Blur and contrast as pictorial depth cues

OBJECTIVE: Infusion of GH secretagogues appears to be a novel endocrine approach to reverse the catabolic state of critical illness, through amplification of the endogenously blunted GH secretion associated with a substantial IGF-I rise. Here we report the dynamic characteristics of spontaneous nightly TSH and PRL secretion during prolonged critical illness, together with the concomitant effects exerted by the administration of GH-secretagogues, GH-releasing hormone (GHRH) and GH-releasing peptide-2 (GHRP-2) in particular, on night-time TSH and PRL secretion. PATIENTS AND DESIGN: Twenty-six critically ill adults (mean +/- SEM age: 63 +/- 2 years) were studied during two consecutive nights (2100-0600 h). According to a weighed randomization, they received 1 of 4 combinations of infusions, within a randomized, cross-over design for each combination: placebo (one night) and GHRH (the next night) (n = 4); placebo and GHRP-2 (n = 10); GHRH and GHRP-2 (n = 6); GHRP-2 and GHRH + GHRP-2 (n = 6). Peptide infusions (duration 21 hours) were started after a bolus of 1 microgram/kg at 0900 h and infused (1 microgram/kg/h) until 0600 h. MEASUREMENTS: Serum concentrations of TSH and PRL were determined by IRMA every 20 minutes and T4, T3 and rT3 by RIA at 2100 h and 0600 h in each study night. Hormone secretion was quantified using deconvolution analysis. RESULTS: During prolonged critical illness, mean night-time serum concentrations of TSH (1.25 +/- 0.42 mlU/l) and PRL (9.4 +/- 0.9 micrograms/l) were low-normal. However, the proportion of TSH and PRL that was released in a pulsatile fashion was low (32 +/- 6% and 16 +/- 2.6%) and no nocturnal TSH or PRL surges were observed. The serum levels of T3 (0.64 +/- 0.06 nmol/l) were low and were positively related to the number of TSH bursts (R2 = 0.32; P = 0.03) and to the log of pulsatile TSH production (R2 = 0.34; P = 0.03). GHRP-2 infusion further reduced the proportion of TSH released in a pulsatile fashion to half that during placebo infusion (P = 0.02), without altering mean TSH levels. GHRH infusion increased mean TSH levels and pulsatile TSH production, 2-fold compared to placebo (P = 0.03) and 3-fold compared to GHRP-2 (P = 0.008). The addition of GHRP-2 to GHRH infusion abolished the stimulatory effect of GHRH on pulsatile TSH secretion. GHRP-2 infusion induced a small increase in mean PRL levels (21%; P = 0.02) and basal PRL secretion rate (49%; P = 0.02) compared to placebo, as did GHRH and GHRH + GHRP-2. CONCLUSIONS: The characterization of the specific pattern of anterior pituitary function during prolonged critical illness is herewith extended to the dynamics of TSH and PRL secretion: mean serum levels are low-normal, no noctumal surge is observed and the pulsatile fractions of TSH and PRL release are reduced, as was shown previously for GH. Low circulating thyroid hormone levels appear positively correlated with the reduced pulsatile TSH secretion, suggesting that they have, at least in part, a neuroendocrine origin. Finally, the opposite effects of different GH-secretagogues on TSH secretion further delineate particular linkages between the somatotrophic and thyrotrophic axes during critical illness.     

The effect of lithium on calcium-induced changes in adrenocorticotrophin levels

The calcium receptor (CaR) plays a central role in calcium (Ca) sensing by the parathyroid gland and other organs, including the brain. Chronic lithium (Li) therapy causes a significant alteration in Ca-sensing by the CaR-expressing parathyroid chief cells through an unknown mechanism, shifting the PTH set-point (the level of Ca that half-maximally suppresses PTH secretion) to the right. Ca is known to stimulate ACTH levels in normal subjects, and baseline ACTH levels are increased in patients with bipolar disorder. Because the stimulation of ACTH secretion by Ca likely involves the CaR, the aim of this study was to investigate the effects of Li on Ca-induced changes in ACTH levels, using Ca and citrate infusions in seven Li-treated patients and seven controls. During the Ca infusion, increments in serum-ionized Ca concentration (Ca(i)) were accompanied by increments in ACTH levels that were significantly greater in the Li-treated group, P = 0.014, by ANOVA. Also, cortisol levels increased significantly in the Li-treated, but not the control group, during the Ca infusion, P < 0.0001. There was a statistically significant shift in the midpoint of the Ca(i)/ACTH curve, to the right, in the Li-treated group, compared with the controls (P = 0.042), that was largely caused by an effect of Li on Ca(i). However, for comparable levels of Ca(i), there were no significant differences in the levels of ACTH between the two groups. Therefore, within the physiological range of Ca, there was no effect of Li on Ca(i)-induced change in ACTH levels.     

