Abstract: Central serotonergic regulation could have a role in the course of pituitary-dependent Cushing's disease. We studied the effects of ritanserin and ketanserin, two related selective 5HT2 receptor antagonists, in 11 patients with Cushing's disease. Treatment lasted from 1 month to 1 year (up to 4 years in one patient). Daily doses were 10-15 mg for ritanserin, and 40-80 mg for ketanserin. Since the two drugs share the same mechanism of action and no qualitative or quantitative differences in response to their administration were observed, the results were pooled together. Patients were assessed by clinical and hormonal evaluation. Urinary cortisol and ACTH were considered the parameters of interest. Short-term response: after 1 month, there was a significant decrease of urinary cortisol from 781 (160) to 331 (215) nmol/d (P < 0.02) while ACTH was 9.8 (1.5) pmol/L baseline and again 8.8 (2.2) pmol/L at 1 month (P = NS). For 9 patients, hormonal parameters were available after 1 week of treatment. In this case, also ACTH levels were significantly decreased (from 9.6 (1.7) to 5.2 (1.3) pmol/L; P < 0.01) together with urinary cortisol (from 781 (194) to 372 (165) nmol/d; P < 0.01). Long-term response: in 3 patients, hormonal parameters failed to respond to serotonin receptor antagonists, which were thus discontinued. An improvement was recorded in the remaining 8 patients, that was prolonged in 3, and transient in 5. In 3 of these latter patients, a marked increase of ACTH was observed before treatment discontinuation. Ketanserin was given to 2 patients with Nelson's syndrome, with only transient ACTH decrease in one, and no changes in ACTH response to CRH after 1 month treatment in both cases. An inhibitory effect of ritanserin and ketanserin on ACTH and cortisol production in Cushing's disease appeared to be limited both in terms of duration of response and number of patients with a satisfactory outcome. However, the results may provide a better understanding of serotonergic modulation in Cushing's disease and lead to therapeutic developments.

Abstract: We report the case of a B-cell type pituitary lymphoma in a 65 year-old male immunocompetent patient who presented with hypogonadotropic hypogonadism and central hypothyroidism and subsequently developed pulmonary lymphoma. Only three cases of pituitary lymphoma have been previously reported, one in a patient with acquired immunodeficiency syndrome, one case of T-cell lymphoma reported in the Japanese literature, and one case of B-cell lymphoma. The previously reported immunocompetent patients presented with signs and symptoms of optic chiasm compression as contrasted to our patient's endocrinologic presentation. B-cell lymphoma of the pituitary gland is a exceedingly rare though distinct clinical entity.

Abstract: The objective of this study is to determine whether pergolide therapy is an effective modality for the de novo treatment of patients with macroprolactinomas Twenty-two consecutive patients with macroprolactinomas were included in the study and followed prospectively These included 16 men and 6 women in whom pregnancy was not of concern Pergolide was administered once or twice a day depending on the patient's preference Ten patients received 01 mg daily as a maintenance regimen and in the others the daily dose ranged from 005 to 05 mg Eight patients reported minor but tolerable side effects One patient had to be switched to cabergoline because of intolerable nausea After a mean of 12 months (range, 3–36), mean PRL levels declined from 3,135 ng/ml (range, 126–31,513) to 50 ng/ml (3–573), representing a mean PRL suppression of 88% (range, 0–99) PRL levels became normal in 15 patients and decreased to 25–40 ng/ml in 3 others The mean tumor volume shrinkage was 25% or greater in 19 patients (86%), 50% or greater in 17 patients (77%), and 75% or greater in 10 patients (45%) Visual abnormalities were reversible after pergolide therapy in all but 1 of 12 patients with initially abnormal formal visual testing Two out of 4 premenopausal women did not normalize PRL levels and had persistent oligomenorrhea Testosterone was low in 14 men at presentation and normalized in 3 with pergolide therapy We conclude that pergolide is a safe, inexpensive, and generally well-tolerated dopamine agonist for the treatment of macroprolactinomas in men and women in whom pregnancy is not of concern In these specific populations, pergolide may become the first-line therapy for treatment of macroprolactinomas

Abstract: Prolactin (PRL)-secreting pituitary adenomas are the most common functioning pituitary tumors. Medical treatment with dopamine agonists is the therapy of choice for macroprolactinomas (≥10 mm). Withdrawal of bromocriptine after weeks or months of uninterrupted therapy has been associated with rapid tumor re-expansion as evidenced by x-ray and CT scanning of the pituitary region. We report a patient with a giant macroprolactinoma who had a dramatic response to bromocriptine (tumor volume shrinkage of 53% within a month) but rapid re-expansion to its original dimensions one week after discontinuation of bromocriptine. To our knowledge, this is the first time that the rapid shrinkage/re-expansion of a macroprolactinoma has been documented with serial MRI scans.

