Development of Graves' hyperthyroidism during the early phase of pregnancy in a patient with pre-existing and long-standing Hashimoto's hypothyroidism.
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Adult↗
Biomedical subjects
M Doga
Publications and source records attributed to M Doga.
Growth hormone deficiency in the adult.
Growth hormone deficiency (GHD) in adults may be of either adult or childhood onset and may occur as isolated GHD or as multiple hormone deficiencies. Adult-onset GHD (AoGHD) usually results from damage to the pituitary gland or hypothalamus. GH is frequently undetectable in normal subjects and thus GHD cannot be distinguished from the normal state using a single random GH measurement. In general, a stimulation test is required to recognize GHD. Insulin tolerance test (ITT) has been considered the gold standard by the most important scientific societies, although alternative tests, in particular GHRH plus arginine have been proposed as valuable alternative to ITT. The clinical syndrome associated with AoGHD is characterized by a wide array of symptoms and important chronic complications, such as cardiovascular complications, which may be responsible for an increased mortality. The rationale for GH replacement in adults GHD patients is justified by the beneficial effects on some clinical end-points, such as quality of life (QoL) and cardiovascular risk factors, whereas the effects on mortality risk are still controversial. Over the recent years, guidelines on the use of rhGH as a substitution treatment in adult hypopituitarism have been issued by international (Growth hormone research society-GRS, Endocrine Society) and relevant national (National Institute of Clinical Excellence-UK, NICE) institutions. The aim of the paper is to review and discuss these guidelines.
Adult↗
Cardiovascular risk in aging and obesity: is there a role for GH.
GH has significant impact in adults. In fact, patients with the GH deficiency (GHD) syndrome are now recognized as having an increased cardiovascular risk. The effects of human aging on GH secretion have been evaluated by a number of researchers. Studies of 24 h secretion of GH have shown variable reductions in most 24-h GH secretory parameters in middle-aged and in older men and women, resulting in a decrease in plasma levels of its anabolic mediator IGF-I. Obesity is also associated with several endocrine and metabolic abnormalities. These include decreased serum GH concentrations, reduced GH half-life, frequency of GH secretory episodes and daily GH production rate. The mechanism of the low GH in obesity is not completely understood nor is it clear whether its relationship with visceral adiposity is causal. The aim of this article will be to review the available clinical data concerning the potential involvement of "subclinical" or perhaps better "functional" GHD, which is observed in aging and obesity, in the increase in cardiovascular risk which characterizes these two conditions.
Age Factors↗
Diagnostic and therapeutic consensus on acromegaly.
In February 1999 and May 2000, two workshops were held in Cortina, Italy and Montecarlo, respectively, to develop a consensus defining the diagnosis and treatment of acromegaly. The workshops were sponsored by the Italian Society of Endocrinology, the Pituitary Society and European Neuroendocrine Association. Partecipants from all over the world included endocrinologists, neurosurgeons and radiotherapists skilled in the management of acromegaly. This review paper summarizes the main points of the two consensus statements published following these two workshops.
Acromegaly↗
GH deficiency in the adult and bone.
GH acts on various tissues and organs, like liver, kidney, bone and muscle. There are no conclusive data on adult onset GH deficiency (GHD) effects on bone remodeling. In fact reduced, increased or unchanged values of serum markers of bone formation and resorption have been described. However, a direct link between GHD and reduced bone mass in hypopituitarism is supported by reports that GH replacement therapy can improve bone mineral density (BMD) in these patients. Recently, many studies have shown an increased prevalence of osteoporosis in adult-onset GHD patients, and the fracture rate in these subjects seems to be twice that in the non-GH-deficient population. Long-term studies in these years have described a BMD increase in GHD patients during treatment with GH alone or in combination with biphosphonates. To understand if these BMD changes may result in a reduction of fracture risk, it is necessary to carry out a longitudinal follow-up of large cohorts of GHD adults on GH replacement therapy.
Adult↗
Diagnosis and treatment of acromegaly and its complications: consensus guidelines.
In February 1999, May 2000 and April 2002, three workshops were held in Cortina, Montecarlo and Versailles, respectively, to develop a consensus defining the diagnosis and treatment of acromegaly and its complications. The workshops were sponsored by the Pituitary Society and European Neuroendocrine Association. Invited international participants included endocrinologists, neurosurgeons and radiotherapists skilled in the management of acromegaly. This review paper summarizes the main points of the three consensus statements published following these three workshops.
Acromegaly↗
Bisphosphonates in the treatment of glucocorticoid-induced osteoporosis.
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Animals↗
Ectopic secretion of growth hormone-releasing hormone (GHRH) in neuroendocrine tumors: relevant clinical aspects.
