Serum osteocalcin levels in patients with GH deficiency before and during GH treatment.
Explore the source record for details and available documents.
Biomedical subjects
Publications and source records attributed to G Faglia.
Explore the source record for details and available documents.
Microprolactinoma is a particular pathological situation characterized by the presence of increased hypothalamic dopaminergic tone reactive to tumoral hyperprolactinemia. Since dopamine (DA) is a physiological regulating factor of the secretion of thyroid-stimulating hormone (TSH), we investigated the responses of serum TSH (holo-TSH) and its subunits (alpha-subunit: alpha-sub, and TSH-beta) to thyrotropin-releasing hormone (TRH) and domperidone (DOM; an antidopaminergic drug acting outside the blood-brain barrier) in 36 euthyroid subjects (20 controls and 16 patients with microprolactinoma) in order to evaluate the possible in vivo effects of DA excess on TSH subunit secretion. No significant difference in serum TSH increase after TRH (200 micrograms i.v.) was observed between patients with microprolactinoma and controls (TSH net incremental area under the curve, nAUC: 146 +/- 9, mean +/- SE, and 143 +/- 7.7 micrograms/l/60 min, respectively), while serum alpha-sub and TSH-beta responses were markedly reduced in patients with microprolactinoma as compared to those found in normals (alpha-sub nAUC: 3.0 +/- 0.5 vs. 19.8 +/- 2.2 micrograms/l/60 min, p less than 0.001; TSH-beta nAUC: 5.0 +/- 0.8 vs. 9.5 +/- 0.9 micrograms/l/60 min, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Thyroid function was investigated during and after pregnancy in 12 healthy euthyroid women. During pregnancy, serum total T4 (TT4) levels were significantly elevated and nearly stable, while thyroxine-binding globulin (TBG) levels progressively increased till the 7th month. A slight elevation, though not significant, of free T4 (fT4) was recorded in early pregnancy. In the following months, fT4, free T3 (fT3) and the T4/TBG ratio progressively diminished, reaching a plateau at the 7th month. Serum TSH levels, measured by an ultrasensitive immunofluorometric assay, were comparable to postpartum values during the first trimester and showed a moderate upward trend with the progression of pregnancy. The evaluation of 24-hour TSH profiles was performed in 5 women during the first trimester of pregnancy. In all women, the circadian rhythm of TSH was present with a normal nocturnal surge, though anticipated in 1 case. In summary (1) during the first trimester of pregnancy, the increased thyroid activity does not seem to be only sustained by pituitary TSH which remains unmodified; the negative correlation between TSH and hCG levels might suggest that hCG also stimulates the gland to increase thyroid hormone output, and the presence of a normal TSH circadian rhythm indicates that the central mechanism of neuroregulation of the pituitary-thyroid axis is preserved in early pregnancy, and (2) in late pregnancy, a marked decrease in free thyroid hormone fractions is accompanied by serum TSH levels still in the normal range, indicating a modification of thyroid homeostasis which might recognize various etiological factors.
The recent availability of a Tyr3-substituted octreotide (SDZ 204-090) for radioiodination has allowed somatostatin (SRIH) receptor binding to be studied in vivo, and receptor-positive tumors of different origins to be visualized with a gamma-camera. This prompted us to investigate whether this compound could be used for external imaging of functionless pituitary adenomas displaying SRIH receptors. Eight patients with functionless pituitary adenomas, three patients with acromegaly, and three with macroprolactinoma were injected iv with 123I-labeled Tyr3-octreotide and then scanned with a gamma-camera. Positive scans were obtained in the three acromegalics and in two of the eight patients with functionless pituitary tumors. The patients with macroprolactinoma had negative scans. The diagnosis of functionless pituitary adenomas was confirmed by light and electron microscopic examination as well as immunocytochemical studies. In vitro binding of [125I]Tyr11-SRIH to cell membranes was evaluated in four functionless and three GH-secreting adenomas removed from seven of the patients. All of the GH-secreting as well as one of the four functionless adenomas had high affinity SRIH-binding sites, without differences in number or affinity, whereas SRIH-binding sites were not detected in the others. Positive scans were observed only in patients bearing tumors with high affinity SRIH-binding sites. In conclusion, [123I]Tyr3-octreotide appears to be a promising tool for singling out, in vivo, patients with functionless pituitary tumors displaying SRIH receptors who might potentially benefit from octreotide treatment.