Vasoactive intestinal peptide-induced prolactin release in hypothyroid patients

VIP is an established prolactin-releasing factor. VIP gene expression at the anterior pituitary level and the central nervous system is regulated by thyroid hormones. On the other hand, primary hypothyroidism leads in many cases to amenorrhea, galactorrhea and hyperprolactinemia. In this study we assessed prolactin responses to VIP (75 micrograms iv infusion over 12 min) in a group of six hypothyroid women (mean age +/- SE, 38.8 +/- 3.3 yr; serum TSH levels, mU/L, 116.3 +/- 23.9), before treatment and after normalization of thyroid hormone levels during thyroxine (T4) replacement therapy (100-150 micrograms/day over 12-16 weeks). Furthermore, we assessed if VIP infusion had any effects on serum GH levels in these patients. In hypothyroid women, VIP infusion increased serum prolactin concentrations with peak levels being attained at 15 min (28.8 +/- 3.4 micrograms/L). The Area Under the Curve (AUC) was 1921 +/- 103 micrograms/L/2h. PRL responses to VIP were unchanged after T4 therapy, both in terms of peak levels (28.7 +/- 2.2 micrograms/L, NS) and of AUC (2079 +/- 261 micrograms/L/2h, NS). Serum GH levels were unaffected by VIP administration. In conclusion our study shows that, in hypothyroid patients, restoration of normal thyroid hormone levels by thyroxine replacement therapy does not affect lactotroph responsiveness to VIP. Therefore, our data do not support the hypothesis that VIP might contribute to the hypothyroid-induced hyperprolactinemia seen in man.     

Hormonal changes and pituitary histological and immunocytochemical studies of patients with multiple organ failure

OBJECTIVE: We investigated the correlation between the endogenous hormonal changes of pituitary-adrenal and pituitary-thyroid hormones and the prognosis of patients in multiple organ failure, and elucidated the mechanism of blunted thyrotropin (TSH) secretion by histological and immunocytochemical studies of anterior pituitary glands. PATIENTS: Forty-three patients were studied who had been admitted to the intensive care unit of Sapporo Medical University Hospital and had been diagnosed as having multiple organ failure. MEASUREMENTS: Pituitary adrenal hormones [corticotropin (ACTH), cortisol] and pituitary thyroid hormones [TSH, triiodothyronin (T3), free-T3, thyroxine (T4), free-T4, thyroxine-binding globulin (TBG)] were measured, and TSH and prolactin (PRL) responses thyrotropin-releasing hormone (TRH) were examined within 24 hours of admission to the ICU. Individual variables were compared between survivors (n = 19) and nonsurvivors (n = 24). Thirteen patients (five survivors, eight nonsurvivors) were investigated again before discharge from the ICU or death. Morphology was examined by hematoxilin-eosin staining, and avidin-biotin-peroxidase complex immunostaining was used to demonstrate the spectrum of TSH in 14 nonsurvivors. RESULTS: (1) ACTH levels remained within the normal range, while cortisol levels increased to above normal levels. Neither hormone showed significant differences between survivors and nonsurvivors. In nonsurvivors, cortisol levels decreased before death despite the increased ACTH levels. (2) T3 and free-T3 levels decreased markedly to below normal values, and reverse-T3 levels increased markedly to above normal values. Nonsurvivors showed significant differences in TSH, T4 and reverse-T3 levels compared with survivors. (3) TSH response to TRH was blunted in both groups but PRL response to TRH was normal. Nonsurvivors showed severely depressed TSH response. Nonsurvivors continued to show blunted TSH response to TRH, while this improved in survivors. (4) The histological study did not show very serious damages to anterior pituitary glands as TSH secretion was depressed. Many TSH immunoreactive cells were also observed by immunocytochemical study. CONCLUSION: Decreased cortisol, low T4 levels and blunted TSH response to TRH correlated with mortality in MOF patients. Histological and immunocytological studies suggest that blunted TSH secretion is not caused by pituitary damages or TSH exhaustion but by disturbances in TSH secretion. This blunted TSH secretion is reversible and its improvement is an indicator of survival.     

Recurrent goiter, hyperthyroidism, galactorrhea and amenorrhea due to a thyrotropin and prolactin-producing pituitary tumor

A 22-year-old woman with recurrent goiter, hyperthyroidism, galactorrhea, and amenorrhea due to a pituitary tumor is described. She had been treated surgically twice for recurrent goiter with tracheal compression. Despite clinical signs of hyperthyroidism and slightly elevated plasma thyroid hormone levels (T4: 11 mug/dl; T3: 189 ng/dl), without thyroid hormone replacement therapy the basal TSH level was elevated up to 23 muU/ml and could not be suppressed by exogenous thyroid hormones: even when the serum thyroid hormone levels were raised into the thyrotoxic range (T4: 16.2 mug/dl T3: 392 ng/dl), the basal TSH fluctuated between 12 and 29 muU/ml. The basal PRL level was elevated up to 6000 muU/ml. The administration of TRH (200 mug iv) led only to small increments of TSH and PRL levels. Bromocriptin (5 mg p.o.) or l-dopa (0.5 g p.o.) suppressed TSH and PRL values significantly. After transsphenoidal hypophysectomy, TSH and PRL were below normal and the patient development panhypopituitarism. The adenoma showed two cell types which could be identified as lactotrophs and thyrotrophs by electronmicroscopy and immunofluorescence. From these data we conclude that the patient had a pituitary tumor with an overproduction of thyrotropin and prolactin.     

