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.     

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.     

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.     

Circadian responsiveness of the hypothalamic-pituitary axis

Five healthy men 25-38 years old were subjected to simultaneous composite intravenous stimulation tests of insulin hypoglycemia (0.1 U/kg), thyrotropin-releasing hormone (TRH, 100 mug), and luteinizing hormone-releasing hormone (LHRH, 50 mug) at weekly intervals to study the circadian responsiveness of the hypothalamic-adenohypophyseal axis at 0600, 1200, 1800, and 0000 hours. Blood sugar (BS), LH, follicle-stimulating hormone, TSH, prolactin, cortisol (C), growth hormone, and testosterone (T) levels were estimated before and after the administration of drugs. Comparisons were made between basal and delta values (difference between basal and peak or nadir levels) at different tests. Significant circadian variations in BS, GH, C, and, to a lesser extent PRL, responses were observed 0600 h basal and delta BS values were the lowest, delta BS was highest at 0000 h accompanied by maximal hypoglycemic symptoms; the delta values of both C and GH were significantly higher at 0600 h and 0000 h; highest mean delta PRL was observed at 0600; at 1800 h the basal plasma PRL level was maximum but the delta PRL was lowest. Plasma TSH, LH, and FSH responses did not show significant circadian variations. These results suggest that circadian variations are evident when stimuli act through central or hypothalamic mechanisms; however, direct stimulation of the adenohypophysis resulted in indentical responses at different periods tested.     

Prolactin bioactivity and the duration of lactational amenorrhea

In our population, only half of fully nursing women remain amenorrheic 6 months postpartum. The other half recover their menstrual cycles between 90-180 days postpartum in spite of a high suckling frequency and elevated immunoreactive PRL (IR-PRL) concentrations. To further investigate the association of PRL with the recovery of ovarian function, we compared PRL bioactivity (BIO-PRL) 3-4 months postpartum in fully nursing amenorrheic women who subsequently experienced long (> 180 days; n = 5) or short (< 180 days; n = 5) lactational amenorrhea. In the present study, BIO-PRL in plasma was measured by the Nb2 lymphoma cell assay in samples taken before and 30 min after a suckling episode at 0800, 1600 and 2400 h. Women in the long amenorrhea group had higher overall mean BIO-PRL (mean +/- SE, 129.9 +/- 12.1 micrograms/L) than nursing women in the short amenorrhea group (66.6 +/- 5.2 micrograms/L; P < 0.05). Mean basal values were similar, but the women in the long amenorrhea group had more BIO-PRL in response to suckling (160.1 +/- 4.0 vs. 71.9 +/- 6.7 micrograms/L; P < 0.05). Compared with their respective basal values, nursing women in the long amenorrhea group demonstrated increased BIO-PRL in response to suckling, whereas the other group did not. The relationships between BIO-PRL and IR-PRL were similar in the two groups of nursing women before suckling. However, after suckling, the long amenorrhea group had significantly higher BIO-PRL levels than IR-PRL levels (P < 0.05, by likelihood test) than the short amenorrhea group. This suggests that suckling differentially changes in each group either the composition of PRL present or substances that may modify the bioactivity of PRL in plasma.     

TRH stimulation as an attempt at demonstration of the induction and involution of prolactin-secreting pituitary cells in pregnancy and puerperium and in pathological hyperprolactinemia

The present paper discusses the relationship between functional hypertrophia or hyperplasia of the prolactin secreting cells in the pituitary and actual pituitary prolactin reserves in pregnant and post partum women. 35 randomly selected post partum patients from the 3rd to 12th day p.p. and 14 women in their 11th to 14th weeks of pregnancy volunteered to undergo a standard TRH-test. The control group consisted of 60 normoprolactinemic patients. Eleven pathologically hyperprolactinemic patients were compared to the normoprolactinemic and physiologically hyperprolactinemic groups. In all cases, plasma prolactin showed a linear decrease from the 3rd to 12th days post partum. The TRH induced increase became correspondingly greater as the basal prolactin levels decreased, i.e. an inverse relationship between these two parameters was seen. The TRH-induced increase was also always greater than the increase caused by suckling. A connection between prolactin and parity was not found. The inverse relationship between basal prolactin levels and the actual reserves which could be released by TRH stimulation can be explained in that there are two regulatory systems for prolactin. The estrogens stimulate basal prolactin and inhibit prolactin reserves. The actual prolactin reserve is, on the one hand, directly dependent on the degree of endogenous neurohormonal stimulation and, on the other hand, indirectly dependent on the endogenous estrogens through a feedback mechanism. The TRH-stimulation test is not suitable for determining a functional hypertrophia or hyperplasia of lactotropic pituitary cells.     