The effects of hypothalamic peptides (TRH, GnRH, arginine vasopressin, vasoactive intestinal peptide, GHRH, CRH, and SRIH) on cytosolic free calcium concentrations ([Ca2+]i) and adenylyl cyclase (AC) activity were evaluated in 12 nonfunctioning pituitary adenomas. TRH, GnRH, and arginine vasopressin induced a marked [Ca2+]i rise in 10/12, 4/12, and 2/5 tumors, respectively. The transients induced by these peptides were due to both Ca2+ mobilization from the intracellular stores and Ca2+ influx from the extracellular medium. AC activity was evaluated in 10 adenomas; 1 microM vasoactive intestinal peptide induced a 2- to 6-fold stimulation of the enzyme activity in all tumors, while neither GHRH nor CRH were effective. Moreover, in 5/10 tumors 1 microM SRIH reduced both AC activity and [Ca2+]i, while in 2/10 the peptide caused a significant rise in [Ca2+]i despite the AC inhibition and in 3/10 SRIH did not modify either AC activity or [Ca2+]i. This study indicates that in nonfunctioning pituitary adenomas a wide spectrum of hypothalamic peptides modulate [Ca2+]i and AC activity. Moreover, the presence of biologically active receptors may offer a possible target for therapeutic intervention.
UNLABELLED: Circulating GH consists of several molecular size species with different biological activity. A reduced sensitivity of some monoclonal antibodies towards high-molecular weight GH variants has been reported. The aim of the present work was to evaluate the molecular size species of circulating GH using Sephadex G-100 gel filtration chromatography in acromegalic patients and in normal subjects employing both RIA and an immunoradiometric assay for all GH determinations. In 6 normal subjects, studied under GHRH stimulation, little GH was 69.8 +/- 6% (mean +/- SD), big GH (44 kD) 26.4 +/- 6% and big-big GH (greater than 80 kD) 2.8 +/- 4%, in IRMA, with a good correspondence with RIA results (70.8 +/- 8, 27.0 +/- 4, and 3.2 +/- 2%, respectively). In 13 untreated acromegalic patients, studied in basal conditions, the little form constituted 76.2 +/- 7%, the big form 18.3 +/- 4%, which is significantly lower than in normals (p less than 0.05), and the big-big form 5.5 +/- 7%. Similar results were obtained with RIA. A clear elevation of big-big GH (21% for both in IRMA, and 15.7 and 27.8% in RIA) was found in 2 patients with IGF-I levels lower than expected on the basis of mean GH concentrations. The study was extended to an additional acromegalic patient, previously operated and irradiated on, characterized by discrepant serum GH levels in RIA (4.6 micrograms/l), and in IRMA (1.4 micrograms/l), and by normal IGF-I levels. Serum GH showed a lack of parallelism to standard GH in RIA, but not in IRMA. RIA immunoreactivity was almost completely composed (92%) of a high molecular weight GH form (greater than 90 kD), not recognized by IRMA. All IRMA immunoreactivity eluted with a Kav corresponding to 19-50 kD. IN CONCLUSION: a. the three main molecular size isomers of serum GH are similarly recognized by IRMA and RIA methods in normal subjects. b. in acromegaly, both quantitative and qualitative modifications of the GH chromatographic profile may be present. In particular, increased amounts of big-big forms, whether or not recognized by monoclonal antibodies, have been observed. Their lower bioactivity, suggested by the normal or lower than expected IGF-I levels, can account for the discrepancy between serum GH levels and the clinical picture or IGF-I levels sometimes observed in acromegaly.