Identification of endocrine cell populations expressing the AT1B subtype of angiotensin II receptors in the anterior pituitary

Angiotensin II (Ang II) participates in the regulation of anterior pituitary hormone secretion by acting either directly on the anterior pituitary or indirectly on the hypothalamus. When applied directly on pituitary cells, Ang II increases both ACTH and PRL secretion and has also been reported to affect GH secretion. Three distinct subtypes of Ang II receptors (AT1A, AT1B, and AT2) have been identified; they are unequally distributed and differently regulated in various tissues. We have previously demonstrated that only AT1A receptors are present in the hypothalamus while anterior pituitary cells express predominantly the AT1B subtype. Using in situ hybridization in combination with immunohistochemistry, the aim of the present study was to identify the phenotype of the endocrine cell expressing AT1B receptor messenger RNA (mRNA) in the anterior pituitary of adult male Sprague-Dawley rats. Expression of AT1B receptor mRNA was present in 33.9 +/- 1.0% of anterior pituitary cells. AT1B mRNA is predominantly expressed by lactotropes (78.2 +/- 2.1% of AT1B mRNA-expressing cells) and to a lower degree by corticotropes (18.3 +/- 2.1%) and is not detectable in somatotropes, mammosomatotropes, gonadotropes, or thyrotropes. These results indicate that in adult male rats, Ang II, which has been shown to be synthesized in gonadotropes, can directly stimulate PRL and ACTH release from lactotropes and corticotropes through activation of AT1B receptors. As only 53.8 +/- 2.7% of lactotropes and 23.6 +/- 2.8% of corticotropes expressed AT1B mRNA, our findings suggest a functional heterogeneity of both cell types regarding their sensitivity to Ang II.     

Suppression of thyrotropin (TSH) and prolactin (PRL) release by pyridoxine in chronic primary hypothyroidism

A single iv dose of pyridoxine (V) (300 mg) caused a significant decrease in the concentration of serum thyrotropin (TSH) in 6 patients with primary hypothyroidism. There was no consistent change in serum thyroxine and triiodothyronine concentrations suring the experiment. The serum prolactin (PRL) levels were also suppressed by pyridoxine administration. These findings suggest that pyridoxine inhibits TSH secretion as well PRL by a direct action on the hypothalamus or pituitary gland.     

Dysregulation of the hypothalamo-pituitary axis in rheumatoid arthritis

OBJECTIVE: To study the dynamic response of the hypothalamo-pituitary- adrenal axis and of prolactin (PRL) pituitary secretion in rheumatoid arthritis (RA). METHODS: We performed a cortisol releasing hormone (CRH) provocation test followed by determination of adrenocorticotropin hormone (ACTH), beta-endorphin, and cortisol concentration, and then a thyrotropin releasing hormone (TRH) provocation test followed by assessment of PRL pituitary secretion in 10 patients with RA and 5 control subjects. All were women under 40 years of age. Hormone concentrations were assessed by radioimmunoassay. RESULTS: Basal PRL cortisol, and ACTH concentrations were similar in patients with RA and controls. We observed a dissociation between the pituitary secretion of beta-endorphin and of ACTH in response to CRH in RA. The ACTH peak and total ACTH production (area under the curve, AUC) were similar in the 2 groups. In contrast, basal beta-endorphin was increased in RA (12.6 +/- 1.41 vs 8.29 +/- 0.144 pg/ml), and the response upregulated (AUC: 83,080 +/- 12,000 vs 54,200 +/- 2400) after CRH compared to controls (p < 0.05). Cortisol adrenal response curve was blunted, but did not reach statistical significance. In contrast, the PRL response to TRH was increased at 120 and 150 min (3461 +/- 303 vs 1897 +/- 520 muIU/ml)(p < 0.01) in patients with RA, independent of disease activity. CONCLUSION: We observed upregulated pituitary PRL secretion in RA, and a dissociation of ACTH stress. The implication concerning the neuroendocrine system in the chronic immune response in RA is discussed.     

