Growth hormone, prolactin and chorionic somatomammotropin in normal and molar pregnancy

Twenty patients with molar pregnancy, ten normal pregnant women and ten healthy non-pregnant women were given 30 g of arginine intravenously. The serum concentration of growth hormone, prolactin and chorionic somatomammotropin (CS) was determined by radioimmunoassay. In addition, serum 17beta-estradiol, estriol and progesterone were also measured. Arginine infusion induced a sharp rise of GH in patients with molar pregnancy and in nonpregnant subjects, but the response in normal pregnancy was blunted. The response of PRL was high in patients with molar pregnancy, blunted in normal pregnancy and very small in nonpregnant subjects. CS did not respond at all to arginine infusion both in normal pregnancy and molar pregnancy. The high response to argine of PRL, normal response of GH and low baseline secretion and no response of CS may be characteristic of molar pregnancy.     

Co-localization of human growth hormone and human prolactin in hormonally pure human growth hormone-producing pituitary adenomas

Co-localization of human growth hormone (hGH) and human prolactin (hPRL) in hGH-producing pituitary adenomas was examined by electron microscopy with immunoblot analysis. At the electron microscopic level using anti-hGH or anti-hPRL polyclonal antibody, hGH and hPRL were found to be co-localized within each of the secretory granules in one of five cases. Double-labeling electron immunocytochemistry using colloidal gold particles of different sizes was effective in demonstrating this co-localization. As an additional step, we performed immunoblot analysis of hGH-producing pituitary adenomas using monoclonal antibodies. Four hGH-producing adenomatous tissue samples contained several hPRL-immunoreactive bands. In Case 2, the main 23K hPRL band was stained especially strongly The immunoblotting analysis of purified hGH using both anti-hPRL polyclonal antibody and monoclonal antibody to asses cross-reaction of the polyclonal anti-hPRL antisera with hGH revealed that both monoclonal and polyclonal antibodies were suitable for determining the co-localization. Double-labeling techniques using anti-hGH and anti-hPRL monoclonal antibodies demonstrated that only a few secretory granules were positive for co-localization of both hGH and hPRL (Case 2). The present study, which used not only polyclonal but also monoclonal antibodies, suggests that some hGH-producing pituitary adenomas contained both hPRL and hGH in the same secretory granules of tumor cells.     

Influence of infused prolactin on hormone binding to tissue slices

The influence of circulating prolactin on the binding of labeled hormone to tissue slices in vitro was investigated in rats bearing dimethylbenzanthracene-induced mammary tumors. Prolactin was infused into four animals over four 30-min periods to give serum levels ranging from 20 to 2000 ng/ml. Serial biopsies of liver and tumor were taken during infusion, and binding of labeled prolactin and insulin measured in tissue slices. Whereas insulin binding remained constant, prolactin binding was significantly depressed in both tissues when samples were obtained at serum prolactin levels greater than 300 ng/ml. This decrease was due to diminished numbers of available binding sites rather than a change in binding-site affinity for prolactin. The data indicate that under the conditions of this experiment, endogenous circulating prolactin may interfere with in vitro measurements of hormone uptake when serum levels excee 300 ng/ml.     

Plasma prolactin responses to thyrotropin-releasing hormone in patients with breast cancer

Plasma human prolactin levels were measured by homologous radioimmunoassay in patients with primary breast cancer and in normal women of similar age. In normal controls mean (+/- SEM) basal plasma prolactin levels were 11.9 +/- 1.5 ng/ml and intravenous injection of synthetic thyrotropin-releasing hormone (TRH), 500 mug, caused a significant rise in plasma prolactin in all subjects examined with a maximum response of 52.6 +/- 3.3 ng/ml (mean +/- SEM). Markedly high plasma prolactin levels and exaggerated plasma prolactin responses to TRH were demonstrated in some patients with breast cancer. However, mean basal plasma prolactin levels and mean plasma prolactin increments following TRH in patients with breast cancer did not differ significantly from those in normal subjects. Plasma prolactin responses to TRH were slightly blunted during the administration of androgen in patients with breast cancer. These results suggest that some of the patients with primary breast cancer have abnormal prolactin secretion.     