Several studies have demonstrated zinc (Zn), prolactin (PRL) and thymulin (Zn-FTS) interplay: Zn inhibits, in a dose related manner, PRL release from lactotropes in vitro and stimulates thymulin synthesis in vivo both in humans and in animals. PRL receptors are present on thymic epithelial cells (TEC); PRL stimulates TEC trophism and activity. Little is known about the influence of PRL on Zn metabolism, though in prolactinomas we found reduced Zn and thymulin circulating levels. For this reason, we evaluated PRL, Zn, bioactive thymulin (Zn-FTS) and total thymulin (T-FTS: Zn-bound plus Zn-unbound form) serum levels in 58 patients with prolactinomas (PRL: 253 +/- 263 micrograms/L), Zn (82 +/- 23 micrograms/dl), Zn-FTS (2.2 +/- 0.20 log2(-1] and T-FTS (3.7 +/- 0.25 log2(-1] were significantly lower (p less than .01) than those found in age matched controls. Zn-unbound bioinactive thymulin form (FTS) levels were in the normal range. Bromocriptine administration (Brc) (2.5-5 mg p.o., b.i.d. for 9 months) to 20 patients with microprolactinomas lowered serum PRL levels (10.5 +/- 6.2 micrograms/L) and significantly increased (p less than .01) Zn (118.6 +/- 14.7 micrograms/dl), Zn-FTS (3.96 +/- 0.7 log2(-1)) and T-FTS (4.66 +/- 0.7 log2(1)) circulating levels. ZnSO4 administration (400 mg p.o. daily for 3 months) to 6 patients with microprolactinomas, significantly increased (p less than .01) Zn (136 +/- 18 micrograms/dl), Zn-FTS (4.5 +/- 0.5 log2(-1)) and T-FTS (5.6 +/- 0.9 log2(-1)) levels, while caused only a slight decrease in serum PRL concentrations (from 95 +/- 8 to 75 +/- 9 micrograms/L; p: NS).(ABSTRACT TRUNCATED AT 250 WORDS)
It has been suggested that children with constitutional growth delay might have a transient immaturity of the neurotransmitter pathways necessary for the control of growth hormone releasing hormone (GHRH) secretion. In this study we evaluated the effects of two consecutive GHRH boluses (1 microgram/kg, i.v.) in nine prepubertal boys with constitutional growth delay. Growth hormone (GH) responses to GHRH administration were similar to that observed in normal children (first GHRH bolus, GH net incremental area under the curve (nAUC) +/- SE: 788 +/- 244 vs 984 +/- 242 ng/ml per hour; second bolus, GHnAUC: 657 +/- 122 vs 541 +/- 129 ng/ml per hour, respectively). These data suggest that no relevant abnormalities in the mechanisms determining the somatotroph sensitivity to GHRH are present in children with constitutional growth delay.
Although somatostatin inhibits a variety of pituitary and non-pituitary hormones, not univocal data on its effects on ACTH release have been reported so far. In this study we investigated the effects of somatostatin or octreotide on ACTH levels of patients with corticotropin hypersecretion: 7 patients with Addison's disease, 2 patients previously adrenalectomized for Cushing's disease, 4 patients with Cushing's disease and 3 patients with ectopic ACTH syndrome. Plasma ACTH and cortisol levels were determined after somatostatin (500 micrograms over 60 min) infusion or octreotide (100 micrograms sc) injection. In 5 other patients with Cushing's disease ACTH and cortisol responses to CRH (1 microgram/kg iv) were evaluated in basal conditions and after octreotide acute administration. In no patients with Addison's disease any inhibitory influence of somatostatin (delta % = -21, -25) or octreotide (delta % = -38 +/- 12 vs -39 +/- 12 after saline) on plasma ACTH was found. Somatostatin did not significantly inhibit plasma ACTH in the two patients previously adrenalectomized for Cushing's disease and in 3 patients with Cushing's syndrome; in other 4 patients with Cushing's syndrome octreotide did not affect plasma ACTH levels. In 5 patients with Cushing's disease the plasma ACTH and cortisol responses to CRH were similar both before (ACTH from 9.9 +/- 1.7 pmol/L to 19.4 +/- 6.1 pmol/L; cortisol from 496 +/- 43.9 nmol/L to 923 +/- 355 nmol/L) and after octreotide injection (ACTH from 8.8 +/- 2.4 pmol/L to 19.1 +/- 8.2 pmol/L; cortisol from 510 +/- 54.6 nmol/L to 735 +/- 220 nmol/L). In conclusion, the acute administration of somatostatin or octreotide is not able to modify ACTH levels in patients with corticotropin hypersecretion either due to hypocortisolemic state or consequent to ACTH-secreting pituitary or ectopic tumors; moreover, octreotide does not affect the pituitary-adrenal responsiveness to CRH in patients with Cushing's disease.