Physicochemical changes in HDL3 after bezafibrate treatment: influence on free cholesterol efflux from human fibroblasts

Presently, aluminum utensils are widely used in the world, especially in the developing countries. However, whether aluminum leaching from such utensils contributes to aluminum accumulation or causes any damage in patients with renal disease remains unknown. We designed a prospective study to evaluate this problem. After excluding patients who were not examined at follow-up or who poorly complied during the study period, the opened randomized study consisted of 42 patients with chronic renal insufficiency (creatinine clearance <60 mL/min and >10 mL/min). All patients had not taken any aluminum-containing agents for 3 months, but used aluminum kitchen utensils for more than 1 year. Twelve patients comprised the control group; the other 30 patients comprised the study group. The aluminum kitchen utensils used by the study group patients were replaced with stainless steel utensils for 3 months, but those used by the control group were not. After 3 months, the decrements of serum aluminum (5.5 +/- 4.6 microg/L v 2.1 +/- 3.5 microg/L; P = 0.012) and daily urine aluminum excretion (14.3 +/- 15.2 microg/d v 2.1 +/- 5.6 microg/d; P = 0.005) in the study group patients were greater than those in the control group patients. The increments of transferrin saturation of the study group patients (1.8% +/- 9.5% v -3.7% +/- 9.5%; P = 0.052) were greater than those of the control group patients. In addition, the increments of iron (r = 0.368, P = 0.035) and transferrin saturation (r = 0.345, P = 0.049) positively correlated with the decrements of daily aluminum excretion in all patients. The study group patients with greater decrements of serum aluminum (>5.5 microg/L) had greater serum iron levels (90.2 +/- 27.7 microg/dL v 71.9 +/- 27.8 microg/dL; P = 0.047) and transferrin saturation (30.5% +/- 11.0% v 23.0% +/- 9.5%; P = 0.046) than those with less decrements of serum aluminum (<5.5 microg/L) after the study. Our study demonstrates that aluminum kitchen utensils may be the important aluminum exposure source for patients with chronic renal insufficiency who are not taking aluminum-containing agents, and hints that the long-term exposure of aluminum leaching from aluminum utensils probably affects iron levels in patients with chronic renal insufficiency. Further studies are clearly needed to confirm this observation.     

Angiotensinergic neurons physiologically inhibit prolactin, growth hormone, and thyroid-stimulating hormone, but not adrenocorticoptropic hormone, release in ovariectomized rats

Angiotensin II (AII)-containing neurons with cell bodies in the rostral medial hypothalamus and axons project to the external layer of the median eminence, so that AII maybe released into the hypophyseal portal vessels for actions on the pituitary gland. Indeed, intrahypothalamic actions of the peptide on the release of hypothalamic hormones and direct actions on the pituitary have been reported. To determine the role of endogenously released AII in hypothalamic-pituitary hormone release, we have determined the effects of central immunoneutralization of AII upon the plasma concentrations of prolactin (PRL), growth hormone (GH), thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH). Specific antiserum directed against AII (AB-AII) or normal rabbit serum (NRS), as a control, was microinjected into third ventricular (3 V) cannulae of conscious, ovariectomized (OVX) rats. Immediately before and at various intervals after this procedure, blood samples were withdrawn through previously implanted external jugular catheters. Three hours after injection of the AB-AII, plasma PRL levels diverged from those of the NRS-injected animals and progressively increased from 4 to 24 h after administration of the antiserum. Results were similar with respect to plasma GH, except that the increase in the AB-AII animals above that in the NRS-injected controls from 4 to 6 h was not significant, but was highly significant on measurement 24 h after injection, at which time plasma GH was three times higher than in control rats. Similarly, following injection of AB-AII, plasma TSH values did not diverge significantly from those of the NRS-injected controls until 3 h after injection. From 3 to 5 h they remained constant and significantly elevated above values in the NRS-injected controls with a further nonsignificant increase at 6 h. At 24 h, there was no longer a difference between the values in both groups. In contrast to the significant elevations in plasma hormone levels observed with respect to PRL, GH, and TSH following injection of the antiserum, there was no change in plasma ACTH between the AB-AII-injected and NRS-injected animals throughout the same period of observation. Previous results by others have shown that intraventricular injection of AII has a suppressive action on the release of PRL, GH, and TSH. Consequently, we believe that the antiserum is acting intrahypothalamically to block the action of AII within the hypothalamus, resulting in the elevation of the three hormones mentioned. Therefore, the AII neurons appear to have a physiologically significant suppressive action on the release of hypothalamic neurohormones controlling the release of PRL, GH, and TSH. In contrast, there apparently is no effect of intrahypothalamically released AII on the secretion of corticotropin-releasing factors under these nonstress conditions. We cannot rule out an action of the antiserum at the pituitary level; however, in view of the fact that the actions of AII directly on the gland are to stimulate PRL, GH, TSH, and ACTH release, it appears that the antiserum was acting at the hypothalamic level.     

