Inversely related evolution of growth hormone and prolactin secretions in long-term tissue cultures of human pituitary adenomas from acromegalic patients

Summary Pituitary tumoral tissue from 20 acromegalic patients was cultured for up to 120 d in a medium containing 5 nM cortisol. In all cultures, growth hormone (GH) release decreased. At the beginning of the culture, prolactin (PRL) was detected in 18 adenomas, varying from 0.5 to 1000 ng per flask per day. Thereafter, in 10 cases PRL secretion increased from 3 to 50 times the basal level, most frequently after a lapse of 9 to 30 d. PRL secretion remained low in three cases, undetectable in one case only. When added at 350 nM, cortisol increased GH secretion up to 20-fold and simultaneously decreased PRL secretion by as much as 10% of the basal level. Withdrawing cortisol reversed the situation. Immunocytochemical studies of the tumor at surgery showed, besides GH immunoreactive (IR) cells, PRL-IR cells (from rare cells to 10% of total cells) in 15 adenomas, correlating with the first days of culture PRL levels. In cultured explants, mitoses were never found. In 5 nM cortisol medium, the number of GH-IR cells decreased and PRL-IR cells increased or appeared. With 350 nM cortisol, the number of GH-IR cells increased, and PRL-IR cells were scarce or absent. Immunoreactivities for GH and PRL were found in different cells. Care was taken to exclude cultures containing normal pituitary tissue, and because no mitoses were found, these results suggest that most somatotropic adenomas can reversibly shift their secretion from GH to PRL in culture. This capacity to secrete PRL, hidden or low in vivo, is revealed by the favorable low cortisol conditions present in vitro.     

Effects of granulocyte-macrophage colony stimulating factor on cortisol, growth hormone, prolactin and melatonin in cancer patients (short communication).

Several interleukins and interferons have been proven to induce endocrine effects. On the contrary, only few data are available about the possible hormonal activity of hemopoietic growth factors. This study was carried out to evaluate the endocrine influence of GM-CSF in humans. The study included nine head and neck cancer patients, evaluated in basal conditions and after an acute subcutaneous injection of GM-CSF at a dose of 3 mcg/kg b.w., by determining serum levels of cortisol, growth hormone (GH), prolactin (PRL) and melatonin. Both cortisol and GH significantly increased in response to GM-CSF, while PRL, and melatonin were not influenced. This preliminary study shows that hemopoietic growth factors, as well as interleukins, may also play endocrine effects in humans.     

Responses of sympathoadrenal and renin angiotensin systems to stress stimuli in humans during real and simulated microgravity

Changes of plasma hormone levels were investigated in human subjects after exposure to physical exercise (WL) and insulin induced hypoglycemia (ITT) during apace flight or after head down bed rest (HDBR). Exaggerated responses of plasma epinephrine (EPI), norepinephrine (NE) and aldosterone (ALD) were observed after WL during space flight as compared to preflight response. Hypoglycemia during space flight induced attenuated responses of EPI, NE and augmented response of ALD. Exposure to WL during HDBR was followed by significantly exaggerated responses of plasma EPI, NE, ALD, PRA and cortisol. In HDBR the responses of plasma EPI, NE and cortisol were reduced and PRA response was exaggerated during ITT. These data indicate that hormonal responses to ITT and WL are similar at real and simulated microgravity.     

Decreased non-MHC-restricted (CD56+) killer cell cytotoxicity after spaceflight.