Combination chemotherapy with cis-platinum and ifosfamide for hormone unresponsive prostate cancer

PURPOSE: There is no effective therapy against hormone refractory prostate cancer. This led us to evaluate the effectiveness and toxicity of cis-platinum (CDDP) and ifosfamide (IFM) combination chemotherapy in the patients with hormone-unresponsive carcinoma of the prostate. METHODS: Patients with hormone-unresponsive prostate cancer were scheduled to receive CDDP 70 mg/m2 intravenously on day 1 and IFM 1.2 g/m2/day intravenously on day 1 through day 5 of 28-day cycle. RESULTS: Twenty seven patients with hormone unresponsive prostate cancer were enrolled onto this trial. Of these patients, seven (26%) demonstrated a partial objective response (PR), and ten (37%) a stable disease (ST). The response duration of PR cases lasted from 6 to 49 months with a median of 16 months and the response duration of PR + ST cases lasted from 3 to 36 months with a median of 10 months. Subjective improvement was obtained in 11 patients (41%). Survival duration of all cases were 4 to 89 months with a median of 23 months and probabilities of survival at 3 years and 5 years were 36% and 24%, respectively. The toxicity of this treatment was mostly mild to moderate, anemia (96%), leukocytopenia (89%), anorexia (81%), alopecia (67%), thrombocytopenia (44%), hematuria (38%), renal dysfunction (19%) and liver dysfunction (7%) were noticed. Severe toxicity was observed in two cases, one acute renal failure and one endotoxin shock. CONCLUSION: We conclude that CDDP and IFM combination chemotherapy was active regimen for hormone unresponsive prostate cancer.     

Growth hormone refractory interval to levodopa stimulation

The GH response to repeat l-dopa stimulation was studied in three phases. In phase I and phase II, 16 normal adults divided into four groups were restimulated at 3, 4, 5, and 6 hours with 500 mg l-dopa and 1000 mg l-dopa, respectively. No response could be elicited at 3 hours and only at 6 hours (500 mg l-dopa) and 5 hours (1000 mg l-dopa) did the repeat responses return in magnitude to that of the initial. The period of decreased responsiveness to GH was terned the "refractory interval". In phase III, addition of an inhibitor of peripheral L-aromatic amino acid decarboxylase (50 mg MK-486) to the restimulation dose shortened but did not eliminate the refractoriness. Our results suggest that the refractory interval is not due to a peripherally located mechanism.     

Altered growth hormone and prolactin responsiveness to TRH in the infant rat

12-day-old female and male pups were killed 10 min after the injection of either saline or thyrotropin releasing hormone (TRH), and plasma growth hormone (GH) and prolactin (PRL) levels were measured by radioimmunoassay (RIA). At all doses used (0.15, 0.3, 0.6 and 1.5 mug/100 g b.w.i.p.), TRH induced a significant, although not dose-related, increase in plasma GH levels, but was effective in releasing PRL only at the greatest dose level (1.5 mug/100 g b.w.). The GH-releasing effect of TRH was even more evident in 12-day-old pups subjected to central sympathectomy of 6-hydroxydopamine (6-OHDA, 60 mug/10 mul intraventricular route) 1 week before; in these animals, TRH was ineffective in releasing PRL even at the greatest dose level (1.5 mug/100 g b.w.). In pups pretreated with 6-OHDA, the GH-lowering effect of insulin hypoglycemia or cold exposure was markedly reduced, while the PRL responses were unmodified. Baseline plasma PRL levels were markedly increased following 6-OHDA administration. It is proposed that in the infant rat the greater GH than PRL responsiveness to TRH, which opposed the pattern of response present in the adult animal, may be due to the existence of a 'physiologic' functional disconnection between the central nervous system (CNS) and the anterior pituitary (AP). Results obtained following central sympathectomy by 6-OHDA, which further disrupted CNS-AP links, substantiate this view.     