The aim of this article is to briefly review the physiology of growth hormone-releasing hormone (GHRH) and the diagnosis and treatment of GHRH-mediated acromegaly. Moreover, the role of GHRH and its antagonists in the pathogenesis and treatment of cancer will be reviewed. Hypothalamic GHRH is secreted into the portal system, binds to specific surface receptors of the somatotroph cell and elicits intracellular signals that modulate pituitary GH synthesis and/or secretion. GHRH-producing neurons have been well characterized in the hypothalamus by immunostaining techniques. Hypothalamic tumors, including hamartomas. choristomas, gliomas. and gangliocitomas. may produce excessive GHRH with subsequent GH hypersecretion and resultant acromegaly. GHRH is synthesized and expressed in multiple extrapituitary tissues. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation and increased GH secretion. The structure of hypothalamic GHRH was infact elucidated from material extracted from pancreatic GHRH-secreting tumors in two patients with acromegaly. Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small-cell lung cancers, adrenal adenomas, and pheochromocitomas which have been reported to secrete GHRH. Acromegaly in these patients. however, is uncommon. In a retrospective survey of 177 acromegalic patients only a single patient was identified with elevated plasma GHRH levels. Measuring GHRH plasma levels therefore provides a precise and cost-effective test for the diagnosis of ectopic acromegaly. Peripheral GHRH levels are not elevated in patients with hypothalamic GHRH- secreting tumors, supporting the notion that excess eutopic hypothalamic GHRH secretion into the hypophyseal portal system does not appreciably enter the systemic circulation. Elevated circulating GHRH levels, a normal or small-size pituitary gland, or clinical and biochemical features of other tumors known to be associated with extrapituitary acromegaly, are all indications for extrapituitary imaging. An enlarged pituitary is, however, often found on MRI of patients with peripheral GHRH-secreting tumors, and the radiologic diagnosis of a pituitary adenoma may be difficult to exclude. Surgical resection of the tumor secreting ectopic GHRH should reverse the hypersecretion of GH, and pituitary surgery should not be necessary in these patients. Nonresectable, disseminated or reccurrent carcinoid syndrome with ectopic GHRH secretion can also be managed medically with long-acting somatostatin analogs (octreotide and lanreotide). The presence of GHRH and its receptors in several extrahypothalamic tissues, including ovary, testis and the digestive tract, suggests that GHRH may have a regulatory role in these tissues. As previously mentioned, biologically or immunologically active GHRH and mRNA encoding GHRH have been found in several human malignant tumors. including cancers of the breast, endometrium and ovary and their cell lines. The synthesis and evaluation of analogs with various modifications revealed that certain hydrophobic and helix-stabilizing amino acid substitutions can produce antagonists with increased GH releasing inhibitory potencies and GHRH receptor-binding affinities in vitro. The review of experimental results of these substances are promising altrough no clinical data are yet available. Finally, the advent of these antagonists has allowed significant progress in the understanding of the role of the central and tissue GHRH-GH-IGFs system in the pathogenesis of tumors.
Acromegaly↗
Clinical review 136: Primary lymphoma of the pituitary: an emerging clinical entity.
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Adult↗
Exercise-induced microalbuminuria in patients with active acromegaly: acute effects of slow-release lanreotide, a long-acting somatostatin analog.
Recent clinical studies have demonstrated an increase of urinary albumin excretion (UAE) at rest in acromegalic patients and, on the other hand, a reduced UAE in patients with growth hormone (GH) deficiency. Physical exercise is known to induce abnormal UAE in patients with diabetes, probably unmasking early glomerular alterations. The effect of exercise on UAE in acromegaly is not known. Moreover, the effect of acute but sustained GH inhibition in acromegaly on UAE at rest and after exercise has never been studied. The aim of our study was to evaluate the acute short-term effects of slow-release lanreotide (SR-L), a long-acting somatostatin analog, on UAE and alpha1-microglobulinuria (A-1-M), a marker of renal tubular damage, at rest and after exercise in 7 normotensive patients with active acromegaly and normal renal function (4 males and 3 females; mean age, 53 +/- 3.1 years; body mass index [BMI], 27.3 +/- 1.1 kg/m2) at baseline and 7 and 14 days after SR-L injection (30 mg). Two of the acromegalic patients were microalbuminuric at rest, and in other 3 cases, UAE was in the borderline range (10 to 20 microg/min). At baseline in the acromegalic subjects, we found a significant increase in UAE at rest with respect to 7 normal subjects considered as a control group. GH and insulin-like growth factor-1 (IGF-1) were also reduced compared with baseline 7 and 14 days after SR-L injection (GH, 13.4 +/- 7.3 and 13.61 +/- 7 v 18.5 +/- 9.3 microg/L, P < .05; IGF-1, 230 +/- 53 and 255 +/- 54 v 275 +/- 64 microg/L). Concomitantly, we observed a significant decrease of UAE at rest and after exercise and 7 and 14 days after SR-L injection as compared with baseline values (27.3 +/- 20.5 and 18.2 +/- 13.7 v 35.3 +/- 12.8 microg/min, P < .05; exercise, 48.5 +/- 24.1 and 18.6 +/- 6.8 v68.3 +/- 39.7 microg/min, P < .05). A-1-M always remained in the normal range (< 12 mg/L) both at rest and after exercise. We can thus conclude that in acromegaly, submaximal exercise induces abnormal increases in microalbuminuria. We hypothesize that this phenomenon may be due to the functional glomeruler involvement. SR-L can significantly reduce UAE at rest and after exercise in the short-term in acromegaly, probably via a decrease in circulating GH levels.
