Growth Hormone-secreting Pituitary Tumors Research Articles

Acromegaly and Gastrointestinal Cancer-Reply

In reply Anand raises two interesting points pertinent to the pathogenesis of gastrointestinal cancer in patients with acromegaly. First, the possibility that the occurrence of growth hormone secreting pituitary tumor and digestive cancer could be the result of common genetic alterations. Alternatively, the sustained growth hormone hypersecretion could act as a promoter of neoplastic growth in an appropriate genetic background. Second, the importance of the sensitivity of target tissues, in this case the gastrointestinal mucosa, to circulating growth factors. There is, indeed, general agreement in the literature that the occurrence of colonic cancer in acromegaly does not merely reflect the entity of growth hormone or insulinlike growth factor—I secretion, and we also argued on this point. 1 It is conceivable that the expression of growth hormone or insulinlike growth factor—I receptors in the gastrointestinal mucosa (genetically determined?) is the key to the neoplastic growth.

Acromegaly

Acromegaly results from growth hormone hypersecretion and is accompanied by deleterious changes in many tissues and organs. Some signs and symptoms of acromegaly respond to growth hormone-lowering therapy, but many are irreversible. Thus, early diagnosis and effective surgical, radiation, and medical therapies are the mainstays of combating this debilitating disease. Over the past several decades, the reestablishment of the transsphenoidal approach to pituitary surgery, the development of magnetic resonance imaging technology, refinements in the delivery of radiotherapy to pituitary tumors, and the development of long-acting somatostatin analogues have greatly improved our ability to effectively treat acromegaly. Advances in our understanding of hypothalamic-pituitary physiology, tumorigenesis, and tumor biology promise to further improve our ability to diagnose and treat patients with growth hormone-secreting pituitary tumors.

ACTIVATING MUTATION IN THE STIMULATORY G PROTEIN GENE IN AN INFANT WITH ADRFNOCORTICONODULAR DYSPLASIA

Infantile Cushing's Syndrome is a rare condition caused by excess cortisol production. We describe an activating mutation in the gene coding for the stimulatory G protein (Gsalpha) in DNA from adrenal tissue in an infant with ACTH independent Cushing's Syndrome. Activating mutations in exons 8 and 9 of the Gsalpha gene have been associated with growth hormone secreting pituitary tumors and McCune-Albright syndrome. Specifically, point mutations coding for an arginine to cysteine or an arginine to histidine substitution at site 201 in exon 8 have been described.The patient in this study was Cushingoid in appearance with poor linear growth by 3 months of age. Evaluation revealed elevated serum cortisol despite low and high dose dexamethasone suppression and undetectable baseline ACTH levels (<3 pg/ml). He underwent bilateral adrenalectomy with subsequent steroid replacement. Adrenal histology revealed bilateral adrenalcortical dysplasia with nodular elements.Genomic DNA was extracted from adrenal tissue and amplified by PCR with primers for Gsalpha exon 8. Using allele specific oligonucleotide hybridization, the amplified DNA was probed for the presence of point mutations which correspond to the known mutations in exon 8. An oligonucleotide probe corresponding to the cysteine substitution at site 201 hybridized with amplified DNA from the patient's adrenal tissue. A “wild type” probe coding for arginine bound to both leukocyte DNA from a normal human control and patient DNA while the probe for the arginine to hisiidine mutation bound to neither patient nor control DNA.We conclude that the arginine to cysteine activating mutation in exon 8 of Gsalpha is present in the adrenal tissue of ihis infant with Cushing's Syndrome. This mutation may be involved in the pathogenesis of adrenocorticonodular dysplasia in some patient's with infantile Cushing's Syndrome.

Increased serum growth hormone concentration in feline hypertrophic cardiomyopathy.