The interrelationships between PRL, thymulin and Zn, were studied in 25 patients with chronic renal failure (CRF) undergoing kidney transplantation and immunosuppressed with cyclosporine A (CsA). The possible role of serum PRL levels in predicting allograft rejection was also investigated. Before the kidney transplant serum PRL levels were significantly higher than in normals (mean +/- SE, 28.3 +/- 7.1 vs 7.5 +/- 0.6 micrograms/l, p less than 0.001) and their response to TRH (200 micrograms iv) was impaired (mean delta % at peak, 45.4 +/- 9.5 vs + 641 +/- 47.5, p less than 0.001). After kidney transplantation a dramatic decrease in serum PRL concentrations was observed in all patients, followed by a slight upward trend in the following two weeks, while TRH test administered on 3rd, 7th and 14th day, induced a progressive increase in serum PRL responses (delta % at peak, 201 +/- 43.3, 220 +/- 37.1 and 305 +/- 15.5, respectively). No difference in serum PRL patterns was observed between patients with (8 cases) and without (17 cases) clinical features and kidney fine needle biopsies suggestive of rejection. Basal serum Zn levels of patients with CRF (18.1 +/- 0.6 mumol/l) were similar to those observed in normals (17.7 +/- 0.2 mumol/l) and without any correlation with serum PRL levels. A decrement in serum Zn was recorded during CsA infusion and on the first day after the surgery, followed by a slight and slow upward trend. Basal serum thymulin titers were low [2.92 +/- 0.18 (1/log2)], were further reduced after CsA infusion [1.68 +/- 0.15 (1/log2)] and returned to the pretransplant levels in the two weeks after grafting.(ABSTRACT TRUNCATED AT 250 WORDS)
Growth hormone overproduction is characterized by increased size of visceral organs as well as growth of bone and soft tissues. We describe a case of a 23-year-old female acromegalic patient, who had been previously unsuccessfully operated upon by transsphenoidal pituitary surgery and then irradiated. In November 1987 a routine X-ray chest examination revealed a mediastinal mass, subsequently confirmed by CT scan. The patient underwent surgical removal of the mass: macroscopical aspect, histological sections and immunocytochemistry showed typical thymic structures without any evidence of neurosecretory activity. No GH-positive cells were found and only small amounts of immunoreactive GHRH like material (9.2 ng/g wet wg) were detected in the tumor extract. Before surgery plasma GHRH levels were not elevated (26 pg/ml); serum GH and IGF-I levels were 27.4 +/- 4.9 micrograms/l and 191 nmol/l, respectively, and remained unchanged after surgery. These data ruled out a GHRH and/or GH ectopic production, confirming the primitive pituitary origin of acromegaly in this patient. It is likely that thymic hyperplasia may be explained by longstanding overproduction of GH and the young age of the patient.
