In vivo responsiveness of morphological variants of growth hormone-producing pituitary adenomas to octreotide

The somatostatin analog, octreotide, is an inhibitor of growth hormone (GH) secretion that has been used to treat patients with GH-producing pituitary tumors. In this study we investigated the in vivo responsiveness to treatment with this analog in patients harboring different morphological types of GH-producing pituitary adenomas. Both GH and insulin-like growth factor I (IGF-I) plasma levels in 30 patients treated with octreotide (300 micrograms/day) for 4 months preoperatively were compared with those from 30 patients who did not receive treatment preoperatively. Tissue samples were studied using ultrastructural and immunohistochemical techniques. Amongst patients harboring densely granulated (DG) adenomas, mean GH levels were reduced to 32 +/- 9% by octreotide, to 30 +/- 7% by surgery and to 26 +/- 9% of baseline by both interventions. Surgery was equally as effective in lowering GH levels in patients with sparsely granulated (SG) adenomas as it was in those with DG adenomas; in patients with SG adenomas, GH levels were reduced by surgery alone to 37 +/- 16% and to 24 +/- 15% when performed following octreotide pretreatment. In contrast, treatment with octreotide alone in patients harbouring SG adenomas reduced GH levels to only 70 +/- 13% of baseline (p < 0.02 compared to surgery alone, or surgery and octreotide). We conclude that the GH inhibitory effects of octreotide are significantly better in patients harboring DG somatotroph adenomas compared with those harboring SG adenomas.     

Intact leptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas and signals human fetal pituitary growth hormone secretion

Leptin, a circulating hormone secreted by adipocytes, communicates peripheral nutritional status to hypothalamic centers affecting satiety, energy expenditure, and body weight. The intact leptin receptor (OB-R), a single membrane-spanning peptide containing an approximately 300-amino acid intracellular domain, is highly expressed in the hypothalamus, whereas shorter OB-R isoforms with truncated cytoplasmic regions resulting from alternative splicing have also been identified. We studied expression of OB-R isoforms in human fetal pituitaries, adult anterior pituitaries, and human pituitary adenomas. Using RT-PCR, messenger ribonucleic acid expression of the OB-R intact isoform was detected in fetal anterior pituitary tissues, but not in adult anterior pituitary glands, whereas both fetal and adult tissues expressed the short forms. Messenger ribonucleic acid of both intact and short OB-R isoforms were expressed in 4 of 5 GH-secreting, all 9 PRL-secreting, and 26 of 29 nonfunctioning pituitary adenomas. Recombinant human leptin (3-6 nmol/L) specifically stimulated GH secretion from primary human fetal pituitary cultures by 40-90% (P < 0.05) without altering fetal ACTH, PRL, or gonadotropin secretion. Thus, the intact OB-R is selectively expressed in human fetal and adult pituitary tumor tissues, but not in normal adult pituitary. Leptin specifically stimulates GH release from normal fetal somatotrophs, substantiating the functionality of its intact receptor in the fetal pituitary. Thus, pituitary adenomas appear to revert to a fetal phenotype of leptin receptor expression.     

Glycoprotein hormone alpha-subunit secretion in non-functioning pituitary adenomas

The aim of the present study was to investigate the prevalence of elevated free glycoprotein hormone alpha-subunit in different pituitary adenomas, to establish the diagnostic value of the basal and stimulated free alpha-subunit secretion in non-functioning adenomas. Serum basal levels of alpha-subunit were increased in 1 of 22 untreated, in 1 of 16 operated patients with non-functioning adenoma, in 6 of 28 untreated, in 1 of 7 operated patients with acromegaly, in 0 of 5 untreated prolactinomas and in 0 of 1 untreated gonadotrop adenoma. Overall free alpha-subunit levels were increased in 9 of 79 cases (11.4%). In 6 of 9 patients with untreated non-functioning adenoma thyrotrop hormone releasing hormone caused an abnormal--paradox--elevation of serum alpha-subunit. These data indicate that measurement of basal and stimulated alpha-subunit is of relatively poor value in the diagnosis of non-functioning pituitary adenomas. The transsphenoidal surgery did not resulted in a change of alpha-subunit secretion neither in patients with non-functioning adenoma nor with acromegaly. The present data confirm the view that non-functioning pituitary adenomas are not homogeneous since this subset of tumors includes adenomas that either do not secrete measurable amounts of free alpha-subunit or produce normal or supranormal amounts of subunits as consequence of still undefined biosynthetic abnormalities.     