Abstract: Objective: This study reports a six year experience with quinagolide (CV205-502) in the treatment of 40 patients with hyperprolactinemia or prolactinoma. Patients and Measurements: Forty patients with hyperprolactinemia were treated with quinagolide (CV 205-502, NorprolacTM) for 2–72 months (mean 31.6 months). The patient's ages ranged from 12 to 53 years and 90% were female. Seventeen had no radiologic evidence of tumor; 11 had microadenomas; and 12 had macroadenomas. Results: All patients had a reduction of the serum prolactin following quinagolide therapy with normalization in 82% with no tumor, 73% with microadenomas, and 67% with macroadenomas. Fifty-five percent of microadenoma and 75% of macroadenoma patients had a decrease in tumor size when assessed by a blinded reviewer. Ten of 38 female patients became pregnant while taking quinagolide. The dosage of quinagolide ranged from 75 to 400 μg/day with a median dose of 100μg/day. A comparison of side effects in a subgroup of 35 patients who had taken bromocriptine prior to quinagolide administration showed a greater than 75% reduction in nausea, vomiting, dizziness, and drowsiness during quinagolide administration. Conclusions: We conclude that quinagolide is a safe and effective long-term alternative to bromocriptine therapy, particularly in those individuals with bromocriptine intolerance.

Abstract: The use of somatostatin analogues for the treatment of acromegaly is now well established. Recently long-acting preparations of octreotide and lanreotide have been introduced. In this study we have assessed the efficacy and tolerability of the long acting somatostatin analogue octreotide LAR in patients with acromegaly, and compared it with lanreotide SR.

Abstract: Salivary gland rests occur in the posterior lobe of the pituitary gland near or often communicating with the Rathke's cleft or its cystic subdivisions, and are usually incidental autopsy findings. They are attributed to the oropharyngeal development of the Rathke's pouch and may rarely give rise to salivary gland-like tumors in the sella. We present a pleomorphic adenoma, a rare tumor of the sellar region, that has not been previously recognized in association with Rathke's cleft cyst. It occurred in a 44-year-old man who presented with hypopituitarism and reduced vision. Magnetic resonance imaging showed a sellar mass with suprasellar extension which was totally removed. It consisted of segments of a cyst wall lined by focally ciliated columnar of cuboid epithelium containing goblet cells. An eosinophilic granular material with cholesterol clefts represented the contents of the cyst. Within its wall there was a tumor with ductal structures and non-ductal varied cellular components including hypercellular areas of spindle and ovoid cells forming interlacing fascicles. Individual cells appeared to float in abundant mucinous material. The appearances were those of a salivary gland pleomorphic adenoma arising within the wall of a Rathke's cleft cyst. The myoepithelial nature of non-ductal tumor cells was confirmed with immunocytochemistry. The existence of seromucous glands communicating with the Rathke's cleft remnants, explains the concomitant occurrence of the tumor and the cyst. This rare neoplasm from salivary gland rest should be considered in the differential diagnosis of unusual sellar and suprasellar tumors.

Abstract: The localization of inhibin/activin (I/A) subunits was investigated in human normal adenohypophysial cells and in 87 pituitary adenomas of different types, using immunohistochemistry. Monoclonal antibodies directed against α, βA and βB subunits of I/A were employed. In normal pituitary, α subunit of inhibin was detected only in FSH-positive gonadotrophs, while βA subunit of I/A was expressed in FSH-positive gonadotrophs, GH-cells and in a few PRL-cells. βB subunit was found in FSH-positive gonadotrophs, TSH-cells and a few LH-positive gonadotrophs. The three subunits of I/A were detected in the majority of nonfunctioning tumors, while functioning adenomas showed a significantly lower expression. This study shows that α, βA and βB subunits of I/A are expressed by specific adenohypophysial cell types and that they are characteristically present in nonfunctioning adenomas. These results suggest that inhibins and activins may play a role in the local regulation of pituitary hormonal secretion both in normal adenohypophysial cells and in pituitary adenomas.

Abstract: Hitherto four relevant cohort studies have been published on the life expectancy of patients with hypopituitarism, two from the UK and two from Sweden. In all four studies patients with acromegaly or Cushing's disease were excluded, and patients with GH replacement were not included. A crude meta-analysis, not considering differences in validity of the study designs, gives an overall Relative Risk (RR) of 1.47, with a relatively small 95% confidence interval of 1.27-1.70. The aim of this critical review was to assess whether lacking validity in the design of one or several of these studies indicates that the true RR might be higher or lower than indicated by meta-analyses. A high frequency of cranial irradiation in one of the Swedish cohorts may explain part of the very high observed RR for cerebrovascular mortality, but there remained a 40% risk increase for cardiac diseases that cannot be explained by irradiation. Some other validity problems, especially seen in the UK studies, will result in under-estimation of the true RR, but for others the direction of bias is uncertain due to lacking information in the original publications. According to our view, it is more probable that the observed overall 50% risk increase for vascular mortality is an under-estimation than an over-estimation of the true RR. This analysis is of a qualitative nature, and it is not possible to quantify to what extent the lacking validity may have affected the RR.

Abstract: There are few long-term studies of cabergoline (CAB) administration in patients with macroprolactinomas. All of these studies included different type of patients, such as patients with idiopathic hyperprolactinemia, microprolactinomas and previously treated or untreated macroprolactinomas. We report a study of CAB treatment conducted exclusively in patients with newly diagnosed, untreated, macroprolactinomas.