Prolactin and thyrotropin responses to thyrotropin-releasing hormone in patients with secondary amenorrhea: the effect of bromocriptine

Prolactin (PRL) and thyrotropin (TSH) responses to a 200 mug intravenous thyrotropin-releasing hormone (TRH) bolus were measured by radioimmunoassay in 11 women with hyperprolactinemic amenorrhea and 9 with normoprolactinemic amenorrhea. In all cases, the tests were carried out under basal conditions and repeated during bromocriptine treatment. In women whose basal PRL level was normal; TRH caused a maximal PRL increment of 85 +/- 25.2 mug/l (mean +/- SE), while those women whose basal PRL level was raised showed a smaller increase (5.2 +/- 11.9 mug/l) (P=0.02). The peak levels were not significantly different in these two groups (95.0 +/- 26.7 and 134.6 +/- 35.9 mug/l) (P is greater than 0.1). During bromocriptine treatment, the raised PRL levels decreased in all cases, but levels over 30 mug/l remained in 3 patients, one of whom turned out to have a pituitary tumor. Prolactin responses to TRH were markedly inhibited in normoprolactinemic patients by the dose of bromocriptine used. The mean maximal net increase of PRL was 2.0 +/- 0.9 mug/l in normoprolactinemic patients and 11.0 +/- 8.1 mug/l in hyperprolactinemic patients taking bromocriptine. After TRH stimulation during bromocriptine, the peak PRL levels in hyperprolactinemic patients were higher (32.7 +/- 10.5 mug/l) than in normoprolactinemic patients (7.2 +/- 1.5 mug/l). Unlike what has been described for hypothyroid patients, the basal TSH level in euthyroid amenorrhea patients was not affected by bromocriptine, and we found that bromocriptine has no effect on the TRH-TSH response.     

Role of protein degradation in the growth of livers after a nutritional shift

Four patients with idiopathic pituitary dwarfism were shown to have growth hormone (GH), adrenocorticotropin (ACTH), and luteinizing hormone (LH) deficiencies. Basal levels of thyrotropin (TSH) were within normal range in three patients and slightly elevated in one. Exaggerated and delayed responses were obtained after TSH-releasing hormone (TRH) stimulation. Serum thyroxine (T4) values were low (2.3 +/- 0.4 mug/100 ml), while triiodothyronine (T3) levels were in the normal range (1.22 +/- 0.25 ng/ml), both rising substantially after exogenous TSH and consecutive TRH administration. Their hypothyroid state was, therefore, probably due to TRH deficiency. To examine the dose of L-T4 necessary to produce inhibition of the TSH response to TRH, 50 mug/m2/day of L-T4 was administered to these patients. At the end of 4 weeks of replacement, serum T4 rose to 5.2 +/- 0.5 mug/100 ml, whereas T3 was unchanged from the previous levels, after which TSH responses to TRH were completely suppressed in all patients. As a control group, six patients with primary hypothyroidism received gradually increasing doses of L-T4 for 4-week periods, and TSH response to TRH was tested at the end of each dosage of L-T4, until complete inhibition of TSH release was obtained. The primary hypothyroid patients required approximately 150 mug/m2/day of L-T4 for suppression of TSH response to TRH. At this dosage, serum T4 and T3 levels were 8.5 +/- 0.9 mug/100 ml and 2.34 +/- 0.5 ng/ml respectively, which were significantly higher than those levels in the pituitary dwarfs (P less than 0.001 for T4 and P less than 0.01 for T3). These observations indicate that the set point of TSH release in feedback inhibition by throxine is low in idiopathic hypopituitarism with TRH deficiency, and TRH seems to control the pituitary sensitivity to feedback regulation of thyroid hormones.     

Hypofunction of the stress axis in Sj?gren's syndrome

OBJECTIVE: To examine the functional integrity of the hypothalamic-pituitary-adrenal (HPA) and thyroid axes in Sj?gren's syndrome (SS) via the assessment of basal and stimulated adrenocorticotropin (ACTH), cortisol, thyroid stimulating hormone (TSH), and prolactin levels. METHODS: Pituitary function of the HPA axis was assessed by determining the basal plasma levels of ACTH in the late afternoon, as well as the ACTH released to ovine corticotropin releasing hormone (oCRH) stimulation; adrenal function was assessed by measuring plasma cortisol levels in the late afternoon at baseline and after release of the endogenous ACTH during oCRH stimulation. Basal and thyrotropin releasing hormone (TRH) stimulated levels of TSH and prolactin were also assessed. Healthy volunteers were used as controls. RESULTS: Patients with SS, compared to controls, were characterized by significantly lower ACTH levels (pg/ml), (5.1 +/- 0.5 vs 11.4 +/- 1.5, respectively; p < 0.05) and cortisol levels (microg/ml), (2.4 +/- 0.6 vs 5.9 +/- 1.2, respectively; p < 0.05). Furthermore, a blunted pituitary and adrenal response to oCRH compared to controls was observed: peak plasma ACTH and cortisol levels for patients with SS were 46.2 +/- 5.4 pg/ml and 15.7 +/- 1.6 microg/ml, respectively, and for controls 61.5 +/- 3.8 and 19.6 +/- 0.7, respectively (p < 0.05). Basal TSH levels were significantly elevated in patients (1.3 +/- 0.3 microIU/ml vs 0.9 +/- 0.05 microIU/ml; p < 0.05). CONCLUSION: The above findings indicate hypoactivity of the HPA axis in patients with SS. Further studies are needed to definitively identify the locus of the defects and assess the significance of the pattern of the perturbations to the pathogenesis and expression of SS.     