Cytotoxic activity of non-major histocompatibility complex-restricted (CD56+) (NMHC) killer cells and cell surface marker expression of peripheral blood mononuclear cells were determined before and after spaceflight. Ten astronauts (9 men, 1 woman) from two space shuttle missions (9- and 10-day duration) participated in the study. Blood samples were collected 10 days before launch, within 3 h after landing, and 3 days after landing. All peripheral blood mononuclear cell preparations were cryopreserved and analyzed simultaneously in a 4-h cytotoxicity (51)Cr release assay using K562 target cells. NMHC killer cell lytic activity was normalized per 1,000 CD56+ cells. When all 10 subjects were considered as one study group, NMHC killer cell numbers did not change significantly during the three sampling periods, but at landing lytic activity had decreased by approximately 40% (P < 0.05) from preflight values. Nine of ten astronauts had decreased lytic activity immediately after flight. NMHC killer cell cytotoxicity of only three astronauts returned toward preflight values by 3 days after landing. Consistent with decreased NMHC killer cell cytotoxicity, urinary cortisol significantly increased after landing compared with preflight levels. Plasma cortisol and ACTH levels at landing were not significantly different from preflight values. No correlation of changes in NMHC killer cell function or hormone levels with factors such as age, gender, mission, or spaceflight experience was found. After landing, expression of the major lymphocyte surface markers (CD3, CD4, CD8, CD14, CD16, CD56), as determined by flow cytometric analysis, did not show any consistent changes from measurements made before flight.     

Glucocorticoids antagonize induction of prolactin-gene expression by calcitriol in rat pituitary tumour cells.

Clonal strains of rat pituitary tumour (GH4C1) cells are known to possess specific intracellular binding sites for calcitriol (1,25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D3). GH4C1 cells respond to calcitriol by a selective increase in prolactin(PRL)-gene expression. The interaction between calcitriol and glucocorticoids was studied by using this cultured-cell model. It was found that cortisol potently antagonized the induction of PRL mRNA and PRL production by calcitriol. The effects were concentration-dependent and were evident at glucocorticoid concentrations that did not alter basal PRL production. Inhibition was half-maximal at 3.2 nM-cortisol and 0.4 nM-dexamethasone. Calcitriol-induced PRL mRNA fell by more than 50% at 25 h and reached the control level 50 h after treatment with cortisol. The inhibition by cortisol of calcitriol induction of PRL production was selective when compared with effects on other inducers of PRL-gene expression [thyroliberin, epidermal growth factor and phorbol myristate acetate ('12-omicron-tetradecanoylphorbol 13-acetate')]. Potent antagonism by glucocorticoids of vitamin D action on specific gene expression has been demonstrated. Further studies with this cultured-cell model may help to explain the mechanism of this hormonal interaction, which assumes particular importance at major sites of vitamin D action such as the intestine.     

Effects of sexual experience, season, and mating stimuli on endocrine concentrations in the adult ram.

Two behavioral trials were conducted to determine the endocrine response of cortisol (C), luteinizing hormone (LH), testosterone (T), prolactin (PRL), and growth hormone (GH) in adult rams during exposure to estrous ewes during the breeding and nonbreeding seasons. One-half of the rams in each season were sexually experienced (SE) and the remainder were sexually inexperienced (SI). All SE rams (100%) achieved at least one ejaculation, but only 33% (summer) and 67% (fall) SI rams achieved ejaculation. In the fall, mean C, T, and GH concentrations were elevated (P less than .001) compared to values measured in the summer, whereas LH and PRL levels were higher (P less than .01) in the summer. Overall levels of C, LH, T, and PRL were higher (P less than .05) in SE rams than in SI rams. Mean GH concentration was higher (P less than .10) in SI than in SE rams during restricted and complete access to estrous ewes. In general, LH, PRL, and GH responses were similar during restricted and complete access to females for both SE and SI rams. Cortisol levels were higher (P less than .06) during periods of mating and T levels were higher (P less than .001) during periods where activity was limited to courtship behavior (nasogenital investigation). Correlations of hormones to reproductive behaviors indicated that mounting and intromission were associated with elevations in C and PRL, whereas elevated LH and T tended to be associated with courtship behaviors. Correlations between GH and behaviors were inconsistent. However, there was an increased coincidence between time of female exposure and hormonal response that occurred in the fall; brief exposure to estrous ewes resulted in increases in concentrations of all hormones examined. The most consistent response was observed in sexually experienced rams during restricted access to females during the breeding season. These results provide new information on the effects of season and level of sexual experience upon hormonal and behavioral characteristics of the ram during mating activity.     