Immunohistochemical detection of glycoprotein hormone alpha subunit in somatoprolactinic and pure somatotroph adenomas

The slow progression of valvular aortic stenosis enables the left ventricular myocardium to adapt itself to the increasing afterload. When myocardial adaption is exhausted, surgical intervention is urgent, the prognosis, however, is already limited. To quantify the hemodynamic severity of aortic stenosis, transaortic pressure gradients (dp) measured by Doppler echocardiography or hemodynamically are inappropriate, because dp is significantly dependent on the transaortic flow volume. In severe aortic stenosis, despite constant narrowing of the aortic valve area, the reduced stroke volume results in decreasing transaortic pressure gradients. With aortic valve resistance or transaortic pressure loss (PL)--the quotient of pressure gradient and stroke volume--the hemodynamic severity of aortic stenosis can be described accurately. If PL is known, a decompensated aortic stenosis (PL > 1 mm Hg/ml) may be differentiated from myocardial failure of another etiology and a concomitant left ventricular outflow tract obstruction. With respect to medical therapy, the prevention of bacterial endocarditis and thromboembolic complications is important. Knowing the potential danger of syncopies and ventricular arrhythmias during exercise with increasing severity of aortic stenosis, patients have to be informed about their limited functional capacity. The occurrence of typical symptoms during the natural history of chronic aortic stenosis (e.g. dizziness, syncopes, angina pectoris, arrhythmias) manifestation of ST-T-alterations or silent myocardial ischemias and demonstration of an inadequate myocardial adaptation to the chronic pressure overload in asymptomatic patients are accepted indications for a surgical intervention. If the indication for surgery remains uncertain, stress tests (e.g. radionuclidventriculography) may be performed to demonstrate an exhausted myocardial adaptation. If the PL and the severity of aortic valve/anulus calcification is known, the progression of a chronic aortic stenosis can be estimated. This might be important, if a cardiosurgical intervention has to be performed for other indications and aortic stenosis is co-existent but does not require an intervention at that time. For prognostic reasons myocardial decompensation due to aortic stenosis is an indication for an urgent surgical intervention. Attempts for medical recompensation or bridging strategies (e.g. balloon valvotomy) worsens the prognosis significantly.     

Transferrin and transferrin receptor in human hypophysis and pituitary adenomas

The activity of three human immunodeficiency virus (HIV) protease inhibitors was investigated in human primary monocytes/macrophages (M/M) chronically infected by HIV-1. Saquinavir, KNI-272, and ritonavir inhibited the replication of HIV-1 in vitro, with EC50s of approximately 0.5-3.3 microM. However, only partial inhibition was achievable, even at the highest concentrations tested. Also, the activity of these drugs in chronically infected M/M was approximately 7- to 26-fold lower than in acutely infected M/M and approximately 2- to 10-fold lower than in chronically infected H9 lymphocytes. When protease inhibitors were removed from cultures of chronically infected M/M, production of virus rapidly returned to the levels found in untreated M/M. Therefore, relatively high concentrations of protease inhibitors are required to suppress HIV-1 production in chronically infected macrophages, and such cells may be a vulnerable point for the escape of virus in patients taking these drugs.     

Cellular receptors for sex steroids in human pituitary adenomas

Cellular receptors for sex steroids (SSRs) were studied in an unselected series of 55 human pituitary tumors. Cytosolic receptors for estrogen (ERcs) and progesterone (PgRcs) were determined in all cases and cytosolic androgen receptors (ARcs) in 47 cases. Nuclear receptors (ERns, PgRns, ARns) were also studied in 33 cases. ERs and PgRs were determined by an ELISA and ARs by [3H]methyltrienolone binding. Where both cytosolic and nuclear receptors were studied (n = 33), ERs, PgRs and ARs were found in at least one subcellular fraction in 66.7, 60.6 and 81.8% of cases respectively, ERs and ARs being mainly recovered from the cytosol and PgRs from the nucleus. No linear correlation was found between pre-operative plasma steroid hormones and their specific cellular receptors. Nonetheless, the differential expression of SSRs according to sex and gonadal status at the time of surgery strongly supports their regulation by the steroid environment in vivo: PgRcs were more frequent in tumors found in women (41.4 vs 15.4%, P < 0.05), whereas a high expression of ERcs and ARcs (> 15 fmol/mg protein) was more common in tumors found in men (34.5 vs 10.3%, P < 0.05 and 54.5 vs 24.0% respectively). PgRs were positively correlated with ERns, indicating the possibility of estrogen priming of their expression, and negatively correlated with ARs in nuclear fractions. SSRs appeared to be widely distributed among pituitary tumors, although, compared with other hormone-secreting groups, prolactinomas displayed a higher ERc expression (34.8 +/- 11.3 vs 4.8 +/- 5.1 fmol/mg protein, P = 0.007) and gonadotroph cell adenomas lower ARc values (1.3 +/- 0.8 vs 38.2 +/- 10.6 fmol/mg protein, P = 0.048). Microadenomas were characterized by a higher PgR expression than macroadenomas, whereas hemorrhagic (macro)adenomas were characterized by a high ER expression (> 90%). The present results indicate that most pituitary tumors are targets for sex steroids, SSR expression being partially triggered by the steroid environment itself. Possible physiopathological and therapeutic implications of these findings are discussed.     