The effect of LHRH and TRH on human interferon-gamma production in vivo and in vitro

Accumulating evidence suggests that hypothalamic luteinizing hormone-releasing hormone (LHRH) and thyrotropin-releasing hormone (TRH) are two hypophysiotropic factors which modulate the immune response. The aim of the present study was to determine the in vivo effects of an intravenous bolus of LHRH and TRH on plasma interferon (IFN)-gamma production in five normoprolactinemic women with irregular menstrual cycles. We also determined prolactin (PRL), thyrotropin (TSH), follicle stimulating hormone (FSH), and luteinizing hormone (LH) levels before and after intravenous administration of LHRH and TRH. The results demonstrate that intravenous bolus of LHRH/TRH increases plasma IFN-gamma levels, with the maximum response 45 min after in vivo administration of hypothalamic peptides and after peak levels of adenohypophyseal hormones (PRL: 15 min; TSH: 30 min; FSH: 30 min; LH: 30 min). In order to investigate a possible direct action of hypothalamic hormones on immune cells, we also evaluated, in the same subjects, the influence of LHRH and TRH on IFN-gamma production by human peripheral blood mononuclear cells (PBMCs), collected before the intravenous administration of the peptides and stimulated in vitro with bacterial superantigen staphylococcal enterotoxin A (SEA) and concanavalin A (Con A). LHRH and TRH, separately and together, significantly enhanced in vitro IFN-gamma production by SEA- and ConA-activated PBMCs. The present results suggest that hypothalamic peptides (LHRH and TRH) directly, and/or indirectly pituitary hormones (PRL, TSH, FSH, and LH) or IL-2, have stimulatory effect on IFN-gamma producing cells and are further evidence of interactions between the neuroendocrine and immune systems.     

Association between the gamma-aminobutyric acid A3 receptor gene and multiple sclerosis

OBJECTIVE: Non-tumour causes of hyperprolactinaemia, including prolactin-elevating drugs, must be excluded. There is a general view that such drugs are unlikely to raise serum PRL above 3000 mU/I, but the literature is confusing. We report 8 patients receiving treatment with neuroleptic drugs, whose serum PRL concentrations were grossly elevated. METHODS: Prolactin was measured using a 2-site immunofluorometric assay (Abbott Laboratories; reference range < 500 mU/l). Seven of the eight women (age range 24-49 years) were symptomatic (galactorrhoea, oligo- or amenorrhoea). RESULTS: Prolactin concentrations ranged from 3600 mU/l to 7300 mU/l. All patients had a normal pituitary CT scan. Five patients were treated with bromocriptine without detriment to their mental state. CONCLUSION: Prolactin can rise to concentrations associated with prolactinomas in patients on neuroleptic drugs. As it is rarely possible to stop the drugs to see if the PRL concentration will decline to normal, neuroradiology is required in these patients to exclude a vision-threatening macroprolactinoma before deciding on medical treatment.     

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.     