Osteocalcin (OC) concentration, a specific index of bone formation, was measured in 29 female patients with microprolactinoma (serum prolactin, PRL: 105 +/- 10.9 ng/ml; mean +/- SE). Mean OC levels were significantly lower than in controls (1.7 +/- 0.2 vs 5.1 +/- 0.3 ng/ml; p less than 0.001), being below the normal range in 28 out of 29 patients. All patients were treated with dopaminergic agents (dihydroergocriptine, bromocriptine or cabergoline). After treatment mean serum PRL levels were significantly reduced (12 +/- 3.1 ng/ml; p less than 0.001), a full normalization being obtained in 26 patients. There were no significant differences in both basal and after treatment PRL levels among patients treated with different drugs, although a greater PRL decrease was induced by cabergoline. Serum OC levels significantly increased after 12 month therapy (4.7 +/- 0.6 ng/ml, p less than 0.001), a normal concentration being reached in 14 of 29 cases. During treatment there were no significant differences in serum estradiol and PRL concentrations between patients who normalized or not their OC levels, while the reduction in PRL levels with respect to baseline was more pronounced in the former group. The absolute increase in OC levels positively correlated with serum PRL decrements (p less than 0.01). It is noteworthy that serum OC normalized in 1/10 patients during dihydroergocriptine, 3/8 during bromocriptine and 10/11 during cabergoline. Four patients, previously treated with dihydroergocriptine and bromocriptine without normalizing OC and PRL levels, underwent a second course of therapy with cabergoline and then normalized OC concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Explore the source record for details and available documents.
Explore the source record for details and available documents.
The differential diagnosis of the various forms of inappropriate secretion of TSH (IST), i.e. generalized thyroid hormone resistance (GRTH), selective pituitary resistance [non-neoplastic IST (nnIST)], and tumoral pituitary TSH hypersecretion [neoplastic IST (nIST)], mainly rests on clinical observation, skull imaging, and measurement of several parameters assessing peripheral thyroid hormone effects. Clinically, patients with GRTH usually display compensated hypothyroidism, while those with nnIST or nIST are hyperthyroid. Since sex hormone-binding globulin (SHBG) measurement has been shown to be a reliable parameter in distinguishing between euthyroid and hyperthyroid states, we evaluated serum SHBG levels in 39 patients with IST (7 with GRTH, 15 with nnIST, and 17 with nIST). The results were compared to those in 68 normal subjects, 76 hyperthyroid patients, and 31 hypothyroid patients. SHBG levels in patients with either GRTH or nnIST were similar to those in controls or hypothyroid patients [GRTH, 40.5 +/- 11.8 (+/- SD) nmol/L (range, 26.4-57.5); nnIST, 29.7 +/- 12.8 nmol/L (range, 6.8-46.8); controls, 36.7 +/- 21.7 nmol/L (range, 5.4-96.5); hypothyroid, 30.8 +/- 14.4 nmol/L (range, 10.4-63.3)]. On the contrary, SHBG levels in patients with either overt hyperthyroidism or nIST were significantly higher than those in the above groups [hyperthyroid, 149 +/- 111 nmol/L (range, 48-557); nIST, 99.5 +/- 54.7 nmol/L (range, 21.6-259)]. The apparent overlap of SHBG values between hyperthyroid patients and controls almost completely disappeared when comparisons were made with control groups matched for age and sex. Additional indices of peripheral thyroid hormone action (basal metabolic rate, cardiac systolic time intervals, and Achilles' reflex time) were normal in patients with GRTH, while they were in the hyperthyroid range in patients with nnIST and nIST. After successful treatment of hyperthyroidism, SHBG levels normalized in patients with nIST, but they did not change in patients with nnIST. In conclusion, the measurement of SHBG in patients with IST is useful in differentiating the neoplastic form from that due to thyroid hormone resistance, but it fails to distinguish between generalized and pituitary resistance to thyroid hormone action. Moreover, the present data suggest that the resistance to thyroid hormone action in patients with nnIST is not selective at the thyrotroph cell level, but also involves the hepatic SHBG-synthesizing cells, thus supporting the view that the various forms of thyroid hormone resistance could represent a continuum of the same defect with variable expression in different tissues.