Growth hormone inhibits lipoprotein lipase activity in human adipose tissue

The in vitro effects of GH on human adipose tissue lipoprotein lipase (LPL) activity and messenger ribonucleic acid (mRNA) levels were studied using a tissue incubation technique. After preincubation for 3 days, abdominal sc adipose tissue pieces were exposed to cortisol (1000 nmol/L) for 3 days to induce LPL activity. Addition of GH (50 micrograms/L) to the cortisol-containing medium during the last 24 h (day 6) caused a decrease by 84 +/- 4% (P < 0.01) in heparin-releasable LPL activity and by 65 +/- 4% (P < 0.01) in total LPL activity. Moreover, the heparin-releasable fraction was reduced from 42% of the total LPL activity with cortisol alone to 17% when both GH and cortisol were present in the incubation medium during the last 24 h (P < 0.01). The reduction in LPL activity in response to GH was not accompanied by a decrease in the level of LPL mRNA measured by a solution hybridization ribonuclease protection assay. In adipose tissue incubated in the control medium for 6 days, the addition of GH alone during the last 24 h caused an insignificant decrease in heparin-releasable LPL activity. Low control activities limited the scope for further decrease. It is concluded that GH counteracts the potent stimulatory effect of glucocorticoids on LPL activity without affecting LPL mRNA levels. Therefore, the inhibition of LPL activity by GH probably occurs during translation and/or posttranslational processing of the enzyme, and the mechanism may involve a decreased channeling of the lipase to the cell surface.     

A wheezy infant unresponsive to bronchodilators

The authors present possibilities of the surgical treatment in bilateral vocal cord paralysis. We described the technique of the operation which is being used in our department in such a cases. 13 patients were analyzed after operations (11 women, 2 men). Bilateral vocal cord paralysis was caused by thyroidectomy (11 cases), virus infection (1 case) and in the course of multiple sclerosis (1 case). Functional results were evaluated by subjective examination, indirect laryngoscopy, spirometry and video-laryngoscopy. The effects of the treatment were satisfied.     

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.     

Growth hormone and its receptor are expressed in human thymic cells

GH has been shown to modulate various functions of the thymus. We now demonstrate the production of human GH (hGH) by human thymic cells, and the expression of GH receptors in thymic epithelial cells (TEC) and in thymocytes at different stages of differentiation. The presence of hGH messenger RNA was shown by RT-PCR in both human thymocytes and in primary cultures of TEC. Moreover, immunoreactive hGH material was detected in culture media of thymocytes and TEC with the use of a sensitive immunoradiometric assay. GH receptor gene expression was shown in TEC in primary cultures and in fetal and postnatal TEC lines as well as in thymocytes. By immunocytochemistry, the presence of GH receptors in the various TEC preparations was confirmed. In cytofluorometric studies with the use of a biotinylated anti-GH receptor monoclonal antibody, we could show that GH receptors are predominantly expressed by immature thymocytes: over 90% of CD3- CD4- CD8- CD19- CD34+ CD2- cells (a phenotype characterizing the most immature T cell progenitors in the thymus) were GH receptor positive. Our results provide a molecular basis for an autocrine/paracrine mode of action of GH in the human thymus.     

A membrane protein associated with the prolactin receptor. Studies with a photoactivatable human growth hormone derivative

Prolactin receptor from rat liver (PRL-R, 42 kDa) was cross-linked to a radiolabeled azidophenacyl derivative of human growth hormone ([125I]AP-hGH) to yield a 63 kDa adduct. In addition, a protein of Mr 50-52 K was detected as a 73 kDa complex. Microsomes incubated with either (a) increasing amounts of [125I]AP-hGH, or (b) a fixed amount of photoprobe and increasing concentrations of unlabeled hGH, showed that the 73/63 kDa band intensity ratio remains constant (0.71-0.77). Once transferred onto nitrocellulose membranes, only the 42 kDa protein is able to bind [125I]AP-hGH or [125I]hGH. Two anti-PRL-R monoclonal antibodies fail to cross-react with proteins of Mr 50-52 K. In membranes solubilized with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS), a significantly lower amount of the 73 kDa complex is detected. Thus, the 50-52 kDa protein appears to be structurally unrelated to, but is presumably associated with the PRL-R. The 73 kDa complex is also detected under low membrane fluidity conditions (1 degree C), indicating that PRL-R associates to this 50-52 kDa protein prior to hormone binding. Perfusion of rat liver with [125I]AP-hGH shows that this associated protein accompanies the receptor along its intracellular pathway.     

Growth hormone and surgery

Growth hormone (GH) is a very potent anabolic agent released in the physiological situation in a pulsative manner from the pituitary gland. GH stimulates the protein synthesis and increases the intracellular transport of amino acids. When GH is administered to surgical patients, nitrogen retention is regularly seen, and in most situations fast mobilization takes place. The present data indicate that GH has a beneficial effect on the healing processes after surgery and trauma.     

