis (AH) may result in empty sella (ES). Aim of the study was to assess the prevalence of serum pituitary antibodies (PitAb) and their correlation with pituitary function in patients with ES.In this casecontrol study 85 patients with primary ES, 16 patients with ES secondary to head trauma, 214 healthy controls, and 16 AH were enrolled in a tertiary referral center.PitAb were assessed in all cases and controls. Endocrine function was assessed by basal hormone measurement and dynamic testing in all ES cases.PitAb prevalence was higher in primary ES (6%) than in healthy subjects (0.5% p=0.003) and lower than in AH patients (50%, p0.0001). PitAb were not found in patients with secondary ES. Hypopituitarism was found in 49% of primary ES and in 62% of secondary ES (p=0.34). A positive correlation between the presence of PitAb and hypopituitarism was found in primary ES (p=0.02).The significant association between pituitary autoimmunity and hypopituitarism suggests that ES, in selected cases, could be the final result of AH.

Background and aims: Ghrelin is an orexigenic hormone produced in the stomach and in other organs, exerting a wide range of metabolic functions, including stimulation of GH secretion. Ghrelin secretion is decreased by iv or oral glucose load as well as during euglycemic-hyperinsulinemic clamp and hypoglycemia. We evaluated the circulating ghrelin levels in GH-deficient (GHD) and in GH-sufficient (GHS) patients during GHRH plus arginine test. Materials and methods: The study group comprised 35 patients, including 20 with pituitary tumors, 12 with empty sella, 2 with short stature, and 1 with post-traumatic isolated GH deficiency. According to the results of GHRH plus arginine test, 14 patients were defined as GHD and 21 as GHS. Patients with central hypothyroidism, hypocorticism, and hypogonadism had been on replacement therapy for at least 3 months at the moment of the study. Blood samples were collected every 20 min up to 60 min after GHRH and arginine administration. Results: By definition, GH response to GHRH plus arginine was higher in GHS than GHD group (p

GH hyperproduction due to ectopic secretion of GHRH is a rare cause of acromegaly. Since 1959, approximately 50 cases of ectopic GHRH production from extrapituitary tumors have been described. Here we report the clinical and biochemical features of a 47-yr-old Caucasian woman with ectopic GHRH syndrome sustained by a bronchial carcinoid. The criteria for the diagnosis of acromegaly due to ectopic GHRH secretion were satisfied in our patient (i.e. confirmation of active GH hypersecretion, unequivocal demonstration of GHRH production and secretion from an extrapituitary tumor and cure of acromegaly after neoplasm removal). The tumor was an atypical carcinoid and there was a familial history of lung and colorectal cancer. Acromegaly was slightly active (mean GH value: 7.4 ng/ml, IGF-I: 436 ng/ml) and after tumor removal there was a progressive decline of GH levels, consistent with remission of pituitary somatotroph hyperplasia. Pituitary radiology showed an empty sella demonstrating for the first time its association with ectopic GHRH syndrome.

Primary empty sella (PES) is a very frequent neuroradiological finding in the general population, that can induce hypopituitarism. Some studies focused on the association of PES with GH deficiency (GHD) or hypogonadotropic hypogonadism (HH), while data regarding the involvement of hypothalamic-pituitary-thyroid (HPT) axis, despite sporadic reports of central hypothyroidism, or the occurrence of hypoadrenalism (HA) are scanty. In this study, thyroid function and TSH response to exogenous TRH injection (TRH/TSH) were investigated in 43 patients [10 men and 33 women; aged (mean +/- SD), 48+/-12 yr] with PES: 22 patients had total and 21 partial PES. Forty healthy subjects (9 men and 31 women; aged 46+/-12 yr) were enrolled as a control group. Central hypothyroidism was found only in 2/43 cases, whereas one patient showed primary hypothyroidism. In euthyroid patients, mean serum TSH levels were significantly lower than controls (TSH: 1.0+/-0.7 vs 1.4+/-0.6 mU/l, p