Assessment of pituitary function after transsphenoidal hypophysectomy in beagle dogs

Pituitary function was assessed in healthy adult beagle dogs before and after hypophysectomy. Anterior pituitary function was tested by use of the combined anterior pituitary (CAP) function test, which consisted of sequential 30-sec intravenous injections of four hypothalamic releasing hormones, in the following order and doses: 1 microgram of corticotropin-releasing hormone (CRH)/kg, 1 microgram of growth hormone-releasing hormone (GHRH)/kg, 10 micrograms of gonadotropin-releasing hormone (GnRH)/kg, and 10 micrograms of thyrotropin-releasing hormone (TRH)/kg. Plasma samples were assayed for adrenocorticotropin (ACTH), cortisol, GH, luteinizing hormone (LH), and prolactin (PRL) at multiple times for 120 min after injection. Pars intermedia function was assessed by the alpha-melanotropin (alpha-MSH) response to the intravenous injection of the dopamine antagonist haloperidol in a dosage of 0.2 mg/kg. Posterior pituitary function was assessed by the plasma vasopressin (AVP) response to the intravenous infusion of 20% saline. Basal plasma ACTH, cortisol, thyroxine, LH. PRL, and AVP concentrations were significantly lower at 10 wk after hypophysectomy than before hypophysectomy. In the CAP test and the haloperidol test, the peaks for the plasma concentrations of ACTH, cortisol, GH, LH, PRL, and alpha-MSH occurred within 45 min after injection. At 2 and 10 wk after hypophysectomy, there were no responses of plasma GH, LH, PRL, and alpha-MSH to stimulation. In four of eight hypophysectomized dogs, there were also no plasma ACTH and cortisol responses, whereas in the other four dogs, plasma ACTH and cortisol responses were significantly attenuated. The basal plasma ACTH and cortisol concentrations were significantly lower in the corticotropic nonresponders than in the responders. Plasma AVP responses were completely abolished by hypophysectomy, although water intake by the dogs was normal. Histopathological examinations at 10 wk after hypophysectomy revealed that adrenocortical atrophy was much more pronounced in the corticotropic nonresponders than in the responders. No residual pituitary tissue was found along the ventral hypothalamic diencephalon. However, in all hypophysectomized dogs that were investigated, islets of pituitary cells were found embedded in fibrous tissue in the sella turcica. A significant positive correlation was found between the number of ACTH-immunopositive cells and the ACTH increment in the CAP test at 10 wk after hypophysectomy. It is concluded that 1) stimulation of the anterior pituitary with multiple hypophysiotropic hormones, stimulation of the pars intermedia with a dopamine antagonist, and stimulation of the neurohypophysis with hypertonic saline do not cause side effects that would prohibit routine use, 2) in the routine stimulation of the anterior pituitary and the pars intermedia, blood sampling can be confined to the first 45 min, 3) the ACTH and cortisol responses to hypophysiotropic stimulation are the most sensitive indicators for residual pituitary function after hypophysectomy, 4) small islets of pituitary cells in the sella turcica, containing corticotropic cells, are the most likely source of the attenuated corticotropic response that may occur after hypophysectomy, and 5) residual AVP release from the hypothalamus after hypophysectomy is sufficient to prevent diabetes insipidus, despite the fact that the AVP response to hypertonic saline infusion is completely abolished.     

Hot water swallows improve symptoms and accelerate esophageal clearance in esophageal motility disorders