Endocrine effects of human recombinant interleukin-3 in cancer patients.

It is known that several cytokines can exert hormonal effects. At present, no data are available about the possible influence of IL-3 on the endocrine system. In order to investigate the endocrine effects of IL-3 in humans, we have evaluated serum levels of cortisol, beta-endorphin, GH, PRL, FSH, LH, TSH and melatonin in response to intravenous injection of IL-3 at a dose of 1 mcg/kg b.w. at 6.00 p.m. The study was performed in 5 non-small cell lung cancer patients. GH increased significantly in response to IL-3. PRL showed a progressive decrease after IL-3 injection, but its variations were not statistically significant. All other hormones, including cortisol, were not affected by IL-3. This preliminary study shows that IL-3 may exert endocrine effects in humans, which would seem at variance with previously reported results on most other cytokines.     

Growth hormone and prolactin actions on osmoregulation and energy metabolism of gilthead sea bream (Sparus auratus)

The gilthead sea bream (Sparus auratus) is an euryhaline fish where prolactin (PRL) and growth hormone (GH) play a role in the adaptation to different environmental salinities. To find out the role of these pituitary hormones in osmoregulation and energy metabolism, fish were implanted with slow release implants of ovine GH (oGH, 5 microg g(-1) body mass) or ovine prolactin (oPRL, 5 microg g(-1) body mass), and sampled 7 days after the start of the treatment. GH increased branchial Na(+),K(+)-ATPase activity and decreased sodium levels in line with its predicted hypoosmoregulatory action. GH had metabolic effects as indicated by lowered plasma protein and lactate levels, while glucose, triglycerides and plasma cortisol levels were not affected. Also, GH changed liver glucose and lipid metabolism, stimulated branchial and renal glucose metabolism and glycolytic activity, and enhanced glycogenolysis in brain. PRL induced hypernatremia. Furthermore, this hormone decreased liver lipid oxidation potential, and increased glucose availability in kidney and brain. Both hormones have opposite osmoregulatory effects and different metabolic effects. These metabolic changes may support a role for both hormones in the control of energy metabolism in fish that could be related to the metabolic changes occurring during osmotic acclimation.     

Changes in growth hormone and prolactin messenger ribonucleic acid levels during seawater adaptation of amago salmon (Oncorhynchus rhodurus).

To examine the changes in secretion of growth hormone (GH) and prolactin (PRL) with reference to their osmoregulatory roles, changes in pituitary mRNA levels and plasma concentrations of these hormones were examined during seawater adaptation in silvery juveniles (smolts) and precociously mature males (dark parr) of amago salmon (Oncorhynchus rhodurus). Transfer to seawater increased plasma sodium levels in both smolts and dark parr. Smolts adjusted their plasma sodium to the level associated with seawater-adaptation (165 mEq/liter) within 3 days, whereas no adjustment was seen in dark parr; the latter failed to survive in seawater for more than 3 days. In smolts, plasma GH levels increased significantly 1 day after transfer, whereas there was no significant change in dark parr. An increase in GH mRNA levels was observed in smolts in association with increased plasma GH, whereas there was no change in dark parr. In contrast, a reduction in plasma PRL levels was consistently observed in both smolts and dark parr after transfer to seawater. However, there was no significant change in PRL mRNA levels in either smolts or dark parr. These results suggest that both gene expression and release of GH are activated by seawater transfer only in smolts with adequate seawater adaptability, whereas PRL gene expression is decreased after seawater transfer regardless of seawater adaptability.     