Immunoreactive growth hormone in human peripheral T lymphocytes: encoding sequence of cDNA identical to that of the pituitary human growth hormone

Circadian rhythms produce daily changes in critical elements of athletic performance. We explored the significance of performing at different circadian times in the National Football League (NFL) over the last 25 seasons. West Coast (WC) NFL teams should have a circadian advantage over East Coast (EC) teams during Monday Night Football (MNF) games because WC teams are essentially playing closer to the proposed peak athletic performance time of day. Retrospective data analysis was applied to all games involving WC versus EC teams playing on MNF with start times of 9:00 p.m. Eastern Standard Time (EST) from the 1970-1994 seasons. Logistic regression analysis of win-loss records relative to point spreads and home-field advantage was examined. West Coast teams win more often (p < 0.01) and by more points per game than EC teams. West Coast teams are performing significantly (p < 0.01) better than is predicted by the Las Vegas odds (the point spread). This apparent advantage enhances home-field advantage for WC teams and essentially eliminates the beneficial effects of home-field advantage for EC teams during MNF games. These results support the presence of an enhancement of athletic performance at certain circadian times of the day.     

Effects of hormone replacement on growth hormone and prolactin exercise responses in postmenopausal women

Studies were conducted to identify a 64-kD thylakoid membrane protein of unknown function. The protein was extracted from chloroplast thylakoids under low ionic strength conditions and purified to homogeneity by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Four peptides generated from the proteolytic cleavage of the wheat 64-kD protein were sequenced and found to be identical to internal sequences of the chloroplast-coupling factor (CF1) alpha-subunit. Antibodies for the 64-kD protein also recognized the alpha-subunit of CF1. Both the 64-kD protein and the 61-kD CF1 alpha-subunit were present in the monocots barley (Hordeum vulgare), maize (Zea mays), oat (Avena sativa), and wheat (Triticum aestivum); but the dicots pea (Pisum sativum), soybean (Glycine max Merr.), and spinach (Spinacia oleracea) contained only a single polypeptide corresponding to the CF1 alpha-subunit. The 64-kD protein accumulated in response to high irradiance (1000 mumol photons m-2 s-1) and declined in response to low irradiance (80 mumol photons m-2 s-1) treatments. Thus, the 64-kD protein was identified as an irradiance-dependent isoform of the CF1 alpha-subunit found only in monocots. Analysis of purified CF1 complexes showed that the 64-kD protein represented up to 15% of the total CF1 alpha-subunit.     

Mammosomatotroph adenoma cells secrete both growth hormone and prolactin

Pituitary adenoma cells from a mammosomatotroph adenoma obtained from a 21-year-old female presenting with acromegaly and amenorrhea were investigated by sandwich cell immunoblot assay, immunohistochemistry, and electron microscopy. The new, simple technique of sandwich cell immunoblot assay could detect two hormones secreted in the same one cell, and found that 89% of mammosomatotrophs secreted both growth hormone (GH) and prolactin (PRL). Immunohistochemistry showed that the tumor cells were positive for both GH and PRL. Electron microscopy showed cells contained granules ranging in size form 150 to 500 nm. This is the first demonstration of both GH and PRL in the same mammosomatotroph cell. Sandwich cell immunoblot assay can measure the amount of secreted hormone, allowing a new approach to the investigation of mammosomatotroph adenomas.     