Abstract: The modern views on the anatomical and physiological interactions between the hypothalamus, pituitary and thyroid gland have emerged only in the last fifty years, although their historical roots may be found in a number of ancient and still poorly known ideas and observations. The regulation of energy body stores and temperature by the hypothalamic-pituitary-thyroid axis, for example, is a classical case of “fixitee du mileu interieur” in the sense originally suggested by Claude Bernard in the late 1800s, i.e. a homeostatic mechanism, but already 2100 year before Aristotle had stated that the brain was necessary for the maintenance of body integrity by regulating food intake and behavior in relation to body temperature, the latter primarily determined by the heat of the circulating blood. Five hundred years later Galen of Pergamon reported fundamental discoveries in the anatomy of the third ventricle region, including the location of the pituitary gland inside the sella turcica embodied in a vascular network, the rete mirabilis, and observed nerves adjoining the “soft flesh” in the neck, i.e. the thyroid gland. He first proposed that the energy of the body (the vital spirit) was carryed through the arteries at the level of the rete mirabilis, where it was transformed into nerve inpulse (the animal spirit), eventually tranferred by the nerves to the periphery of the body, “glands” included, raising implicitly the possibility for a nervous influence over the thyroid activity. The Galenic model remained virtually unaltered up to the beginning of the 14th century, when the mediaeval anatomist Mondino de' Liuzzi put forth the idea that the thyroid gland interacted with the heat of the blood circulating in the internal carotid arteries due to their anatomical relation with the thyroid. This interaction enriched the vital spirit, i.e. the energy of the body, prior to its “pituitary” transformation into animal spirit, i.e. to nerve inpulse directed to the periphery of the body. In addition, Mondino envisaged the possibility that the third ventricle was implicated in the regulation of the animal behavior by processing sensory, cognitive and emotional informations. No trace of these Mondino's ideas can be found throughout the Renaissance, despite the leading anatomical work of the period, the Fabrica by Andreas Vesalius, remained apparently prone to the Galenic dogma of the rete mirabilis. After Vesalius, the Galenic anatomy and physiology of the infundibular region survived for at least two more centuries, and we owe Luigi Galvani, the discoverer of animal electricity, the first detailed anatomical observation that in humans the nasal secretions were not a drainage waste of the brain ventricles, as postulated by Galen, but the product of nasal mucous glands. From an epistemological standpoint, Aristotle anticipated the possibility that the “set point” for energy intake and behavioral adaptation was determined by the interplay between the brain activity and a thermogenic principle present in the circulating blood, in a manner very close to a circuitry devoted to maintain the energetic and thermic stady state of the living organism (homeostasis). The Galenic modelling of brain-thyroid interaction is an evolution of the Aristotelian one, since it postulates an anatomical and functional loop linking the transport of body energy to the brain through the arteries, and the transformation of this energy into neural output directed to the peripheral glands, “thyroid” included, by the mediation of the pituitary gland. Finally, the proposal by Mondino de' Liuzzi provides a scheme of brain-thyroid interaction that merges together the “homeostatic” Aristotelian with the “pituitary/autonomic” Galenic models, suggesting that the thyroid plays a “thermoregulatory” role linked to the control of body energy. This remarkable set of ideas has never been credited to Mondino by the modern historical critique, possibly due to the impact that the methodological reform of anatomy by Vesalius, resulting in the denial of much Galenic tradition, had on the way to interpret Mondino's work from the late Renaissance up to the 20th century. The current concepts of the regulation by peripheral nerves of the thyroid blood flow and/or secretion seems to have been anticipated by anecdotal observations in the Egyptian and Roman times. In the second half of the 18th century the belief by Luigi Galvani that the peripheral nerves were carrying electrical impulses can be considered the first theoretical statement derived from an empirical evidence, i.e. the animal electricity, supporting the Galenic idea that autonomic fibers might influence the secretion of “humors” from peripheral glands, thyroid included. However, only during the last century and first half of the present one it is possible to recognize anatomical and physiological observations that, although controversial like those of W.B. Cannon on experimental hyperthyroidism, opened the way to the current evidence of an autonomic control of the thyroid function.

Abstract: Background: Somatostatin analogues are nowadays the milestone in the medical treatment of acromegaly. We evaluated the effects of a new 60 mg longer-acting formulation of lanreotide (LAN60) on GH/IGF-I levels and tumor size. Patients: Twenty-one acromegalics entered a prospective monocentric open study. Eight were consecutive “de novo” patients (group I). Thirteen patients sensitive to SA (GH levels < 2.5 μg/l and/or IGF-I normalization on chronic LAN 30 mg (LAN30) treatment) were switched to LAN60 (group II). Protocol: LAN60 was administered IM for 6 cycles at 28 day intervals. In group I when GH/IGF-I remained pathological, the intervals were shortened to 21 days for the last three cycles. Controls: GH/IGF-I at the end of the 1st, 3rd and 6th cycle; MRI at the end of the study in all patients in group I bearing an adenoma. Results: Group I. GH (p = 0.00638, below 2.5 μg/l in two patients) and IGF-I (p = 0.0289, normalized in 5) significantly decreased. In one of two patients shortening the LAN60 schedule was more effective in suppressing GH/IGF-I. Group II. No change in GH and IGF-I levels was observed with the administration of LAN60, instead of LAN30. On LAN60 GH remained below 2.5 μg/l in 8/10 patients and IGF-I normal in 11/11 patients that had attained those values on LAN30. Tumor markedly shrank (23% to 64% vs basal), from 1400 (664–1680) mm3 to 520 (500–960) mm3 (median, interquartile, p = 0.0218) in all the 5 evaluable patients. Conclusion: LAN60 is a very effective and longer-lasting formulation for the treatment of acromegaly. A closer administration schedule might achieve greater efficacy. Its effectiveness in shrinking tumor opens new perspectives in the therapy of acromegaly.