In vivo interaction of baclofen, TRH and serotonin on PRL and TSH secretion in the developing and adult male and female rats

Gamma-aminobutyric acid (GABA) is involved in the neural control of hypophyseal hormones, including PRL and TSH. In the present work we investigated the ontogeny of the effect of baclofen, a GABA B agonist, on basal PRL and TSH release and in the presence of releasing stimulus which act at two different levels: TRH, at the hypophyseal level, and serotonin, at the central nervous system. Ages studied were 4, 12, 20, 28-29, 37-38 day-old and adult male and female animals. Rats of each age and sex were separated in groups and each group received two intraperitoneally injections, one 45 minutes after the other: saline-saline, saline-TRH, baclofen-saline, baclofen-TRH, saline-serotonin or baclofen-serotonin. Rats were decapitated 15 minutes after the last injection and serum hormones were measured by RIA. Baclofen (7 mg/kg) significantly elevated basal prolactin levels at 4, 12 and 20 days of age and the stimulating effect increased with age. At 28 days of age baclofen significantly inhibited PRL whereas from 38 days of age onwards it had no effect on basal PRL levels. No sex differences were evident. Interaction of TRH (4 microg/kg) and baclofen on PRL secretion resulted in an additive effect on days 4 and 12, this effect was not observed when baclofen was administered with serotonin (10 mg/kg). In 28 day-old and older animals baclofen completely blunted the PRL releasing effect of TRH or serotonin. Again, no sex differences were observed. With regard to TSH, baclofen did not alter either basal or TRH stimulated TSH secretion regardless of sex and age. The present experiments indicate that GABA B receptors are involved in the regulation of basal and stimulated PRL secretion from the first days of life to adulthood. Receptor activation results in stimulation or inhibition of PRL release depending on the age of the animals and the site of action. This GABA B regulation of PRL secretion is sex independent. In contrast, pituitary GABA B receptors do not seem to be involved in the regulation of TSH secretion.     

Comparison between TRH-stimulated TSH and basal TSH measurement by a commercial immunoradiometric assay in the management of thyroid disease

In order to assess the current diagnostic role of the TRH test following the introduction of more sensitive "second generation" TSH assays, we studied a series of 259 outpatients, 237 women and 22 men, mean age 44.7 years (range 12-82), 91 of whom (35%) with untreated simple goiter, 133 (51%) with simple nodular goiter on steady state I-thyroxine treatment, 18 (7%) with overt or subclinical hyperthyroidism and 17 (7%) with overt or subclinical hypothyroidism, compared to a control group of 26 euthyroid healthy subjects. Serum TSH was measured by a commercial immunoradiometric assay (clinical sensitivity 0.1 microU/ml). TSH response to TRH was evaluated 30 minutes after giving 200 micrograms TRH i.v. bolus, the results being analyzed both as absolute increase (delta-TSH=stimulated TSH minus basal TSH) and as relative increase (R-TSH stimulated TSH/basal TSH). Using cut-off values of 0.3-3.2 microU/ml, basal TSH measurement was able to detect hypothyroidism (specificity = 100%) and to exclude hyperthyroidism (sensivity = 96.9%), but failed to accurately prove hyperthyroidism (specificity = 93.4%) and, above all, to exclude hypothyroidism (sensitivity = 35.3%) in our ambulatory patients. The delta-TSH values showed a basal TSH dependent linear increase (r = + 0.87, p < 0.001) both including only patients (n = 139) with basal TSH level in the euthyroidism range and including all patients (n = 223) having TSH responsive to TRH. All the patients with detectable basal TSH level displayed detectable TSH response to TRH, as did 19 (= 23.5%) of 81 patients with undetectable (< 0.1 microU/ml) basal value. In particular: a) for subnormal but detectable basal TSH ranging between 0.1 and 0.2 microU/ml, TSH was always hyporesponsive (delta-TSH < or = 2.5 microU/ml), while between 0.2 and 0.3 microU/ml TSH was hyporesponsive in 72.2% and normoresponsive (delta-TSH > 2.5 and < or = 11.9 microU/ml) in the remaining 27.8%; b) for basal TSH values within the normal range (0.3-3.2 microU/ml). TSH was hyporesponsive in 13.7%, normoresponsive in 74.8% and hyperresponsive in 11.5%; c) for high basal TSH values TSH was always hyperresponsive. The analysis of R TSH showed relatively constant values in the range of euthyroidism and hypothyroidism (m +/- SD: 7.4 +/- 2.3 and 7.7 +/- 3.1, respectively), and a marked differentiation of hyperthyroid patients whose R-TSH values were significantly lower (4.2 +/- 3.4) but had a wide individual variability. Linear regression analysis of basal or stimulated TSH and circulating thyroid hormones showed a close negative relationship, being highly significant between delta-TSH and T4 (r = 0.57, p < 0.001) and delta-TSH and FT4 (r = 0.46, p < 0.001). In conclusion, after the introduction of current second generation TSH immunoradiometric assay, the diagnostic role of the TRH test is greatly limited but not to be excluded: it can provide additional information to that obtained with simple basal TSH measurement in the diagnosis of subclinical hypothyroidism and in the precise evaluation of the degree of TSH suppression in patients with a subnormal basal TSH, either for endogenous thyrotoxicosis or I.-thyroxine treatment.     