Serum growth hormone concentration was measured by radioimmunoassay in 31 cats with hypertrophic cardiomyopathy, 38 normal cats, and 35 cats with other cardiac disease. Cats with hypertrophic cardiomyopathy had a significantly increased serum growth hormone concentration when compared with normal cats and cats with other cardiac disease. The serum growth hormone concentration in cats with hypertrophic cardiomyopathy was less than that previously reported in cats with growth hormone secreting pituitary tumors. Pituitary tumors were not identified in eight of the cats with hypertrophic cardiomyopathy examined at necropsy. An increased serum growth hormone concentration may be measured in cats with hypertrophic cardiomyopathy but it is unclear if the increased serum growth hormone concentration is a cause or effect of hypertrophic cardiomyopathy.

Clinical, Biochemical, and Morphological Correlates in Patients Bearing Growth Hormone-Secreting Pituitary Tumors with or without Constitutively Active Adenylyl Cyclase

Somatic mutations in the alpha-chain (alpha s) of the stimulatory regulatory protein of adenylyl cyclase (Gs) causing constitutive activation of the enzyme have been identified in a subset of human GH-secreting pituitary adenomas. This study reports on the differences between acromegalic patients bearing tumors without (group 1; n = 51) or with (group 2; n = 29) this alteration. No difference in age, sex, clinical features, duration of the disease, or cure rate was observed between the two groups. By contrast, group 2 patients had higher basal GH levels than group 1. Moreover, a significant difference in sellar morphology was found; group 2 patients more frequently showed sellas of normal size (grade I) than group 1. Hypersecretory activity of group 2 tumors was also apparent at electron microscopy; contrary to those of group 1, cells of group 2 tumors were densely granulated and showed prominent rough endoplasmic reticulum and Golgi complex. With respect to group 1, group 2 patients were less responsive to GH-releasing hormone, while they were more sensitive to somatostatin- and dopamine-induced GH inhibition. These results suggest that patients with constitutively active adenylyl cyclase have hyperactive tumors; the sensitivity of these tumors to inhibitory agents (somatostatin and dopamine), possibly counteracting the expression of activating mutations, might explain the low rate of tumor growth.

Somatostatin receptor imaging with 123I-Tyr 3-octreotide : S.W.J. Lamberts, W. Bakker, J-C. Reubi and E.P. Krenning. Department of Medicine, Erasmus University, Rotterdam and Sandoz, Berne, Switzerland

Somatostatin receptors have been shown to be present at all main sites of its action, such as the anterior pituitary gland, the exocrine and endocrine pancreas, the mucosa of the gastrointestinal tract and the central nervous system (1, 2). Somatostatin receptors can be measured by two different approaches (3). First by direct biochemical techniques, i.e. binding studies on tissue homogenates in vitro, which allow precise characterization of the affinities and kinetics of these receptors. Secondly, receptors can also be visualized in tissue sections with autoradiography. This last method has the advantage of identifying histologically the tissues containing these receptors. High numbers of high affinity somatostatin receptors have been found on most growth hormone secreting pituitary tumors, as well as on many endocrine pancreatic tumors and carcinoids (4, 5). These receptors probably form the pathophysiological basis for the successful control of hormonal hypersecretion by most of these tumors during treatment with octreotide (Sandostatin). Several other human tumor types have also been recognized to contain large numbers of high affinity somatostatin receptors. All 27 meningiomas investigated contained these receptors, while well-differentiated glia-derived brain tumors like most oligo-dendrogliomas and (low-grade) astrocytomas, but not glioblastomas contain somatostatin receptors (6-9). Somatostatin receptors have also been found on 20-40% of human breast cancers (10).

Abnormal growth hormone release following luteinizing hormone releasing hormone in anorexia nervosa.