Control of prolactin and growth hormone secretion in mice by obesity

Prolactin (PRL) and growth hormone (GH) secretions in mice rendered obese by the administration of gold thioglucose (GTG) are abnormal. The objective of the present experiments was to determine whether the effects were related to the drug or to the resultant obesity. Perphenazine-induced PRL release in normal mice and in GTG-injected non-obese mice was compared to that of GTG-injected obese mice after the initial development of obesity, after body weight reduction by diet control and after the resumption of obesity by ad lib. feeding. The GTG-injected mice which did not become obese had greater (50%) than normal levels of serum PRL following perphenazine stimulation in 2 of 3 experiments. This suggested that the injection of GTG directly affected the control mechanism for PRL secretion, but that the abnormal PRL secretion was probably not the cause of obesity that develops after GTG treatment. Perphenazine-induced PRL levels in mice rendered obese with GTG were much greater (2-3 times higher than normal). However, the unusually high levels of PRL were totally abolished when the body weights of these mice were brought down to normal by dietary restriction. Conversely, when obesity was permitted to recur by giving the mice free access to food, PRL levels reverted back to the original obese pattern. The concentrations of GH were usually lower than normal in GTG-obese mice, and these levels were also more often associated with the development of obesity than with the injection of GTG. The data show a marked influence of obesity on the control of PRL and GH secretions in the mouse.     

Molecular analysis of p21 and p27 genes in human pituitary adenomas

OBJECTIVES: To determine the prevalence of thyroid dysfunction in institutionalised elderly people in Cape Town and to assess the usefulness of an abnormal thyroid-stimulating hormone (TSH) concentration as a screening test in this group. DESIGN: Cross-sectional survey. SETTING: Four old-age homes in Cape Town. SUBJECTS: Old-age home residents aged 60 years and over. OUTCOME MEASURES: Serum concentrations of TSH, free thyroxine and free tri-iodothyronine. RESULTS: Serum TSH estimations were performed on 658 participants, and were abnormal in 103 (15.6%)-41 (6.2%) being elevated (> 5.0 microU/ml) and 62 (9.4%) being low (> 0.4 microU/ml). There were 3 newly diagnosed cases of hyperthyroidism and 7 of hypothyroidism. Subclinical disease was diagnosed in 40 subjects. The overall prevalence of thyroid dysfunction in this population was 11.2%. In 22 (3.4%) this had previously been recognised, while in 50 (7.8%) the dysfunction was newly diagnosed by the current survey. The positive predictive value of a TSH concentration > 20 microU/ml in predicting hypothyroidism is 67%, while it will predict 100% of cases of subclinical hypothyroidism. A TSH concentration < 0.1 microU/ml will predict 23% of cases of hyperthyroidism, but 81% of cases of subclinical disease. CONCLUSIONS: The prevalence of thyroid dysfunction in institutionalised elderly people in Cape Town is similar to that reported for elderly people in other centres. Thyroid dysfunction had not previously been recognised in approximately two-thirds of the subjects in this study. The serum TSH concentration is a reliable screening test for thyroid dysfunction in the elderly, but is less useful if used to identify biochemical thyroid disease. An elevated TSH concentration is a better predictor of thyroid dysfunction in the elderly than a depressed TSH concentration.     

Properties of growth hormone and prolactin hypersecretion by the human infant on the day of birth

The neonatal period is the only interval in postnatal life characterized by physiologically elevated plasma concentrations of GH and PRL, two hormones of common origin. To study the secretion of GH and PRL on the day of birth, we obtained at regular intervals (every 20 min for 6 h) blood from seven polycythemic newborns (gestational age 34-41 weeks; birthweight 1600-3960 g; postnatal age 6-23 h) during a therapeutic, standardized, isovolumetric, partial exchange transfusion. Serum GH concentrations were measured by RIA and PRL levels by immunoradiometric assay. Deconvolution analysis of the profiles revealed that all infants displayed a pulsatile pattern of amplified GH release (range 9-191 micrograms/L). Bursts of GH secretion occurred at a median interval of 73 min. The median serum GH half-life was 18 min. All infants had continuously elevated serum PRL concentrations (range 86-191 micrograms/L) and none appeared to release PRL episodically. There was no significant cross-correlation between the secretion of GH and PRL. Mean serum GH concentrations during the 6-h study were higher than in cord serum at birth, whereas PRL and insulin-like growth factor-1 levels were lower than at birth. In conclusion, the neonatal hypersomatotropism appears to be characterized by high-amplitude, high-frequency, pulsatile secretion of GH without a prolonged GH half-life, whereas hyperprolactinemia seems to result from GH-independent, continuous PRL release. The immediate postnatal rise of GH secretion in the human newborn may be related to decreased inhibition by circulating insulin-like growth factor-1.     