Somatic mutations in the alpha-chain (alpha s) of the stimulatory regulatory protein of adenylyl cyclase (Gs) causing constitutive activation of the enzyme have been identified in a subset of human GH-secreting pituitary adenomas. This study reports on the differences between acromegalic patients bearing tumors without (group 1; n = 51) or with (group 2; n = 29) this alteration. No difference in age, sex, clinical features, duration of the disease, or cure rate was observed between the two groups. By contrast, group 2 patients had higher basal GH levels than group 1. Moreover, a significant difference in sellar morphology was found; group 2 patients more frequently showed sellas of normal size (grade I) than group 1. Hypersecretory activity of group 2 tumors was also apparent at electron microscopy; contrary to those of group 1, cells of group 2 tumors were densely granulated and showed prominent rough endoplasmic reticulum and Golgi complex. With respect to group 1, group 2 patients were less responsive to GH-releasing hormone, while they were more sensitive to somatostatin- and dopamine-induced GH inhibition. These results suggest that patients with constitutively active adenylyl cyclase have hyperactive tumors; the sensitivity of these tumors to inhibitory agents (somatostatin and dopamine), possibly counteracting the expression of activating mutations, might explain the low rate of tumor growth.
The case of a 7-year-old boy affected with precocious puberty and a large intra- and suprasellar pituitary tumour is described. He had hyperprolactinemia and elevated serum LH, FSH and testosterone concentrations. Pre-operative dynamic hormonal studies showed a rise of PRL, LH and FSH levels after TRH (200 micrograms iv) and a rise of LH and FSH after GnRH (100 micrograms iv). Dopamine infusion (4 micrograms.kg-1.min-1 for 180 min) did not affect gonadotropins and greatly reduced serum PRL. GnRH analogue (buserelin, 0.5 mg sc t.i.d. for 10 days) administration inhibited both LH and FSH, but did not affect PRL concentration. Serum LH and FSH increased after ethinyl-estradiol (0.5 mg orally) administration, and were not affected by bromocriptine (5-7.5 mg/day for 10 days), which decreased serum PRL levels. The patient underwent transfrontal neurosurgery and a large tumour mass was completely removed. Morphological study of the excised tumour, by electron microscope double label immunotechnique, revealed that a large number of tumour cells (70-85%) were positive for PRL, LH and FSH, co-localized in the same secretory granule. After neurosurgery, serum PRL, LH, FSH and testosterone levels fell to within the normal limits. Two months later the patient was well and signs of precocious puberty had partially regressed; hormone levels were in the normal range and MR imaging control did not demonstrate any residual lesion in the sellar region.
The influence of beta-adrenergic blockade by oral propranolol on the variability of GH responses to GHRH and on GH responsiveness to repeated GHRH administrations was investigated. Eight normal volunteers underwent three tests on three separate occasions. Each test consisted of two administrations of 80 micrograms GHRH at 2-h intervals without other medication (test 1) or combined with oral administration of 80 mg propranolol 90 min before the first (test 2) or the second GHRH injection (test 3). In test 1 GH levels increased significantly after the first, but not the second GHRH bolus (net incremental area under the curve [nAUC], mean +/- SD: 1453 +/- 974 and 178 +/- 309 micrograms.l-1.(120 min)-1, respectively). In test 2 basal GH secretion was not influenced by propranolol administration, whereas the GH response to the first GHRH injection was significantly greater than in test 1 (2327 +/- 1814 micrograms.l-1.(120 min)-1; p less than 0.05). However, individual subjects showed the same variability of GH response as in test 1. The GH response to the second GHRH bolus remained negligible. In test 3 administration of propranolol 90 min before the second GHRH bolus led to a clear GH increase (690 +/- 1002 micrograms.l-1.(120 min)-1), not significantly different from the GH response to the first bolus (1796 +/- 1375 micrograms.l-1.(120 min)-1). However, only 4 subjects showed a marked restoration of the GH responsiveness to the second GHRH administration. In conclusion, oral administration of propranolol is able to increase GH responsiveness to GHRH without changing the great individual variability. The response to a repeated GHRH stimulation is only partially restored by propranolol.