Pituitary apoplexy has been reported as a rare complication of dynamic testing used for the study of pituitary functional reserve. In 1993, a diagnosis of non-secreting macroadenoma with moderate functional hyperprolactinaemia was made in a 43-year-old woman. Soon after the start of therapy with bromocriptine up to 5 mg/die, the patient complained of nausea and postural hypotension. As the symptoms persisted even when the dose was reduced to 2.5 mg/die, the patient was transferred to therapy with quinagolide at the dosage of 37.5 microg/die. PRL levels quickly normalized (range 1.4-5.7 ng/ml) as well as menstrual cycles, and no side-effect was reported. In 1995 a sellar magnetic resonance imaging (MRI) showed no shrinkage of the known macroadenoma. In 1996, few hours after a gonadotropin-releasing-hormone (GnRH) test, which showed normal LH and FSH response and with baseline PRL levels in the normal range, the patient started complaining of severe frontal headache, nausea and vomiting. No gross visual defects were present. An emergency computed tomography (CT) showed no evident hemorrhagic infarction in the macroadenoma. The symptoms completely resolved in few days with steroidal and antiemetic therapy. A new MRI performed in 1998 showed a partial empty sella and PRL levels were in the normal range under dopaminergic treatment. The pituitary functional reserve proved normal on dynamic testing. The temporal association between the onset of symptoms and the GnRH test strongly suggests an association between the two events. No evident signs of pituitary apoplexy (either on emergency CT or hormonal evaluation) were detected. The authors suggest that GnRH can cause severe side-effects that mimic pituitary apoplexy without related morphological evidence and that, in our particular case, it can have caused the gradual disappearance of the non-secreting macroadenoma. Moreover, a causal role of the chronic dopaminergic treatment cannot be completely ruled out.

The aim of this study was to investigate TSH and PRL response to TRH and domperidone, an antidopaminergic drug which does not cross the blood-brain barrier, in 16 patients with primary empty sella (PES) and either normal or elevated plasma PRL level and to compare it with the response observed in 8 patients with prolactinoma. In the patients with PES and hyperprolactinemia, the PRL response to TRH was significantly lower than in the controls and the patients with PES and normal PRL, which suggests there is impaired PRL synthesis and release in cases of PES with hyperpro-lactinemia. The TSH response to domperidone was significantly elevated in patients with PES and either normal or elevated PRL, as in patients with prolactinoma. The PRL response to domperidone was significantly reduced in patients with PES and hyperprolactinemia as in patients with prolactinoma. These results suggest that in PES as in prolactinoma the inhibiting dopaminergic tone is increased on the thyrotropic cells and reduced on the lactotropic cells in PES with elevated PRL and that some patients with PES might bear a microprolactinoma in the bottom of the sella which remained undetected by the CT scan.

Two cases of Langerhans cell histiocytosis (LCH) expressing as Hand-Schuller-Christian syndrome with diabetes insipidus, hyperprolactinemia and empty sella are here reported. Up-to-date this four-fold association is lacking in world literature and it is here discussed in the light if LCH is a cancer or the clinical expression of an immunologic disorder.

A 47-year-old woman affected by Addison's disease, inadequately treated with corticosteroids for 14 yr, was referred to our clinic. As a x-ray of skull revealed an enlarged sella turcica, a more thorough study of hypothalamic-pituitary function and of the sellar region was performed. The normal suppression of high plasma ACTH levels induced by hydrocortisone infusion and the normal pattern of ACTH, TSH, PRL, LH and FSH to appropriate stimuli (CRH, TRH, GnRH) excluded the possible existence of an ACTH-secreting adenoma; the CT scan images showed the presence of an empty sella. The impaired GH rise after GHRH may be attributed to either the empty sella or the adrenal failure. This is the first patient with Addison's disease and empty sella, in whom the hypothalamic-pituitary function has been studied by the administration of four releasing hormones.