Dose-response of prolactin and thyrotropin to N3im-methyl-thyrotropin releasing hormone in euthyroid men

The synthetic N3im-methyl analogue of thyrotropin releasing hormone (methyl-TRH) was administered intravenously to 15 euthyroid men, ages 36-62, in graded doses from 6.25 mug to 500 mug in order to establish the range of response of prolactin (PRL), TSH, T3 and T4 to various doses of methyl-TRH. There was a dose-related rise in serum TSH, PRL, T3, and T4 which gave a nearly linear relationship when the integrated area of response was used as an index of response to the various doses of methyl-TRH. All 15 men had a clear elevation in TSH, PRL, T3 and T4 following the lowest dose of methyl-TRH TESTED (6.25 mug). There was considerable variability in the response to methyl-TRH among the individuals. One hundred mug of methyl-TRH gave a maximum TSH response; a 25 mug dose elicited a maximum PRL response.     

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.     

Growth hormone and bone

It is well known that GH is important in the regulation of longitudinal bone growth. Its role in the regulation of bone metabolism in man has not been understood until recently. Several in vivo and in vitro studies have demonstrated that GH is important in the regulation of both bone formation and bone resorption. In Figure 9 a simplified model for the cellular effects of GH in the regulation of bone remodeling is presented (Fig. 9). GH increases bone formation in two ways: via a direct interaction with GHRs on osteoblasts and via an induction of endocrine and autocrine/paracrine IGF-I. It is difficult to say how much of the GH effect is mediated by IGFs and how much is IGF-independent. GH treatment also results in increased bone resorption. It is still unknown whether osteoclasts express functional GHRs, but recent in vitro studies indicate that GH regulates osteoclast formation in bone marrow cultures. Possible modulations of the GH/IGF axis by glucocorticoids and estrogens are also included in Fig. 9. GH deficiency results in a decreased bone mass in both man and experimental animals. Long-term treatment (> 18 months) of GHD patients with GH results in an increased bone mass. GH treatment also increases bone mass and the total mechanical strength of bones in rats with a normal GH secretion. Recent clinical studies demonstrate that GH treatment of patients with normal GH secretion increases biochemical markers for both bone formation and bone resorption. Because of the short duration of GH treatment in man with normal GH secretion, the effect on bone mass is still inconclusive. Interestingly, GH treatment to GHD adults initially results in increased bone resorption with an increased number of bone-remodeling units and more newly produced unmineralized bone, resulting in an apparent low or unchanged bone mass. However, GH treatment for more than 18 months gives increased bone formation and bone mineralization of newly produced bone and a concomitant increase in bone mass as determined with DEXA. Thus, the action of GH on bone metabolism in GHD adults is 2-fold: it stimulates both bone resorption and bone formation. We therefore propose "the biphasic model" of GH action in bone remodeling (Fig. 10). According to this model, GH initially increases bone resorption with a concomitant bone loss that is followed by a phase of increased bone formation. After the moment when bone formation is stimulated more than bone resorption (transition point), bone mass is increased. However, a net gain of bone mass caused by GH may take some time as the initial decrease in bone mass must first be replaced (Fig. 10). When all clinical studies of GH treatment of GHD adults are taken into account, it appears that the "transition point" occurs after approximately 6 months and that a net increase of bone mass will be seen after 12-18 months of GH treatment. It should be emphasized that the biphasic model of GH action in bone remodeling is based on findings in GHD adults. It remains to be clarified whether or not it is valid for subjects with normal GH secretion. A treatment intended to increase the effects of GH/IGF-I axis on bone metabolism might include: 1) GH, 2) IGF, 3) other hormones/factors increasing the local IGF-I production in bone, and 4) GH-releasing factors. Other hormones/growth factors increasing local IGF may be important but are not discussed in this article. IGF-I has been shown to increase bone mass in animal models and biochemical markers in humans. However, no effect on bone mass has yet been presented in humans. Because the financial cost for GH treatment is high it has been suggested that GH-releasing factors might be used to stimulate the GH/IGF-I axis. The advantage of GH-releasing factors over GH is that some of them can be administered orally and that they may induce a more physiological GH secretion. (ABSTRACT TRUNCATED)