Abstract: Aim: Several studies have demonstrated the efficacy of octreotide LAR administered intramuscularly at 4-week intervals in the treatment of acromegaly. In contrast, few data are available on the time course of GH and IGF-1 plasma levels following octreotide LAR withdrawal. This prompted us to study these parameters for up to 20 weeks following drug withdrawal in a group of 18 acromegalic patients treated for one year Design and patients: We studied 18 patients treated with octreotide LAR 10 mg (n = 2), 20 mg (n = 15) and 30 mg (n = 1) every 4 weeks for one year. GH (mean level during a 4-hour daily profile) and IGF-1 concentrations were measured at the end of treatment, just before the last injection (baseline) and then 15 ± 2weeks (first control) after the last injection. In patients with GH levels below 2.5 μg/L and/or normal IGF-1at the first control, a second control was performed four to eight weeks later. Results: After one year of treatment with octreotide LAR, the mean plasma GH concentration was 1.91 ± 1.25 μg/L (mean ± SE) and the mean IGF-1 concentration was 440 ± 251 μg/L. Among the 18 patients, 13 had mean plasma GH concentrations below 2.5 μg/L and seven could be considered as well-controlled (normal IGF1 and mean GH levels below 2.5 μg/L). After treatment withdrawal, the plasma GH concentration remained below 2.5 μg/L at the first and the second controls in 2 of the 13 (15%) patients with suppressed GH levels on baseline. Among the seven well-controlled patients on baseline (GH levels below 2.5 μg/L and normal IGF-1), one (15%) remained well-controlled, one (15%) kept GH levels below 2.5 μg/L but increased IGF-1 levels, and one (15%) kept normal IGF-1 levels but increased mean GH levels at the first control. This hormonal status remained unchanged at the second control in these 3 patients. Conclusions: These results show long-lasting suppression of GH secretion after treatment withdrawal in some acromegalic patients treated for 12 months with octreotide LAR. The duration of GH suppression after treatment withdrawal is variable. Mean GH levels remained below 2.5 μg/L in 15% of our patients for up to 21 weeks following withdrawal of octreotide LAR. In practice, it may be preferable to wait several months after long-acting somatostatin analog withdrawal before reassessing hormone status. Owing this long-lasting effect, a dose reduction to 10 mg and/or a longer interval between injections could be considered for very good responders, as this would lead to considerable cost savings without affecting GH or IGF-1 control.

Abstract: Silent pituitary adenomas occur in 25–40% of all clinically apparent pituitary tumours. However, the subsequent development of florid Cushing's disease in a patient with a previous non-functioning tumour is extremely rare. We describe a 47 year-old woman presenting initially with a large, invasive and recurrent, non-functioning pituitary tumour. Histopathologic study of the initial tissue did not stain for any hormones. Six years after the initial presentation, she manifested florid ACTH dependent Cushing's syndrome. A recurrent invasive pituitary macroadenoma necessitated a third transphenoidal surgery. The resected specimen, in this instance, revealed positive staining for ACTH, FSH, prolactin, and growth hormone on immunocytochemistry. An incomplete response to surgical, radiation and medical therapy necessitated a bilateral adrenalectomy to control the hypercortisolism, which resulted in remarkable clinical improvement. We also review five previous case reports from the revision literature of similar transformations from non-secreting pituitary adenomas to Cushing's disease. This subset of patients may represent yet another entity in the widening spectrum of Cushing's syndrome.