Measurement of adenohypophyseal hormones in the cerebrospinal fluid (CSF) was recently proposed as an useful procedure to differentiate pituitary intra and extrasellar tumors. So far, data reported are conflicting. We measured the concentrations of GH, TSH, LH and PRL in CSF and plasma in 30 controls and in 37 patients with various pituitary diseases (18 intrasellar adenomas, 14 extrasellar adenomas and 5 empty sella syndromes). The concentrations of examined hormones in CSF were very low or undetectable in all control subjects. In most patients with pituitary tumors, adenohypophyseal hormones were found to be present in CSF, in great amounts. No significant differences were found between intra and extrasellar tumors. In agreement with recently reported data, no significant correlation was found between GH, TSH, FSH and LH levels in CSF and plasma, while a significant correlation (p less than 0.01) was obtained between CSF and plasma levels of PRL, either in all patients or in those with extrasellar tumors only. All patients bearing an empty sella had PRL detectable in CSF: in 2 cases PRL levels were very high. In conclusion our data do not confirm that measurement of adenohypophyseal hormones in CSF represents an useful screening to differentiate tumors with extrasellar extension. PRL data deserve interest in order to gain understanding of the hormone dynamics between CSF and vascular compartments.

A 63-year-old woman, married with 1 child was referred because of weight gain, cold intolerance and fatigue. Initial laboratory studies revealed decreased serum thyroxine, highly elevated TSH levels and positive-antithyroglobulin antibodies. Skull x-ray and visual fields were normal. Fasting plasma Cortisol and the response to iv ACTH were normal. Serum levels of FSH (7.4 mlU/ml) and LH (6.8 mlU/ml) were low for her age and did not rise in response to LHRH. Serum GH levels were low and did not respond to L-dopa. Following the administration of thyrotropin-releasing hormone (TRH), prolactin (PRL) response was normal. The patient was maintained on L-thyroxine (0.15 mg/day). Serum TSH levels decreased to normal levels (1.8μU/ml). Periodic examination of visual fields and x-ray of skull were normal. Three yr later x-ray of skull revealed an enlarged sella turcica. Hormonal studies revealed low basal levels of FSH and LH and absent response to LHRH. Basal PRL levels were normal but PRL response to TRH and metoclopramide was blunted, thus indicating decreased prolactin reserve. Serum TSH levels remained unchanged following TRH (1.5–2.5 μU/ml). Following insulin-induced hypoglycemia there was noGH or PRL response while Cortisol response was intact. Computerized axial tomography of the skull and sell turcica were compatible with an empty sella with no evidence of suprasellar mass or hydrocephalus. These findings suggest that this patient had primary hypothyroidism associated with empty sella syndrome and development of hypopituitarism while being euthyroid.

Adipsic hypernatremia, a rare disorder, usually secondary to a hypothalamic lesion, is caused by the combination of partial central diabetes insipidus with hypo- or adipsia. We studied a patient who presented with a global hypothalamic dysfunction including adipsic hypernatremia. An extensive work-up disclosed the presence of pseudotumor cerebri and an empty sella turcica. Although endocrine abnormalities including true diabetes insipidus have been reported in conjunction with pseudotumor cerebri or an empty sella, no patient described presented such a global hypothalamic dysfunction or adipsic hypernatremia. The increased intracranial pressure is postulated to be the responsible mechanism for both the empty sella and the hypothalamic dysfunction.

GH secretion was studied in 47 patients with empty sella syndrome (ESS), using the GH response to the L-dopa test and determinations of the somatomedin levels. A high frequency of low responders (56%) was found, which is in accordance with previous reports on ESS. However, a true GH deficiency as judged by low levels of somatomedin A, was suspected in only 2 out of 41 patients with otherwise normal pituitary function and in 5 out of 6 patients with other pituitary insufficiences. The impaired GH responsiveness in the remaining patients seemed to be attributed to their overweight and/or postmenopausal age (estrogen deficiency) and not to a true GH deficiency, which was excluded by normal levels of somatomedin.