Circadian rhythms of salivary cortisol content during long-term space flight

Adaptation mechanisms of adrenal function related to secretion of cortisol were studied under conditions of microgravity. Parameters of diurnal rhythms of salivary cortisol were studied by Russian cosmonauts on board orbital station Mir during long-term space flights (SF). The preflight circadian rhythms of salivary cortisol in cosmonauts were characterized by the morning maximum occurring at 9∶43 a.m., the fluctuation amplitude 6.05 nmol/1, and the daily average concentration 8.79 nmol/l. The characteristics of cortisol diurnal rhythm changed under conditions of long-term space flight. On average, the rhythm measure and amplitude decreased after two months of flight. The postflight maximum concentration of free cortisol tended to occur later in the day. Evidently, the motor activity during SF, i.e., prophylactic exercises along with other factors, significantly influenced the parameters of cortisol circadian rhythm that was revealed by the individual variability of findings during the flight. After the long-term SF, individual ratios of salivary and plasma cortisol levels increased against the background of increased plasma content of the hormone, i.e., the fraction of free, physiologically active hormone in the total pool of circulating molecules decreased.     

Effects of osmotic pressure on prolactin and growth hormone secretion from organ-cultured eel pituitary

Summary Effects of medium osmotic pressure on the release of prolactin (PRL) and growth hormone (GH) from the pituitary of the Japanese eel, Anguilla japonica, were examined during long-term organ culture in a defined medium. Prolactin and GH release, as measured by homologous radioimmunoassays, increased gradually for 7 days during incubation in isosmotic medium (295 mOsmolal). On day 7, 3 to 5 times more PRL and GH were released than on day 1. The amount of GH released was about 100 times greater than that of PRL. Electron microscopic observation revealed that both PRL and GH cells were in good condition after 7 days incubation. The reduction of medium osmotic pressure from 295 (isosmotic) to 235 or 260 mOsmolal significantly stimulated PRL release for 4 days. By contrast, an increase in medium osmolality from 295 to 360 mOsmolal was without effect. These treatments produced no significant alterations in GH release. The stimulatory effect of hyposmotic medium (235 mOsmolal) was no longer evident by 12 h after the pituitaries were returned to isosmotic medium. The isosmotic but low-sodium medium, prepared by adding mannitol to the hyposmotic medium, did not stimulate PRL release from the pituitary. These results indicate that plasma osmolality may be an important physiological factor controlling PRL release during freshwater adaptation of the eel.Abbreviations GH growth hormone - OAPBS PBS with 1% ovalbumin - PAGE polyacrylamide gel electrophoresis - PBS phosphatebuffered saline - PRL prolactin - rER rough endoplasmic reticulum     

GH3 cell secretion of growth hormone and prolactin increaseases spontaneously during perfifusion

Summary GH₃ cell secretory activity was studied in long-term perifusion to define previously reported spontaneous increases in growth hormone (GH) and prolactin production (PRL). Mechanically harvested cells (1×10⁷/column) were perifused at 4 ml/h for 72 h. A basal period of variable duration (8 to 12 h), during which hormone secretion was stable, was followed by steadily increasing secretion rates. Changes in cell number were not sufficient to acount for increased jormone secretion rates: a) there was no significant change in cell count after 72 h (0.97±0.03×10⁷;n=18); b) mean cell column DNA content increased 25.5% above the base value, whereas GH secretion rose 385% and PRL rose 178% (n=5). Observed differences in the duration of the basal secretion period, the basal secretory rate, and the magnitude of secretory rate increase were associated with several variables: a) variablility within a subline was a function of passage number: GH secretion decreased and PRL secretion increased with subculture number; b) cells with identical lot and freeze numbers, but received at different times, behaved differently; c) the presence of an antifungal agent (nystatin) altered hormone secretion reproducibly. Conclusions: a) rates of GH and PRL secretion rise spontaneously in perifusion without a proportional increase in GH₃ cell number; b) fluctuations in the rate of GH₃ cell secretion of GH and PRL are not entirely random but are determined by several definable variables. Supported by a grant to MES from the National Institutes of Health (AM33388) and in part by the Medical Research Service of the Veterans Administration.     