Abstract: Pituitary gland is an uncommon site of a primary cancer. Of more than 600 cases of pituitary tumors seen at the KFSHR their follow-up data provide information on the natural history of this cancer. Patient #1; a 46 year old lady with Cushing's disease (CD) presented with an enlarged right cervical lymph node (LN) 2 years after having undergone a partial hypophysectomy through transsphenoidal surgery (PHYPX/TSS) and ERT for an invasive pituitary tumor. Patient #2; a 26 year old man presented with CD and underwent bilateral adrenalectomy (ADx) and pituitary ERT. Thirty-nine months later he developed Nelson's syndrome and a PHYPX/TSS was performed. Incidentally discovered hepatic metastases in this patient and an excisional biopsy of the LN in patient #1 showed histological features very similar to the pituitary tumor, and they stained strongly positive for ACTH. Perinuclear spherical hyalinized cytoplasmic inclusions were seen in the LN biopsy that corresponded to bundles of type 1 microfilaments (specific for pituitary ACTH-producing cells) seen by electron microscopy. A whole body 18-Fluoro-2-Deoxy-D-Glucose positron emission (FDG-PET) scanning, showed an intense uptake in the neck mass. A trial of octreotide did not change the exceedingly high levels of ACTH in patient #2, further supporting the diagnosis of ACTH-PPC. The clinical course of 102 months prior to his demise showed continued progression of the primary and the metastatic tumor. Patient #1, is alive at 15 months follow-up; hypercortisolemia is controlled using ketoconazole. ACTH-PPC should be entertained in a patient with CD presenting with persistent cervical lymphadenopathy. The clinical course in our patients suggests that the emergence of PC may involve a proliferative continuum from a pre-existing PA to an invasive tumor, culminating in a carcinoma. Adjunctive events such as ERT/ADx may predispose to the evolution of PC in genetically susceptible individuals. Because ERT is an effective treatment for PA its use will continue; it is important to be aware of the possible complication of primary pituitary carcinoma.

Abstract: It is widely accepted that glucagon stimulates GH, ACTH and cortisol release in humans, though the mechanisms underlying these effects are unclear. Aim of the present study was to evaluate the stimulatory effect of intramuscolar (im) and intravenous (iv) glucagon (GLU) administration on ACTH, cortisol (F) and GH release in normal adult subjects and to compare its effect on hypothalamo-pituitary adrenal (HPA) axis with that of hCRH. To this goal, in 6 normal young women (26–32 yrs, 50–58 kg) we studied the ACTH and F responses to either im or iv GLU (1 mg, approximately 0.017 mg/kg in subjects of 54.1 ± 1.6 kg) administration as well as to iv hCRH (2.0 μg/kg) or placebo administration. The GH and glucose variations after GLU administration were also studied. Iv GLU did not modify the spontaneous decrease of ACTH and cortisol levels observed after placebo. Conversely, im GLU elicited clear-cut ACTH and F responses (peak vs baseline, mean ± SEM: 53.0 ± 15.2 vs 19.0 ± 1.5 pg/ml, p < 0.05 and 222.3 ± 23.8 vs 158.3 ± 7.0 μg/l, p < 0.05) which were higher than those recorded after hCRH (28.1 ± 4.6 vs 17.4 ± 3.1 pg/ml, p < 0.02 and 182.7 ± 22.8 vs 114.8 ± 12.3 μg/l p < 0.02), though this difference did not attain statistical significance. Also GH rise was recorded after im but not after iv GLU administration (11.6 ± 3.4 vs 3.3 ± 0.7 μg/l, p < 0.05). Thirty min after both iv and im GLU administration glucose levels showed a similar increase followed by similar decrease. The intramuscular administration of GLU induced negligible side-effects in some subject (mild and transient nausea) which, on the contrary, were clear in all subjects after its intravenous administration (nausea, vomiting, tachicardia). In conclusion, glucagon “per se” is not an ACTH, cortisol and GH secretagogue. After intramuscular administration glucagon is a stimulus of HPA axis at least as effective as hCRH. The mechanisms underlying the ACTH, cortisol and GH responses to im glucagon unlikely include glucose variations or stress.

Abstract: We studied the effects of cortisol withdrawal and patterned replacement upon spontaneous GH secretion and circadian rhythmicity in 7 patients with Addison's disease. Hydrocortisone was administered in physiological daily total dosages, and all resulting plasma cortisol values were 2-15 micrograms/dl. It was given in 3 pulsatile modes: simulating "physiological" rhythm, "reverse" diurnal rhythmicity and "continuous" pulsatility. All modes of cortisol administration increased mean 24 h, GH pulse amplitude and interpulse GH levels. During saline infusions circadian GH rhythmicity was preserved, with GH being at its highest between 2400-0400 h. Administration of hydrocortisone in any mode did not modify circadian GH rhythmicity. We conclude: Cortisol replacement in physiological daily doses increases GH output in patients with Addison's disease by augmenting GH pulse amplitude and interpulse levels. This is likely due to the attenuation of hypothalamic somatostatin (SRIF) secretion by physiologic levels of cortisol. By inference, it implies that cortisol deficiency leads to diminution of GH output with low GH pulse amplitude, likely as a result of an augmented hypothalamic somatostatin secretion. However, circadian rhythmicity of GH secretion is glucocorticoid-independent.