Revision of the nomenclature for the Bacillus thuringiensis pesticidal crystal proteins

The aim of this prospective study was to evaluate the bone mineral density (BMD) at lumbar spine and femoral neck levels and biochemical parameters of bone turnover in 20 consecutive hyperprolactinemic males before and after an 18-month treatment with different dopamine agonists. Six patients received bromocriptine at a dose of 2.5-10 mg/day; 7 patients received quinagolide at a dose of 0.075-0.3 mg/day; 7 patients received cabergoline at a dose of 0.5-1.5 mg/week. BMD, serum PRL, testosterone, dihydrotestosterone, and osteocalcin (OC), and urinary cross-linked N-telopeptides of type I collagen (Ntx) levels were measured before and every 6 months during treatment. At study entry, BMD values were lower in patients than controls at both lumbar spine (0.82 +/- 0.03 vs. 1.18 +/- 0.01 g/cm2; P < 0.001) and femoral neck (0.85 +/- 0.02 vs. 0.92 +/- 0.02 g/cm2; P < 0.05) levels. Osteopenia or osteoporosis was diagnosed in 16 patients at the lumbar spine and in 6 of them at the femoral neck level. A significant inverse correlation was found between lumbar spine and femoral neck BMD values and both PRL levels and disease duration (P < 0.01). In the 20 patients, serum OC levels were significantly lower (2.1 +/- 0.1 vs. 9.3 +/- 2.4 microg/L; P < 0.01), whereas Ntx levels were significantly higher (157.8 +/- 1.1 vs. 96.4 +/- 7.4 nmol bone collagen equivalent/mmol creatinine; P < 0.001) than control values. A significant inverse correlation was found between serum PRL and OC (P < 0.01), but not Ntx, levels. After 18 months of treatment, serum PRL levels were suppressed, and gonadal function was restored in all 20 patients, as shown by the normalization of serum T (from 2.2 +/- 0.2 to 5.0 +/- 0.2 microg/L) and dihydrotestosterone (0.3 +/- 0.02 vs. 0.5 +/- 0.01 nmol/L) levels, without any significant difference among groups. A progressive significant increase in serum OC levels together with a significant decrease in Ntx levels were observed after 6, 12, and 18 months of treatment in the 3 groups of patients. A slight, although significant, increase in BMD values was recorded in all patients after 18 months of bromocriptine, quinagolide, and cabergoline treatment, serum OC levels were normalized after treatment, whereas neither urinary Ntx levels nor BMD values were normalized by 18 months of treatment with dopaminergic agents. In conclusion, treatment with bromocriptine, quinagolide, and cabergoline for 18 months, although successfull in suppressing serum PRL levels and restoring gonadal function, was unable to restore lumbar spine and femoral neck BMD and normalize Ntx levels. However, BMD was slightly increased during treatment, suggesting that additional bone loss was prevented after treatment of hyperprolactinemia.     