We studied the luteinizing hormone (LH), follicle stimulating hormone (FSH) and growth hormone (GH) secretion following an i.v. injection of 0.1 mg of luteinizing hormone releasing hormone (LHRH) in patients with anorexia nervosa, who showed the GH secretion after thyrotropin releasing hormone (TRH). Five out of 11 patients had an elevated plasma GH level in a fasting state. The administration of LHRH resulted in a significant increase in the plasma GH concentrations in 3 of the 11 patients. Three other patients also showed an elevation of the plasma GH concentration to 7.0, 18.4 and 29.6 ng/ml, which were 212, 175 and 191% of the preinjection levels, respectively. There is a positive correlation between the basal and peak plasma GH levels after LHRH. These increases, however, were related to neither the plasma gonadotropin responses to LHRH nor the plasma GH responses to TRH. The basal levels of plasma LH were reduced in 8 patients and normal responses to LHRH were observed in only one patient. Although plasma FSH was undetectable in 5 patients, the FSH response to LHRH appeared normal in 9 patients. These results indicate that an elevation of the plasma GH level after LHRH is not confined to patients with a GH secreting pituitary tumor but observed in subjects with anorexia nervosa and further suggest that the GH responsiveness to non-specific hypothalamic releasing hormones may be due to the impaired hypothalamic control in anorexia nervosa.

Intracranial and intraspinal dissemination from a growth hormone-secreting pituitary tumor

A 48-year-old woman developed multiple intracranial and intraspinal metastases from an invasive growth hormone-secreting pituitary adenoma after surgery and radiation therapy. This is the first reported case to show that the cells in the metastatic tumors and in the cerebrospinal fluid contained growth hormone.

The medical treatment of the hypersecreting pituitary gland.

Pituitary adenomas may produce local endocrine and neurological effects, as well as systemic metabolic complications due to hormonal hypersecretion. Medical therapy with pharmacological agents has been developed and is based on the neurotransmitter regulation of normal pituitary hormonal secretion. 189 patients with secretory pituitary adenomas underwent medical therapy for the hypersecretory state. 156 of these were prolactin-secreting adenomas, 16 of which were in males. The response of bromocriptine was almost universal with lowering of serum prolactin and reversal of the clinical symptoms, as well as tumor shrinkage of most large adenomas with suprasellar extension. 23 patients with acromegaly were treated with bromocriptine, with 11 noting clinical improvement, and decreased tumor size in two. Five patients with Cushing's disease were treated with cyproheptadine, with only one showing a biochemical and clinical improvement. Two patients with Nelson's syndrome each had progressive tumor growth stabilized with cyproheptadine and bromocriptine in one, and sodium valproate in the other. There appears to be a role for medical therapy in the majority of prolactin-secreting pituitary tumors, some growth hormone secreting pituitary tumors, and selected adrenocorticotropin secreting-pituitary tumors.

Gonadotropin Secretion During Prolonged Hyperprolactinemia: Basal Secretion and the Stimulatory Feedback Effect of Estrogen 1

Inoculation of cyclic female rats with the prolactin (Prl)/growth hormone-secreting pituitary tumor, MtT.W15, resulted in a cessation of estrous cyclicity within 5--10 days. Associated with this acyclicity was a persistently low serum concentration of estradiol and marked increases in both circulating Prl and progesterone. At Day 26 of acyclicity, basal serum luteinizing hormone (LH) values measured in samples taken every 20 min from 0900--1100 h were significantly reduced when compared to cyclic, nontumor animals on diestrus Day 2. There was no difference in basal follicle-stimulating hormone (FSH) concentrations. In a separate group of acyclic, tumor-bearing females 42--56 days after transplantation, a single s.c. injection of 20 micrograms estradiol benzoate (EB) at 1030 h elicited significant increases in both serum LH and FSH values between 1700 and 1830 h on the next day. The magnitude of the LH surge was reduced and that of FSH was increased in tumor-bearing animals when compared to cyclic, nontumor females given a similar EB injection on diestrus Day 1. These results demonstrate that chronic hyperprolactinemia is associated with inhibition of basal LH secretion and ovarian estrogen production and an increase in circulating progesterone concentrations. Nevertheless, the stimulatory feedback effects of estrogen on LH and FSH release are still present and functioning in acyclic female rats under chronically hyperprolactinemic conditions. These data suggest that the cessation of regular ovulatory cycles associated with hyperprolactinemia may be due to a deficiency of LH and/or estrogen secretion, but not to a lack of central nervous system response to the stimulatory feedback action of estrogen.