Abstract: Chromogranin A (CgA), pancreastatin (PST), intervening-peptide (IP) and WE-14 antisera were employed to investigate the proteolysis of CgA in 50 pituitary adenomas. All non-functioning (NF) pituitary tumours (n = 28) exhibited CgA immunoreactivity. PST, IP and WE-14 immunostaining was observed in 85%, 89% and 67%, respectively. CgA, PST and 1P immunostaining were comparable in the majority of NF tumours, while less intense WE-14 immunoreactivity was detected in a subpopulation of NF tumour cells. Approximately half of the functioning pituitary tumours expressed CgA immunoreactivity. Six of nine ACTH-secreting tumours displayed CgA and IP immunostaining; four of these tumours displayed PST immunoreactivity. WE-14 immunoreactivity was detected in one corticotroph tumour. Three of six growth hormone (GH) secreting tumours displayed CgA immunostaining, two exhibited PST and IP, and one exhibited WE-14 immunoreactivity. Clusters of WE-14 immunopositive cells were detected in one GH tumour. One of seven prolactinomas exhibited weak CgA immunostaining, while weak IP and WE-14 immunostaining was detected in an additional tumour. No PST immunostaining was detected in prolactinomas. Therefore CgA is a valuable marker of NF pituitary tumours, however it is a more sporadic marker of functioning adenomas. In general, the cellular pattern and intensities of CgA, PST and IP immunoreactivity were comparable in the majority of pituitary adenomas. In contrast, WE-14 immunostaining was observed in a subpopulation of tumour cells. The pathophysiological significance of the proteolysis of CgA to generate bioactive peptides in both NF and functioning pituitary adenomas remains to be established.

Abstract: Recent studies have demonstrated the occurrence of endocannabinoids and their CB1 receptor subtype in the anterior pituitary gland, despite previous evidence suggesting their exclusive presence and action in the neuroendocrine hypothalamus The present study was designed to examine the potential changes in these CB1 receptors located in the anterior pituitary gland in three different experimental situations, which are known to affect anterior pituitary function: (i) estrogen-induced pituitary tumorization, (ii) presence of ectopic pituitaries, and (iii) chronic treatment with D1 or D2 dopaminergic receptor agonists or antagonists Results were as follows Induction of pituitary tumorization by implantation of silastic capsules containing diethylstilbestrol, a synthetic estrogen, produced the expected body weight loss and increase in pituitary weight and plasma prolactin (PRL) levels In hyperplastic pituitaries, both CB1 receptor mRNA levels and immunoreactivity decreased significantly Double labelling studies demonstrated that CB1 receptors colocalized, in pituitary tumors, with PRL- or luteinizing hormone-containing cells, as they did in normal pituitaries Plasma PRL levels were also increased in rats bearing ectopic pituitaries implanted under the kidney capsule As previously reported, this increase was originated by the hormone release from the ectopic gland, because the normotopic pituitary collaborated scarcely to elevate PRL levels since it was hypofunctional due to the activation of peripheral PRL-induced feedback mechanisms However, in this hypofunctional anterior pituitary, there were not any changes in CB1 receptor mRNA levels and immunoreactivity Finally, chronic treatment with SKF38393, a D1 receptor agonist, or bromocriptine, a D2 receptor agonist, or with their corresponding antagonists, SCH 23390 or sulpiride, respectively, did not alter CB1 receptor mRNA levels and immunoreactivity, although produced the expected changes in plasma PRL levels In summary, estrogen-induced pituitary tumorization was associated with a marked reduction in CB1 receptors, despite the fact that these receptors were located, among others, on lactotroph cells which develop hyperplasia during tumor induction Whether this decrease is associated with the ethiology of pituitary tumor induction and whether their pharmacological activation might affect tumorization process are presently unknown, but this will be subjected of further research

Abstract: Leukemia inhibitory factor (LIF) is a pleiotropic, neuropoietic cytokine found in bovine, murine, and human fetal and adult pituitary cells, mostly in corticotrophs and somatotrophs In addition, it has been found in a few GH- and ACTH-producing human pituitary adenomas The aim of our study was to investigate the presence of LIF in various morphologic types of human pituitary adenomas Ninety-eight operated pituitary adenomas diagnosed by light microscopy and classified by pituitary hormone immunocytochemistry and electron microscopy were studied Sixty-eight tumors were functioning and included 15 densely granulated (DG) and 10 sparsely granulated (SG) somatotroph (SM) adenomas, 5 lactotroph (LT), 7 mixed SM-LT and 31 corticotroph (CRT) adenomas The remaining 30 nonfunctioning tumors included 11 gonadotroph (GON) and 19 null cell (NULL) adenomas For immunocytochemical demonstration of LIF, a specific polyclonal antiserum was applied on formalin-fixed, paraffin-embedded tissues The immunohistoscore ranging from 1 to 64 grades was determined by multiplying the immunostaining grade (1–4) by the staining intensity grade (1–4), and by the heterogeneity grade (1–4) Ninety adenomas (92%) were variably immunopositive for LIF LIF was expressed in 775% of CRT, 818% of GON, 933% of DG-SM, and in all SG-SM, LT, SM-LT and NULL adenomas LT adenomas showed the highest immunostaining grade, followed by SG-SM, GON, NULL, SM-LT, DG-SM, LT and CRT adenomas GON adenomas showed the highest immunohistoscore, followed by NULL, DG-SM, SM-LT, SG-SM, LT and CRT adenomas Nonfunctioning tumors showed a significantly higher immunohistoscore compared to functioning adenomas (p < 001) We conclude that LIF expression is frequent in all types of functioning and nonfunctioning pituitary adenomas

Abstract: We describe four young patients (age 19–34 years) with hypopituitarism following closed head injury. The diagnosis was made by demonstration of low basal pituitary hormone levels and dynamic tests showing low pituitary reserve. The time interval between the injury and diagnosis of hypopituitarism was between three weeks and two months demonstrating the difficulty and complexity of making this diagnosis. Three of our patients (all patients suffering from anterior pituitary hormone deficiency) had ACTH deficiency, a condition which may be life threatening if left undiagnosed; these patients also demonstrated central hypothyroidism. Hypogonadotrophic hypogonadism occurred in three of the patients and was treated with hormonal replacement. Diabetes insipidus was the only insult in one of our patients, accompanied other hormonal deficits in two, and did not appear at all in another patient. Information about skull damage was available for three of the patients, and included skull base and facial bone fractures, probably reflecting the extent of injury necessary to cause hypopituitarism. All patients regained normal lives with adequate hormonal replacement therapy.