Influence of Environmental Salinity on Messenger RNA Levels of Growth Hormone, Prolactin, and Somatolactin in Pituitary of the Channel Catfish (Ictalurus punctatus)

Pituitary growth hormone (GH), prolactin (PRL), and somatolactin (SL) messenger RNA levels in channel catfish (Ictalurus punctatus) were examined under various environmental and physiological conditions. Catfish were sampled following salinity challenge, during the winter (December) and spring or summer (April or July), and at different sizes (15–18 g, 620–664 g, and 956–1134 g). When catfish (956–1134 g) were transferred from freshwater to saline water containing 8 ppt NaCl, their plasma [Na⁺] increased significantly above values in the freshwater control group until they were transferred back to freshwater. Pituitary GH mRNA levels were low for the first 24 hours following transfer to saline water, but thereafter were significantly elevated above control values until the fish were transferred back to freshwater. Pituitary GH mRNA levels were highest in July and lowest in December. Growth hormone mRNA levels were also elevated in the size groups 15–18 g and 956–1134 g in July when compared with December values. Pituitary PRL mRNA levels increased for the first 24 hours following transfer to saline water (956–1134 g), but thereafter were significantly lower than control values until the fish were transferred back to freshwater. Pituitary PRL mRNA levels were highest in April and July and lowest in December, and were also elevated in the size groups 620–664 g and 956–1134 g. Pituitary SL mRNA levels were unaffected in catfish transferred to saline water; however, levels were significantly elevated in catfish of the 956–1134-g size group sampled in April when compared with December. These results suggest the involvement of GH in adaptation to brackish water and of PRL in adaptation to freshwater in the catfish, and seasonal and size-related differences in pituitary GH, PRL, and SL mRNA levels. Received May 17, 2000; accepted October 30, 2000     

Infradian rhythmicity in lactogenic hormone (prolactin,growth hormone,cortisol and thyroid hormone) secretion throughout the lactation cycle in mithun cows (Bos frontalis): variation among strains

The role of lactogenic hormones (prolactin, growth hormone, cortisol and thyroid hormone) on lactation yield in Mithun cows as well as their rhythmicity throughout the lactation cycle were studied in Mizoram (n = 4) and Nagaland (n = 7) strain of mithun (Bos frontalis). Blood samples were collected from all the animals from the day of calving to the complete dry off at an interval of 15 days. All the hormones were estimated in the serum by commercially available ELISA kits. Plasma level of cortisol (μg/dl), growth hormone (GH, in ng/ml), prolactin (PRL, in μIU/ml), triiodothyronine (T₃, in nmol/μl) and thyroxin (T₄, in ng/ml) were 20.84 ± 0.29, 28.08 ± 0.56, 9.87 ± 0.20, 27.82 ± 0.56 and 51.33 ± 0.48, respectively, in mithun irrespective of strains during the lactation period. Levels of all the hormones varied significantly (p ≤ 0.01) during different days of lactation cycle but, there was no significant difference among strain. Levels of PRL, GH, cortisol and T₃ were significantly (p < 0.01) higher around calving and declined sharply. The hormones remained in almost steady state during mid-lactation and declined during late lactation. All the hormones stated above were positively correlated with lactational yield thus their role on lactogenesis and galactopoiesis was established.     

Comparison of pituitary responses to physical exercise in athletes and sedentary subjects

Serum growth hormone (GH), prolactin (PRL), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH) levels were evaluated before and after a bicycle ergometer exercise test in 8 male competitive volleyball players and in 8 sedentary healthy males of the same age. Increased serum GH and cortisol values after exercise in both groups were found, whereas an exercise-induced PRL release was observed in athletes only. Serum levels of LH, FSH and TSH were unaffected by the test in all subjects. A possible role of training in conditioning the hypothalamopituitary exercise-induced secretion is suggested.     