The mechanism of action of the synthetic growth hormone (GH)releasing peptide hexarelin is not yet fully understood. Although a direct effect on pituitary cells has been demonstrated, the peptide is also active at hypothalamic level, where specific binding sites have been found. The observation that hexarelin acts synergistically with GH-releasing hormone (GHRH) in releasing GH has suggested that it might suppress endogenous somatostatin secretion. As somatostatin is also inhibitory on TSH secretion, to verify the occurrence of modifications of the somatostatinergic tone induced by hexarelin, we studied its effects on TRH-induced TSH secretion. Seven normal subjects (4 women and 3 men aged 24-29 years) underwent the following tests on 3 different days: a) TRH (200 micrograms/l i.v.) + placebo; b) hexarelin (1 microgram/Kg bw i.v.) + placebo c) combined TRH + hexarelin administration. Hexarelin induced significant and similar increases in serum GH levels when given in combination either with placebo or with TRH (1217 +/- 470 vs 986 +/- 208 micrograms/min/l p:NS), while no modifications of GH levels were seen after TRH + placebo. Serum TSH levels were unmodified by hexarelin + placebo injection. The TSH increase elicited by hexarelin + TRH was superimposable to that elicited by TRH + placebo (1124 +/- 530 and 1273 +/- 380 mU/min/l respectively). Circulating PRL levels slightly increased after hexarelin + placebo too (897 micrograms/min/l), and the PRL response to hexarelin + TRH was slightly, although not significantly, greater than that observed after TRH + placebo (2680 +/- 1517 and 2243 +/- 1108 micrograms/min/l, respectively). In conclusion, our data show that hexarelin does not alter basal and TRH-stimulated TSH secretion, thus suggesting that it does not inhibit somatostatin release. Furthermore a modest PRL-releasing effect of this peptide has been confirmed.     

An ovarian leiomyoma: a case report

OBJECTIVES: To investigate the dynamic parathyroid response to rapidly induced, sustained hypocalcaemia in patients with acute malaria and in healthy volunteers. DESIGN: Serum intact parathormone (PTH) concentrations were measured on samples taken before and during a variable-rate tri-sodium citrate infusion designed to 'clamp' the whole blood ionised calcium concentration 0.20 mmol L-1 below baseline for 120 min. SUBJECTS: Six Malaysian patients aged 17-42 years with acute malaria, four of whom were restudied in convalescence, and 12 healthy controls aged 19-36 years. MAIN OUTCOME MEASURES: Whole-blood ionised calcium and serum intact PTH concentrations. RESULTS: The mean (SD baseline ionised calcium was lower in the malaria patients than in controls (1.09 +/- 0.06 vs. 1.18 +/- 0.03 mmol L-1, respectively; P = 0.01) but PTH concentrations were similar (3.0 +/- 1.8 vs. 3.3 +/- 1.3 pmol L(-1); P = 0.33). Target whole-blood ionised calcium concentrations were achieved more rapidly in the controls than the patients (within 15 vs. 30 min) despite significantly more citrate being required in the patients (area under the citrate infusion-time curve 0.95 (0.25 vs. 0.57 +/- 0.09 mmol kg-1; P < 0.01). The ratio of the change in serum PTH to that in ionised calcium (delta PTH/ delta Ca2+), calculated to adjust for differences in initial rate of fall of ionised calcium, was similar during the first 5 min of the clamp (132 +/- 75 x 10(-6) vs. 131 +/- 43 x 10(-6) in patients and controls, respectively, P > 0.05), as were steady-state serum PTH levels during the second hour (7.0 +/- 2.2 pmol L-1 in each case). Convalescent patients had normal basal ionised calcium levels but the lowest serum intact PTH levels before and during the clamp, consistent with an increase in skeletal PTH sensitivity after treatment. CONCLUSIONS: There is a decreased ionised calcium 'set point' for basal PTH secretion but a normal PTH response to acute hypocalcaemia in malaria. Skeletal resistance may attenuate the effects of the PTH response but patients with malaria appear relatively resistant to the calcium chelating effects of citrated blood products.     

Release of prolactin as well as adrenocorticotropin after administration of arginine-vasopressin to healthy men

The study was undertaken to obtain simultaneous measurements of circulating anterior pituitary hormone levels after the i.v. injection of arginine-vasopressin (AVP). Nine healthy men, mean age 31 years (range 24-41), received single blind with at least one week apart, after resting in the supine position for 30 min, AVP 0.26 microgram/kg body weight i.v. (Pitressin, Parke-Davis) or saline in randomized order. Blood samples were taken at 0, 10, 20, 30, 45 and 60 min for analyses of serum or plasma levels of ACTH, prolactin, TSH, GH, FSH, LH and AVP. The hormone responses after AVP or saline were calculated as the area under the curve (AUC) 0-60 min as well as the change in hormone levels from 0 to 10 min to pick up possible short lasting effects when there was no significant difference in AUC between AVP and control. As expected the highest plasma concentration of AVP was measured 10 min after the injection of AVP and well comparable to those in other studies where AVP was observed to release ACTH. The AUC:s for both ACTH and prolactin levels were significantly increased after AVP in comparison with saline (p = 0.008 and p = 0.038, respectively). The AUC:s for the other hormones measured were not significantly changed after AVP, but there were small but significant changes in the 0-10 min values for TSH and LH after AVP compared to saline. It is concluded that AVP has the potency to release not only ACTH but also prolactin in healthy men.     