Abstract: The management of pituitary macroadenomas which lead to gigantism may require multiple therapeutical approaches, including medical treatment, surgery, and radiation therapy. Transsphenoidal surgery (TSS) during early childhood that achieves total removal of a growth hormone (GH) secreting tumor is rarely reported. The surgeon is confronted with special problems regarding the infantile anatomy. In this case, a 3.5 year old child, the youngest successfully treated by TSS so far, suffered from a GH- and prolactin (PRL) secreting macroadenoma of the pituitary gland. The girl initially presented with an increasing growth rate, later with breast development, and finally, at the age of 2.8 years, with galactorrhea and secretion of blood from the nipples. Increased levels of GH [122 μg/l], insulin-like growth factor (IGF-1) [830 μg/l], insulin-like growth factor binding protein 3 (IGFBP-3) [8.6 mg/l] and PRL [590 μg/l] were found. MRI scans revealed a macroadenoma of 2.7 cm diameter. An eight-week trial of relatively low dose dopamine agonists led to a reduction of PRL, while the GH- and IGF-1 levels remained unchanged; the tumor showed only little shrinkage. Since there was chiasma compression, we opted for early TSS. A complete tumor removal was achieved despite the difficulties of a narrow approach. After TSS, low levels of GH, IGF-1, and PRL documented a complete tumor removal, but persistent diabetes insipidus and anterior lobe deficits resulted from surgery. In summary, if primary medical therapy alone is unable to adequately reduce hormone hypersecretion and tumor size in early childhood, TSS is recommended. Thus, radiation therapy may be reserved for surgical failure.

Abstract: The cyclic somatostatin analog, octreotide, forms the mainstay of medical treatment for acromegaly. In addition to lowering circulating growth hormone levels and shrinking tumor size, octreotide may provide symptomatic relief of headaches associated with growth hormone secreting tumors. The majority of reported complications of octreotide therapy are gastrointestinal and metabolic. The present case illustrates the development of acute bilateral cavernous sinus syndrome with loss of eye movement bilaterally during octreotide therapy. Serial MRI examination suggest tumor infarction as the etiology. The symptoms resolved over 2 months as the tumor shrunk in size and growth hormone was dramatically reduced.

Abstract: The pituitary corticotrope AtT-20 stable cell line has been used as a model system to study peptide secretion, glucocorticoid regulation, and several other processes. In order to better understand this model cell line, a phage cDNA library was generated from AtT-20/D-16v cell mRNA and cDNA sequences were obtained for 317 clones repre- senting 203 known genes and 48 novel cDNAs. The sequenc- ing results revealed the prevalence of the mouse leukemia virus in this cell line and also identified a number of puta- tively secreted molecules that were not previously recog- nized as being secreted from AtT-20/D-16v cells or pituitary corticotropes. Nine completely novel cDNAs and 39 cDNAs homologous to known ESTs were also identified. A listing of other genes known to be expressed in AtT-20/D-16v cells is also provided.

Abstract: We report a case of acromegaly with relatively low GH secretion in a patient with GH-secreting pituitary macroadenoma. The 44-year-old male patient presented with left temporal hemianopsia and characteristic acromegalic face, but had relatively low baseline and post-glucose GH levels. IGF-1 and IGFBP-1 were elevated. Transsphenoidal surgery did not achieve clinical or biochemiacl remission, and the patient still had elevated IGF-1 levels with low GH. Histological examination of the resected tumor revealed a pituitary adenoma stained weakly for GH. The patient was treated then with monthly injections of Sandostatin-LAR, with clinical improvement and suppression of IGF-I to the normal range. This is a rare case of acromegaly without elevated GH levels, and good response to treatment with somatostatin analog, as expected in classical GH-secreting pituitary adenomas.