Hyperthyroidism and acromegaly due to a thyrotropin- and growth hormone-secreting pituitary tumor. Lack of hormonal response to bromocriptine: Carlson HE, Linfoot JA, Braunstein GD, Kovacs K, Young RT: Am J Med 1983; 74: 915–923

Hyperthyroidism and acromegaly due to a thyrotropin- and growth hormone-secreting pituitary tumor. Lack of hormonal response to bromocriptine: Carlson HE, Linfoot JA, Braunstein GD, Kovacs K, Young RT: Am J Med 1983; 74: 915–923

Hyperthyroidism and acromegaly due to a thyrotropin- and growth hormone-secreting pituitary tumor: Lack of hormonal response to bromocriptine

A 47-year-old woman with acromegaly and hyperthyroidism was found to have an inappropriately normal serum thyrotropin level (1.5 to 2.5 μU/ml) that responded poorly to thyrotropin-releasing hormone but showed partial responsiveness to changes in circulating thyroid hormones. Serum alpha-subunit levels were high-normal and showed a normal response to thyrotropin-releasing hormone. Growth hormone and thyrotropin hypersecretion persisted despite radiotherapy and bromocriptine treatment. Selective trans-sphenoidal removal of a pituitary adenoma led to normalization of both growth hormone and thyrotropin levels. Both thyrotropes and somatotropes were demonstrated in the adenoma by the immunoperoxidase technique and electron microscopy.

Interrelationships between tumour size, age, plasma growth hormone and incidence of extrasellar extension in acromegalic patients.

Abstract. In 44 consecutive acromegalic patients we studied the interrelationships between tumour size, age, incidence of extrasellar extension, growth hormone levels and 'tumour growth'. These parameters were compared with results from a previous study in 62 prolactinoma patients. It appeared that the incidence of extrasellar extension in acromegalic patients was lower than in the prolactinoma patients (32 versus 44%). In acromegalic patients extrasellar extension occurred on the average at a lateral sellar and tumour area of almost 1 cm2 larger than in prolactinoma patients (with respect to sellar size generally above 3 cm2 versus 2 cm2, with respect to tumour size generally above 4 cm2 versus 3 cm2). Log tumour size and log basal growth hormone level were positively correlated (P &lt; 0.0005). In the acromegalic patients there was a negative correlation between the size of the pituitary tumour and the age of the patient (P &lt; 0.005) in contrast to the absence of such a relationship in the prolactinoma patients. In the group of acromegalic patients mean tumour size decreased gradually from the third to the sixth decade (5.0, 3.8, 3.0 and 2.3 cm2, respectively). The interval between the time of appearance of symptoms and the time of diagnosis was significantly shorter in younger patients and in women. The restriction of large tumours (lateral area &gt; 5 cm2) to young patients (&lt; 35 year) and the short period between the appearance of symptoms and the time of diagnosis in these patients indicate that growth hormone secreting pituitary tumours generally grow more rapidly in younger patients.

Cytopathological effects of estradiol on the arcuate nucleus of the female rat. A possible mechanism for pituitary tumorigenesis

Large subcutaneous doses (2 mg/21 days) of estradiol valerate (EV) given over several months will induce a prolactin and growth hormone-secreting pituitary tumor in female rats. The medial basal hypothalami (MBHs) of such EV-treated animals were examined at different time intervals with light and electron microscopes to determine whether EV affects the MBH and to relate any observed effects to the process of tumorigenesis. The MBHs of extensively treated rats exhibited profound glial and neuronal changes. The filament content of astrocytes was greatly increased and large dense pleomorphic inclusions filled both astrocytic perikarya and processes. Degenerating neuronal elements have been observed in the neuropil of extensively treated animals. Dark cells identified as M cells were seen to engage in phagocytosis and were loaded with dense inclusions. Some neurons in MBH contained large quantities of lipofuscin that was different in appearance from that of normal females of the same age. The glial reaction developed gradually. At earlier stages of EV treatment there were fewer reactive glia and these contained fewer inclusions. Myelin figures often occurred in these early inclusions. Reactive glia in EV-treated rats did not appear in the preoptic area, dorsomedial nucleus or lateral hypothalamus but were found in ventromedial nucleus. Retired breeders and starvation-stressed rats resembled normal controls. These pathological changes in MBH may result from a direct effect of EV on the hypothalamus. It is possible that, in addition to its effects on the hypophysis, EV suppresses or injures hypophysiotropic cells in MBH, thus releasing pituitary chromophobes from inhibitory hypothalamic influences. This could result in hypersecretion and neoplasia.