Studies on stannous fluoride toothpaste and gel (1). Antimicrobial properties and staining potential in vitro

Although there is evidence that endogenous opioids, and in particular beta-endorphin (beta-EP), may mediate some of the suppressive effects of hyperprolactinemia on the hypothalamic-pituitary-gonadal (HPG) axis, there is controversy about the effects of prolactin (PRL) on beta-EP and its precursor, proopiomelanocortin (POMC), in the hypothalamus. In this study we have therefore examined the effects of chronic peripheral and intracerebroventricular (i.c.v.) infusion of ovine PRL on POMC gene expression and beta-EP levels in the medial basal hypothalamus (MBH) of castrated male and female rats. Endogenous pituitary and plasma PRL levels were determined by RIA with an antiserum to rat PRL which does not crossreact with oPRL. Suppression of endogenous rPRL levels was used as a confirmation of the biological effectiveness of the infused oPRL. POMC mRNA was measured in the MBH by solution hybridization assay. In the first experiment oPRL (5 microg/microl/h) or vehicle was infused for 2 weeks by osmotic minipump into the right lateral ventricle of ovariectomized rats. The mean plasma concentration of rPRL declined from 3.7+/-1.0 ng/ml in the controls to 1.4+/-0.13 ng/ml in the oPRL infused animals (P<0.05); pituitary rPRL content similarly decreased from 39.1+/-4.6 microg to 20.4+/-3.7 microg (P<0.02). There was no significant change in the concentration of POMC mRNA or beta-EP in the MBH of the oPRL treated animals. In the second experiment oPRL was infused for 1 week into the third ventricle of orchiectomized rats. Again despite a fall in endogenous PRL levels, there was no significant change in POMC or beta-EP in the MBH. In the third experiment oPRL was infused subcutaneously into orchiectomized rats for 2 weeks. Mean plasma oPRL levels were 150+/-7.3 ng/ml after 1 week and 58+/-7.5 ng/ml after 2 weeks. Pituitary rPRL content was again suppressed in the oPRL treated animals but no change in POMC or beta-EP was detected in the MBH. We conclude that oPRL can be infused both peripherally and centrally for up to 2 weeks with resulting suppression of endogenous pituitary PRL content and release. Under these conditions no effects on the concentrations of POMC mRNA or beta-EP could be demonstrated in the hypothalamus. These results suggest that either PRL has nongenomic effects on hypothalamic beta-EP or that endogenous opioids other than beta-EP mediate the suppressive effects of PRL on the HPG axis.     

Cortisol differentially regulates pituitary-adrenal function in the sheep fetus after disconnection of the hypothalamus and pituitary

We have investigated the effects of a 5 day infusion of cortisol into fetal sheep, in which the hypothalamus and pituitary were surgically disconnected (HPD), on fetal pituitary-adrenal function. Fetal HPD and vascular catheterization were carried out at between 104 and 124 days gestation. Cortisol was administered (3.5 mg 24 h-1) for 120 h between 134 and 140 days (HPD + F group; n = 5) and saline was administered during the same gestational age range to HPD (HPD group; n = 12) and intact fetal sheep (Intact group; n = 6). Cortisol infusion into the HPD fetal sheep did not suppress the mRNA levels for Proopiomelanocortin (POMC) in the fetal anterior pituitary at 139/140 days gestation (POMC mRNA: 18S rRNA: Intact 0.40 +/- 0.05; HPD 0.56 +/- 0.07; HPD + F 0.49 +/- 0.07). Similarly, there was no significant effect of either HPD or cortisol infusion on the plasma concentrations of immunoreactive (ir) ACTH or ACTH(1-39). The adrenal: fetal body weight ratio was significantly higher, however, in the HPD + F (88.4 +/- 8.7 mg kg-1) and Intact groups (84.1 +/- 5.6 mg kg-1) when compared with the HPD fetal sheep (63.7 +/- 5.4 mg kg-1). The ratio of total IGF-II mRNA: 18S rRNA was similar in the adrenals of the Intact (0.48 +/- 0.09), HPD (0.78 +/- 0.09) and HPD + F (0.71 +/- 0.11) groups. The ratios of CYPIIA1, 3 beta-HSD and CYP21A1 mRNA: 18S rRNA were significantly lower in adrenals from the HPD group when compared to those in the Intact group and were not restored to normal by cortisol infusion. We have therefore demonstrated that cortisol does not act directly at the fetal pituitary to suppress POMC synthesis or ACTH secretion in late gestation. Cortisol does, however, stimulate fetal adrenal growth after HPD in the absence of any effects on adrenal IGF-II or steroidogenic enzyme mRNA levels. The data provide evidence that an intact hypothalamic-pituitary axis and cortisol each play an important role in the stimulation of adrenal growth and steroidogenesis which occurs during the last 10-15 days of gestation in the sheep.