Abstract: Previous in vivo findings show that in the virtual absence of progesterone (P), the antiprogestin RU486 reduces LH and FSH secretion in proestrous rats, indicating that activation of P receptor (PR) can occur in the absence of the cognate ligand. The present study investigates, in vitro, whether or not the inhibitory effect of antiprogestin RU486 on gonadotropin secretion in the absence of P is estrous cycle dependent, and whether its specific expression in proestrus mirrors the high estrogen (E2) background. In the first experiment we investigated the effect of RU486 (10 nM) and/or LHRH (10 nM) on LH and FSH secretion in incubated pituitaries collected on each day of the estrous cycle of the rat. In the second experiment, we determined the effect of RU486 and/or LHRH on preovulatory LH and FSH release by pituitaries from female rats that were ovariectomized (OVX), treated with the antiestrogen LY117018-HCL (Eli Lilly & Co.), or injected with 20 μg of estradiol benzoate (EB). The third experiment investigated the effect of RU486 and/or LHRH on LH and FSH release by pituitaries collected from intact or EB-treated (0.1 mg/kg over three consecutive days) male rats. RU486 reduced both basal and LHRH-stimulated LH and FSH secretion in proestrous pituitaries from normal 4-day cyclic rats. By contrast, in diestrous pituitaries, RU486 increased both parameters of LH secretion but was without effect on FSH release. RU486 was also without effect in pituitaries collected from rats in estrus or metestrus, or from OVX or antiestrogen-treated rats. Moreover, EB injection or treatment induced the full inhibitory effect of RU486 in pituitaries from female and male rats, respectively. The above results suggested that P occupancy of the receptor is not required for the formation or function of the active receptor and hence for preovulatory LH and FSH secretion, and that this form of PR activation at pituitary level is E2-dependent and not genetically determined.

Abstract: We report a case of hepatolithiasis (intrahepatic stone) complicated by gram-negative sepsis in a 37 year old male with acromegaly being treated with octreotide. As a child, he had suffered a traumatic injury to his liver requiring the surgical repair of a laceration. This is the first reported case of hepatolithiasis during octreotide therapy. Gallstones and bile sludge are common side effects of octreotide therapy but rarely become symptomatic or require treatment. Hepatolithiasis is uncommon in western countries but is quite prevalent in East Asia and is often associated with a predisposing condition that causes intrahepatic bile stasis (eg. bile duct stricture). In addition to its known effect on gallbladder stasis, octreotide alters bile acid composition and may thus hasten intrahepatic sludge and stone formation. Extra caution should be taken in using octreotide or its long-acting analog in patients otherwise predisposed to intrahepatic bile stasis.

Abstract: The effect of a 6 hour continuous infusion of Hexarelin (100 μg/hour) on GH peak frequency, amplitude and duration, GH trough concentrations, the interval between successive peaks and the pituitary responsiveness to GHRH, as well as GH axis and galanin mRNA contents, were examined in conscious adult male rats. Plasma GH concentrations peaked within 15 minutes after the initiation of Hexarelin infusion, but returned to baseline levels by 60 minutes. No significant differences between Hexarelin and saline infused rats were noted for any of the parameters of pulsatile GH release analyzed. However, following a 6 hour infusion, rats treated with Hexarelin demonstrated a greater GH responsiveness to GHRH (ΔGH: 57 ± ng/ml for Hexarelin infused; 21 ± 7 ng/ml for saline infused; p < 0.05). Furthermore, the rats infused with Hexarelin demonstrated decreased GHRH and increased hypothalamic galanin mRNA contents as compared to the saline-infused rats, while hypothalamic somatostatin and pituitary GH mRNA contents appeared unchanged. Rats infused with Hexarelin had lower pituitary galanin mRNA content than did the rats which were infused with saline. Collectively, these results suggest that Hexarelin may not act via alteration of somatostatin synthesis and that suppression of somatostatin's action at the pituitary can not be excluded. The current study also suggests that other hypothalamic pathways aside from those currently defined for the growth axis may be involved in the mechanism by which Hexarelin and the other GH-releasing peptides elicit GH release.

Abstract: Double pituitary adenomas are rare in surgical specimens and the most common clinical feature in reported patients has been acromegaly. We report 3 cases of double pituitary lesions in patients who presented with Cushing's disease. In a 22-year-old man (case 1) with delayed puberty and low testosterone levels, mild hyperprolactinemia was diagnosed and treated with dopamine agonist therapy that reduced the prolactin (PRL) levels to normal. Over a 1-year period Cushing's disease developed gradually and was confirmed with classical endocrine testing. In a 27-year-old woman (case 2) who initially presented with severe depression and morbid obesity there was a gradual onset of Cushing's disease; initially she had minimally elevated serum PRL. In a 33-year-old woman (case 3) there was a 2-year history of Cushing's disease characterized by hirsutism, hypertension and weight gain; serum PRL was normal. Magnetic resonance imaging in all 3 patients revealed a microadenoma that was successfully removed by transsphenoidal pituitary surgery. Histology and immunocytochemistry in case 1 and case 3 revealed a corticotroph cell adenoma and a PRL cell adenoma in separate areas of the pituitary. In case 3 the PRL cell adenoma was "silent" but in case 1 the PRL cell adenoma may have been the cause of the mild hyperprolactinemia. In case 2 nodular corticotroph hyperplasia was the cause of Cushing's disease and a "silent" PRL cell adenoma was also identified. We conclude from these cases and a literature review that double pituitary lesions may occur in patients with Cushing's disease. The corticotroph part of the double lesion may consist of a corticotroph cell adenoma or, as reported in this study, of corticotroph nodular hyperplasia. The counterpart of the double lesion may consist either of a "silent" PRL cell adenoma or a functional PRL cell adenoma causing hyperprolactinemia.