Galanin positively modulates prolactin secretion in normal women

It is widely accepted that, in man, galanin, a neuropeptide, has a clear GH-releasing effect while its stimulatory influence on PRL secretion is matter of debate. To clarify this point, in 6 normal young women (23-35 yr) in their early follicular phase, we studied the effect of galanin (pGAL, 80 pmol/kg. min infused i.v. over 60 min) on both basal and arginine (ARG, 0.5 g/kg i.v. in 30 min), TRH (400 micrograms i.v. as a bolus at 0 min) or metoclopramide (MCP, 10 mg i.v. as a bolus at 0 min)-stimulated PRL secretion. GAL infusion failed to significantly increase basal PRL levels (peak vs baseline: 12.2 +/- 3.6 vs 8.7 +/- 1.2 micrograms/L) but counteracted the spontaneous PRL decrease observed during saline infusion (AUC: 1216.6 +/- 282.1 vs 672.0 +/- 94.5 micrograms.min/L; p < 0.05). GAL infusion clearly enhanced the PRL response to TRH (AUC: 5806.3 +/- 743.0 vs 3952.1 +/- 423.9 micrograms.min/L, p < 0.05) and ARG (AUC: 3676.8 +/- 382.6 vs 2638.9 +/- 287.0 micrograms.min/L, p < 0.05), respectively. On the other hand, GAL failed to modify the MCP-induced PRL response (AUC: 15409.5 +/- 2085.3 vs 14,787.9 +/- 2045.5 micrograms.min/L). The PRL response to MCP was higher than that to TRH (p < 0.01) which, in turn, was higher than that to ARG (p < 0.01). During GAL infusion, the PRL response to TRH or ARG remained lower (p < 0.01) than that after MCP administration. Thus, in conclusion, present data demonstrate that in normal women galanin enhances the PRL response to ARG and TRH but fails to modify that induced by dopamine receptor blockade with metoclopramide. Based on evidence that the inhibition of central dopaminergic activity inhibits the lactotrope responsiveness to dopaminergic antagonists or TRH, it is unlikely that galanin influences PRL secretion via inhibition of dopaminergic tone.     

Long-term treatment with cabergoline, a new long-lasting ergoline derivate, in idiopathic or tumorous hyperprolactinaemia and outcome of drug-induced pregnancy

Cabergoline (CAB), a new long-acting ergoline derivative, was shown to be very effective in reducing PRL levels in normal volunteers and in hyperprolactinemic patients. We evaluated the hormonal changes after discontinuation of long-term therapy with CAB as well as the safety of drug exposure during pregnancy both for mothers and babies. We therefore studied 48 patients (47 females and one male) with pathological hyperprolactinaemia (mean +/- SE, 117.2 +/- 15.2: median 73.2 micrograms/l), treated for 1-82 months (mean +/- SE, 28.3 +/- 3; median 18). After long-term treatment, CAB was withdrawn in 11 patients and PRL levels were persistently normal for almost 15 days and significantly lower (p < 0.05) than basal at 30, 45, 60, 90, 120 days. Three patients had normal PRL levels still at 45 days after treatment discontinuation. Nine patients became pregnant after 1-37 months (mean 12.4) of therapy. In two patients the pregnancy was interrupted spontaneously in one case and voluntarily in the other. In all but one patients after delivery or three-month breast feeding, PRL levels trended towards reduction. In two cases (one with microadenoma and one with idiopathic hyperprolactinaemia) PRL remained in the normal levels for 1-3 years after delivery. In conclusion CAB is able to inhibit plasma PRL levels for long time (up to 120 days) after withdrawal in patients with pathological hyperprolactinaemia treated with long-term therapy.     

Hypothalamic-pituitary-adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test and prolactin stimulation