Daily profiles of plasma prolactin (PRL), growth hormone (GH), insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), testosterone, and melatonin, and of pituitary PRL mRNA and GH mRNA in male Long Evans rats in acute phase of adjuvant arthritis

We studied the effects of adjuvant arthritis (AA) on the endocrine circadian rhythms of plasma prolactin (PRL), growth hormone (GH), insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), testosterone, and melatonin and of pituitary PRL and GH mRNA in male Long Evans rats. Groups of control and AA rats (studied 23 days after AA induction) that were housed under a 12/12 h light/dark cycle (light on at 06:00 h) were killed at 4 h intervals starting at 14:00 h. Cosinor analysis revealed a significant 12 h rhythm in PRL and PRL mRNA (p < 0.001) in controls with peaks at 14:00 h and 02:00 h, respectively. The peak at 02:00 h was abolished in the AA group resulting in a significant 24 h rhythm in parallel with that of PRL (p < 0.05) and PRL mRNA (p < 0.0001). Growth hormone showed no rhythm, but a significant rhythm of GH mRNA was present in both groups (p < 0.0001). Insulin-like growth factor-1 showed a 24 h rhythm in control but not in AA rats. The mean values of GH, GH mRNA, and IGF-1 were significantly reduced in AA. Luteinizing hormone displayed a significant 24 h rhythm (p < 0.01) peaking in the dark period in the control but not AA group. Testosterone showed in phase temporal changes of LH levels with AA abolishing the 02:00 h peak. Melatonin exhibited a significant 24 h rhythm in control (p < 0.001) and AA (p < 0.01) rats with maximum levels during the dark phase; the mesor value was higher in the AA males. These results demonstrate that AA interferes with the rhythms of all the studied hormones except the non-24 h (arrhythmic) GH secretion pattern and the rhythm in melatonin. The persistence of a distinct melatonin rhythm in AA suggests the observed disturbances of hormonal rhythms in this condition do not occur at the level of the pineal gland.     

Increase of circulating levels of thymulin in hyperprolactinemia and acromegaly

The production of thymulin by the thymic epithelium is under complex control involving the endocrine system. Experimental models have suggested that prolactin (PRL) and growth hormone (GH) participate in this regulation but this has not been documented in humans. Using a bioassay we measured circulating thymulin levels in patients with hyperprolactinemia (n = 21), acromegaly (n = 15), or both (n = 6). Thymulin was elevated in these three groups of patients compared with normal subjects or with patients with pituitary disease but no excess in PRL or GH. Contrasting with observations in control groups, thymulin did not decrease as a function of age in patients. No correlation between thymulin and PRL or GH levels was observed while thymulin and insulin-like growth factor 1 levels were correlated. A new radioimmunoassay used in some patients for thymulin determination yielded similar results. Overall these data demonstrate that PRL and GH are involved in the hormonal control of thymulin production by the thymic epithelium in the human.     

Growth hormone response induced by a respiratory muscle endurance training in healthy subjects

To date, the large majority of studies evaluating growth hormone (GH) response to acute physical exercise has been performed involving gross muscle groups. To the best of our knowledge, none has evaluated the effects of a respiratory muscle endurance training (RMET) on hormonal secretions, particularly on GH release, though some respiratory devices have been widely used in athletes to train respiratory muscles and to improve cardiopulmonary function and physical performance. 8 healthy men underwent an incremental progressive RMET protocol of 11 daily sessions, obtained through the use of a specifically designed respiratory device (Spiro Tiger?). The 12th session of RMET (15 min duration: 1 min at a respiration rate of 28 acts/min, 5 min at 32 acts/min, 5 min at 34 acts/min, 4 min at 36 acts/min) was associated with blood samplings for determination of GH, cortisol, ghrelin, glucose, and lactate (LA) levels. GH and cortisol responses significantly increased after a 15-minute RMET session, which, in contrast, inhibited ghrelin secretion. There was a minimal, though significant, increase in LA levels with a significant elevation in glycemia. A 15-minute RMET session, administered after a 11-days incremental progressive RMET protocol, was capable of stimulating GH and cortisol release and suppressing ghrelin secretion. Optimization of incremental progressive RMET protocols would be important to maximize the positive chronic effects of this intervention on somatotropic function and muscle performance.