Effect of 17beta-estradiol on somatostatin receptor expression and inhibitory effects on growth hormone and prolactin release in rat pituitary cell cultures

Predictions of the minimal size an organism must have to swim along stimulus gradients were used to compare the relative advantages of sensory systems employing spatial (simultaneous) and temporal (sequential) gradient detection mechanisms for small free-swimming bacteria, leading to the following conclusions: 1) there are environmental conditions where spatial detection mechanisms can function for smaller organisms than can temporal mechanisms, 2) temporal mechanisms are superior (have a smaller size limit) for the difficult conditions of low concentration and shallow gradients, but 3) observed bacterial chemotaxis occurs mostly under conditions where spatial mechanisms have a smaller size limit, and 4) relevant conditions in the natural environment favor temporal mechanisms in some cases and spatial mechanisms in others. Thus, sensory ecology considerations do not preclude free-swimming bacteria from employing spatial detection mechanisms, as has been thought, and microbiologists should be on the lookout for them. If spatial mechanisms do not occur, the explanation should be sought elsewhere.     

The growth hormone secretagogue, L-692,429, induces phosphatidylinositol hydrolysis and hormone secretion by human pituitary tumors

L-692,429 is a non-peptidyl GH secretagogue. We examined the effects of L-692,429 on cultured human pituitary tumors removed from patients with acromegaly. Dose-dependent stimulation of GH secretion was observed, with 1 mumol/L leading to 2 or 3-fold increases. Prolactin (PRL) secretion by a mixed somatotrophic-lactotrophic tumor was also stimulated. The effects of L-692,429 were abolished by phloretin and W7 but not Rp-cAMPS. Rate of phosphatidylinositol turnover was markedly increased up to 3-fold by L-692,429. These results show that L-692,429 increases hormone secretion by human pituitary cells via a protein kinase C and Ca2+ dependent mechanism.     

Tumor-specific expression and alternate splicing of messenger ribonucleic acid encoding activin/transforming growth factor-beta receptors in human pituitary adenomas

Activin, a member of the transforming growth factor-beta (TGF beta) cytokine family, acts as a pituitary cell mitogen via a novel family of receptor-linked serine/threonine (Ser/Thr) kinases. Pituitary tumors synthesize activin subunits, and the autocrine action of these growth factors may modulate tumor proliferation. We, therefore, investigated the expression of activin/TGF beta type I receptor messenger ribonucleic acids (mRNAs), designated ALK1 through ALK5 (ALK = activin receptor-like kinase), and type II receptor mRNAs using RT-PCR in 34 human pituitary adenomas of all phenotypes and normal pituitary tissue. ALK2 and ALK5, specific mediators of activin and TGF beta signals, respectively, were found to be expressed only in tumor and not in normal pituitary cells, and ALK2 expression was found only in tumors of a mammosomatotroph cell lineage. ALK1, ALK3, and ALK4 mRNAs were found in both normal and neoplastic pituitary cells. The alternatively spliced cytoplasmic domain of ALK4 consists of 11 kinase subdomains, that are critical for modulating receptor function and intracellular signaling. Truncated forms of the ALK4 cytoplasmic domain lacking these subdomains may attenuate activin signal transduction and affect both tumor phenotype and proliferation via the formation of inactive type I/type II complexes. Three truncated ALK4 receptor mRNAs generated by alternate splicing of the cytoplasmic Ser/Thr kinase domain were found to be tumor specific. One of these truncated receptor mRNAs, ALK4-5, is a novel splice variant that has not been previously described. Expression of the ActRII and T beta RII type II receptor mRNAs, which specifically bind activin and TGF beta, respectively, was highly prevalent among all tumor subtypes and normal pituitary tissue. However, ActRIIB, an activin-specific type II receptor that displays a 3- to 4-fold higher affinity for ligand than ActRII, was expressed in 94% of tumors, but was not prevalent in normal tissue. These data are the first to demonstrate tumor-specific expression of Ser/Thr kinase receptors mRNAs and their splice variants in human pituitary adenomas.     

A role for growth hormone and prolactin in leukaemia and lymphoma?

Growth hormone (GH) and prolactin (PRL) quality as lymphohaemopoietic growth and differentiation factors, and so does insulin-like growth factor (IGF)-I, which mediates many of GH activities. Although there is only limited evidence that endocrine, paracrine or autocrine GH or PRL play a role in human leukaemia and lymphoma, the expression of these factors or their receptors may have diagnostic or therapeutic implications. Indeed, the participation of GH, PRL or IGF-I in the development or progression of certain haematological malignancies or to the antitumour immune response has been documented. Examples discussed in this review include a rat lymphoma in which the PRL receptor acts as an oncogene; the rat Nb2 lymphoma, which is dependent on PRL for growth; and experiments showing that PRL stimulates natural killer cell activity and the development of lymphokine-activated killer cells.