Acromegaly↗
Growth hormone (GH) responses to GH-releasing hormone alone or combined with arginine in patients with adrenal incidentaloma: evidence for enhanced somatostatinergic tone.
Spontaneous and stimulated GH secretion is blunted in hypercortisolemic states due to increased hypothalamic somatostatinergic tone. However, no data are available on the characteristics of GH secretion in patients with incidentally discovered adrenal adenomas. They represent an interesting model for studying GH secretion, as a slight degree of cortisol excess may frequently be observed in such patients who do not present with any clear Cushingoid sign. In the present study, 10 patients (3 men and 7 women, aged 48-63 yr) with an adrenal mass discovered serendipitously underwent, on separate occasions, a GHRH injection alone or combined with an infusion of the functional somatostatin antagonist, arginine. Thirteen age-matched healthy volunteers served as controls. Briefly, arginine (30 g) was infused from -30 to 0 min, and GHRH (100 microg) was injected as a bolus at 0 min, with measurement of serum GH [immunoradiometric assay (IRMA)] every 15 min for 150 min. Plasma IGF-I (RIA after acid-ethanol extraction) was measured in a morning sample. The diagnosis of cortical adenoma was based on computed tomography features and pattern of uptake on adrenal scintigraphy. Patients with obesity and/or diabetes were excluded. The study design included also an endocrine work-up aimed to study the hypothalamic-pituitary-adrenal axis [urinary free cortisol (UFC) excretion, serum cortisol at 0800 h, plasma ACTH at 0800 h, morning cortisol after overnight 1 mg dexamethasone]. Five of 10 patients showed abnormalities of the hypothalamic-pituitary-adrenal axis, including borderline or increased UFC excretion in 4 of them accompanied by blunted ACTH in 2 cases and failure of cortisol to suppress after dexamethasone in 1; the fifth patient displayed low ACTH and resistance to dexamethasone suppression. However, all patients had a unilateral uptake of the tracer on the side of the mass with suppression of the contralateral normal adrenal gland. As a group, the patients displayed greater UFC excretion and lower ACTH concentrations than the controls. GH release after GHRH treatment was blunted in patients bearing adrenal incidentaloma compared with controls (GH peak, 5.7 +/- 5.2 vs. 18.0 +/- 7.0 microg/L; P < 0.0001), whereas GHRH plus arginine was able to elicit a comparable response in the 2 groups (GH peak, 33.5 +/- 20.3 vs. 33.7 +/- 17.5 microg/L; P = NS). The ratio between GH peaks after GHRH plus arginine and after GHRH plus saline was significantly greater in patients than in controls (751 +/- 531% vs. 81 +/- 45%; P = 0.0001). Similar data were obtained when comparing GH area under the curve after GHRH plus saline or GHRH plus arginine between the 2 groups. In summary, the present data suggest that in patients with incidental adrenal adenomas the GH response to GHRH is blunted due to increased somatostatinergic tone, as it can be restored to normal by pretreatment with the functional somatostatin antagonist arginine. The blunted GH release to GHRH may be an early and long lasting sign of autonomous cortisol secretion by the adrenal adenoma.
Adenoma↗
Effect of glucocorticoids on the paradoxical growth hormone response to thyrotropin-releasing hormone in patients with acromegaly.