Basal prolactin (PRL) levels and PRL responsiveness to thyrotropin-releasing hormone (TRH) were studied in 10 women with primary empty sella (PES) syndrome (mean age 38.2 yr). Hyperprolactinemia (34 to 72 ng/ml) was found in 5 patients (hyperprolactinemic PES, H-PES), whereas 5 patients showed normal (9.5 to 19 ng/ml) PRL levels (normoprolactinemic PES, N-PES). The results were compared with those obtained in 10 healthy women (mean age 32.8 yr, PRL = 7 to 15 ng/ml) and in 8 women with a PRL-secreting pituitary microadenoma (MA) (mean age 37.5 yr, PRL = 39 to 85 ng/ml). The mean basal levels of PRL were significantly higher in patients with H-PES (50.8 +/- 13.2 ng/ml) or MA (64.0 +/- 18.3 ng/ml) than in the control group (10.9 +/- 2.6 ng/ml, p less than 0.02) and in the patients with N-PES (13.9 +/- 3.7 ng/ml, p less than 0.02). In contrast, the relative maximum response (RMR) of PRL to TRH (peak PRL/basal PRL) was significantly lower in the patients with PES (both H-PES and N-PES) or MA (1.4 +/- 0.4, 2.3 +/- 0.7 and 1.2 +/- 0.2, respectively) than in the control subjects (3.6 +/- 1.1; p less than 0.02, less than 0.05 and less than 0.02, respectively). Our results show that the pituitary responsiveness to the acute stimulation with TRH is significantly decreased both in patients with a PRL-secreting pituitary MA and in those with PES. Therefore, the clinical value of the TRH test in distinguishing the PES syndromes from prolactinomas seems to be questionable.

During a systematic study of women with idiopathic galactorrhea, we observed several patients with normal random serum prolactin (PRL) levels and normal menses, but abnormal sellar tomograms characteristic of a pituitary adenoma. To test the hypothesis that these women might have intermittent PRL hypersecretion, we studied PRL secretion by sampling blood every half hour for 24 h in 10 patients and for 17.5 h in another, and compared the findings to those of a group of 5 normal women. The mean 24-h PRL of the 10 patients (16.8 ± 7.8 ng/ml; mean ± SD) was not significantly different from that of the normal women (13.6 ± 3.2 ng/ml), and each patient showed a normal sleep-associated PRL increment. Three individuals exhibited an abnormally elevated 24-h PRL (> 20 ng/ml). Increased PRL secretion occurred primarily at night or in the afternoon. Thyrotropin releasing hormone (TRH) administration caused normal or exaggerated PRL responses in all patients tested. High resolution CT scanning of two of the hypersecre-tors suggested a microadenoma in one case. In another case whose PRL was normal over 17.5 h, transsphenoidal surgery, carried out because of the tomographic findings and the symptom of headaches, demonstrated a 5-mm chromophobe adenoma that did not contain PRL by immuno-histochemistry. Postoperatively the galactorrhea persisted. We conclude that most women with galactorrhea, normal PRL., normal menses, and abnormal tomograms have normal PRL secretion. However, a minority of patients with this syndrome do demonstrate intermittent PRL hypersecretion. The etiology of intermittent PRL hypersecretion and its relevance to galactorrhea have not been determined. Furthermore the clinical and pathological significance of the “abnormal” tomograms and their relevance to PRL secretion and galactorrhea are not clear.

The effect of the dopamine agonist bromocriptine (5-40 mg/day) on cerebrospinal fluid proteins and amines was studied in 7 hyperprolactinemic patients, 4 with empty sella syndrome and 3 patients with pituitary adenoma. Small as well as high doses of bromocriptine depressed the endogenously formed dopamine, noradrenalin and adrenalin. Five patients initially exhibited changes consistent with slight to marked blood-cerebrospinal-fluid (CSF) barrier disturbances and 5 abnormal CSF-protein fractions. One CSF-protein fraction (isolelectric points (pI) approximately 5.3 pH-units) became more prominent during bromocriptine treatment. Analyses of his fraction indicated that it represented a transferrin component. It is stated that bromocriptine treatment besides affecting amine and trace metal metabolism also affects protein metabolism.

Alteration of posterior pituitary function in the empty sella syndrome is rare. A case of central diabetes insipidus and clear-cut deficiency of gonadotropins associated with an empty sella is described. Although computed tomographic scan revealed a defect of the diaphragma sellae, other pathogenic mechanisms are considered. Previously documented cases of empty sella syndrome associated with diabetes insipidus are reviewed.

The calcitonin (CT) concentration has been determined in the serum of 17 patients with different pituitary diseases. More or less elevated levels were found in 7 of them. No definite correlation has been observed between the immunoreactive CT and the different pituitary hormones.