OBJECTIVE: To study the response of cortisol and of prolactin (PRL) to specific stimuli in rheumatoid arthritis (RA). METHODS: We measured the response of cortisol to insulin induced hypoglycemia and of PRL to thyrotropin releasing hormone (TRH) in 10 patients with active RA and in 10 paired control subjects. All were women with regular menstrual cycles. They had never received corticosteroids before the study. The PRL concentration was assessed by chemiluminescence immune assay and the cortisol concentration by radioimmunoassay. RESULTS: The basal serum levels of cortisol (14.47+/-2.5 microg/dl) and PRL (10.1+/-1.3 ng/ml) in the RA group were not significantly different from those of the control group (12.3+/-1.1 microg/dl and 13.7+/-2.4 ng/ml, respectively). The peak value of cortisol after hypoglycemia was comparable in both groups (25.5+/-2.4 microg/dl in RA vs. 26.0+/-1.5 ng/ml in controls). The integrated cortisol response to hypoglycemia expressed as area under the response curve (AUC) did not differ significantly in either group (1927+/-196 in RA vs. 1828+/-84 in controls). The interval-specific "delta" cortisol response was significantly higher for the 30 to 45 min interval in controls compared to patients with RA (9.8+/-0.9 microg/dl vs. 6.1+/-1.1 microg/dl; p = 0.02). The peak of PRL after TRH did not differ significantly in both groups (56.4+/-6.4 ng/ml in RA vs. 66.3+/-7.7 ng/ml in controls) and the AUC of PRL secretion after TRH was comparable in both groups (3245+/-321 vs. 4128+/-541). CONCLUSION: Our findings suggest that active RA is associated with subtle dysfunction of the hypothalamic-pituitary-adrenal glucocorticoid function and normal PRL secretion.     

Prolactinomas in children and adolescents. Clinical presentation and long-term follow-up

In this study, we report the clinical presentation, response to medical treatment, and long-term follow-up of 26 patients with prolactinoma (15 macro- and 11 micro-adenomas) diagnosed at the age of 7-17 yr. All patients were first treated with bromocriptine (BRC) at doses ranging from 2.5-20 mg/day orally. BRC was discontinued for intolerance and/or resistance to the drug and was replaced by quinagolide (CV) at doses ranging from 0.075-0.6 mg/day or by cabergoline at doses ranging from 0.5-3.5 mg/week orally. Two patients received external conventional radiotherapy after surgery. In 7 prepubertal males and 6 females with macroprolactinoma, headache and/or visual defects were the first symptoms. All females presented with primary or secondary amenorrhea. Growth arrest was observed in a male patient with microadenoma, whereas all the remaining patients had normal heights, and pubertal development was appropriate for their age. Spontaneous or provocative galactorrhea was observed in 12 patients (3 males and 9 females) and gynecomastia in 4 males. Mean serum PRL concentration (+/-SE) at the time of diagnosis was 1080 +/- 267 microg/L in patients with macroadenoma and 155 +/- 38 microg/L in patients with microadenoma. In 10 patients, BRC normalized PRL levels and caused variable, but significant, tumor shrinkage. CV normalized PRL concentrations and reduced tumor size in 5 patients. Cabergoline normalized PRL concentrations in 7 of 10 patients resistant to CV. Pregnancy occurred in 2 patients while on treatment. Pregnancies were uncomplicated, and the patients delivered normal newborns at term. Only 4 patients are still moderately hyperprolactinemic. Impairment of other pituitary hormone secretion was documented at the time of diagnosis in 7 patients, 5 of whom underwent surgery. Four patients became GH deficient in adult age. In conclusion, the medical treatment with dopaminergic compounds is effective and safe in patients with prolactinoma with onset in childhood, allowing preservation of the anterior pituitary function.     

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.     

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.     

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.     

Reduced dopaminergic inhibition of thyrotrophin release in states of physiological hyperprolactinaemia

We have tested the hypothesis that physiological puerperal hyperprolactinaemia may be secondary to reduced hypothalamic dopaminergic inhibition of prolactin (PRL) release. Nine post-partum females with physiological hyperprolactinaemia (aged 19-40 years; mean basal PRL +/- SE, 2099 +/- 257 mU/1, range 1002-3762 mU/1) were studied and results compared with fourteen normoprolactinaemic females (basal PRL less than 400 mU/1; aged 18-36 years). Puerperal hyperprolactinaemic females showed a reduced TSH response to dopamine (DA) receptor blockade with metoclopramide (10 mg i.v.) compared with normal females over a 60-min period following drug administration (total incremental TSH change, mean +/- SE, mU/1; 0.5 +/- 0.3 v. 3.1 +/- 1.0 P less than 0.005). This finding of reduced dopaminergic inhibition of TSH release in females with physiological puerperal hyperprolactinaemia supports the view that an overall reduction in hypothalamic dopaminergic tone may contribute towards hyperprolactinaemia in post-partum women.