Adrenocorticotrophic and growth hormone secretion. Studies during pneumoencephalography.

The effect of pneumoencephalography on plasma and cerebrospinal fluid (CSF) adrenocorticotrophic (ACTH) and growth hormone concentrations was studied in patients with and without hypothalamicpituitary disorders. In those without hypothalamic-pituitary disease, basal plasma and CSF ACTH levels were approximately equal, whereas plasma growth hormone levels were higher than CSF levels. Associated with the stress of the procedure, both ACTH and growth hormone concentrations increased in the plasma without a corresponding change in CSF levels of these two hormones. In two patients with suprasellar extension of either an ACTH or growth hormone secreting pituitary tumor, basal CSF ACTH or growth hormone levels were higher than in those without suprasellar extension. In contrast, those patients with nonendocrine active pituitary tumors that extended above the sella turcica did not have elevation of CSF ACTH or growth hormone levels.

Ergot-induced inhibition of pituitary tumor growth in rats.

Daily injections of ergocornine or ergonovine, for 3 weeks, into rats carrying a prolactin- and growth hormone-secreting pituitary tumor (MtW15) induced significant regression or inhibition of tumor growth, whereas ergocryptine had no significant effect. Ergocornine caused a decrease in cells and a disappearance or pycnosis of nuclei in the tumor tissue, and a reduced concentration of prolactin in blood.

Thyroid inhibition of rats bearing transplantatble, hormone-producing pituitary tumors.

SummaryImplantation of rats with growth hormone- and prolactin-secreting pituitary tumors cause weight reduction of the host's pituitary gland. This change was accompanied by a decrease in the pituitary content of TSH and a fall in 131I uptake by the thyroid gland in rats with prolactin- and growth hormone-secreting pituitary tumor MtTW5. These results correlated well with the finding that the proportion of organified iodine and the intrathyroid to serum iodine ratio, in the presence of high concentrations of stable iodine, were higher in the tumor bearing rats. The amount of circulating free thyroxine was measured and found to be slightly lower in tumor-bearing rats. It is suggested that the pituitary tumor hormones have a direct suppressive effect on the host's pituitary gland production of TSH and thus indirectly decrease thyroid function.

Hepatic gluconeogenic enzymes, RNA metabolism and amino acid levels in rats carrying transplantable growth hormone-secreting pituitary tumors.

The metabolic effects of a growth hormone-secreting transplantable pituitary tumor, strain MtT.W5, were investigated in the rat. Body weight, liver weight and liver/body weight ratio were markedly elevated. However, the rise in adrenal weight was only proportional to the increment in body weight. The following metabolic alterations were observed in the liver as expressed on a per cell basis. The hepatic enzymes examined were markedly increased: glucose 6-phosphatase, 202%; fructose 1,6-diphosphatase, 301%; malic dehydrogenase, 182%; and malic enzyme, 766%. Liver homogenate and supernatant nitrogen and free amino acid nitrogen were elevated to about 200 %. The hepatic glycogen level was increased 3-fold but blood sugar concentrations were in normal range. The liver RNA level was raised to 238 % and the incorporation of labeled orotate into total hepatic RNA was 180 % of the control values. Adrenalectomy did not reverse or affect these hepatic biochemical alterations. Thus, the metabolic effects observed were not due to a hormone action mediated through the adrenal gland. (Endocrinology79: 865, 1966)