It has been hypothesized that in acromegalic patients, as well as in normal subjects, acute increases in serum cortisol levels may cause an enhancement of hypothalamic somatostatin secretion, which in turn may be responsible for the glucocorticoid-mediated growth hormone (GH) inhibition. The aim of this study was to investigate short-term effects of an intravenous (i.v.) infusion of hydrocortisone on the GH response to thyrotropin-releasing hormone (TRH) in acromegaly. We studied six adult patients with active acromegaly. The group was composed of four women and two men with a mean age of 55.8 +/- 6.4 years (range, 27 to 68) and a mean body mass index of 26.7 +/- 1 kg/m2 (range, 23.3 to 30). All patients underwent the following treatments: (1) hydrocortisone alone: a bolus i.v. injection of hydrocortisone succinate 100 mg in 2 mL saline at time -60 minutes, followed by a 120-minute i.v. infusion of hydrocortisone succinate 250 mg in 250 mL saline from -60 to 60 minutes; (2) TRH+hydrocortisone: a bolus i.v. injection of TRH 200 micrograms 60 minutes after initiation of a 2-hour hydrocortisone infusion; (3) TRH alone: a bolus i.v. injection of TRH at time 0, 60 minutes after initiation of a 2-hour saline infusion. In all six patients, TRH induced large GH increases (absolute peak GH level, 58.1 +/- 23.2 micrograms/L; maximum % GH change with respect to baseline, 1,397.8% +/- 807.8%; range, 205% +/- 5,219%).(ABSTRACT TRUNCATED AT 250 WORDS)
Acromegaly↗
Effect of pyridostigmine on the hydrocortisone-mediated decrease of circulating growth hormone levels in acromegaly.
The aims of our study were to investigate the effect of the acetylcholinesterase inhibitor pyridostigmine (PD) administration on growth hormone (GH) secretion in acromegaly and to investigate the effects of PD on GH levels following an i.v. infusion of hydrocortisone in acromegaly. We studied five adult patients with active acromegaly, three men and two women with a mean age of 60 +/- 5 years (range 47-71 years) and a mean BMI of 27 +/- 0.7 kg/m2 (range 24-28 kg/m2). All the patients underwent: 1) placebo, 2 tablets po or 2) PD, 120 mg po, at time -60 plus a bolus i.v. injection of 100 mg hydrocortisone succinate in 2 ml saline at time 0 followed by an i.v. infusion of 250 mg hydrocortisone succinate in 250 ml saline from 0 to 120 min, or 3) PD, po or 4) placebo, po at time -60 plus a bolus i.v. injection of 2 ml saline followed by an i.v. infusion of 250 ml saline from 0 to 120 min. Serum GH values did not significantly change after PD administration compared to those during placebo treatment and with respect to baseline levels. In all of the acromegalic patients during hydrocortisone succinate infusion, GH values clearly decreased with respect to basal levels in varying degrees, with a nadir between 90 and 180 minutes after the beginning of hydrocortisone infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Acromegaly↗
Physiological role of galanin in the regulation of anterior pituitary function in humans.
The aim of our study was to elucidate the physiological role of the neuropeptide galanin in the regulation of anterior pituitary function in human subjects. Six healthy men (age range 26-35 yr, body mass index range 20-24 kg/m2) underwent in random order 1) an intravenous bolus injection of growth hormone-releasing hormone (GHRH)-(1-29)-NH2 (100 micrograms) + thyrotropin-releasing hormone (TRH, 200 micrograms) + luteinizing hormone-releasing hormone (LHRH, 100 micrograms) + corticotropin-releasing hormone (CRH, 100 micrograms), and 2) intravenous saline (100 ml) at time 0 plus either human galanin (500 micrograms) in saline (100 ml) or saline (100 ml) from -15 to +30 min. Human galanin determined a significant increase in serum GH (GH peak: 11.3 +/- 2.2 micrograms/l) from both baseline and placebo levels. No significant differences were observed between GH values after galanin and those after GHRH alone (24.3 +/- 5.2 micrograms/l). Human galanin significantly enhanced the GH response to GHRH (peak 49.5 +/- 10 micrograms/l) with respect to either GHRH or galanin alone. Human galanin caused a slight decrease in baseline serum adrenocorticotropic hormone (ACTH; 16.3 +/- 2.4 pg/ml) and cortisol levels (8 +/- 1.5 micrograms/dl). Galanin also determined a slight reduction in both the ACTH (peak 27 +/- 8 pg/ml) and cortisol (peak 13.8 +/- 1.3 micrograms/dl) responses to CRH. Baseline and releasing hormone-stimulated secretions of prolactin, thyroid-stimulating hormone, LH, and follicle-stimulating hormone were not altered by galanin. Our data suggest a physiological role for the neuropeptide galanin in the regulation of GH secretion in humans.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocorticotropic Hormone↗
Effect of hydrocortisone on the growth hormone response to growth hormone-releasing hormone in acromegaly.
Our recent data show that acute and sustained hypercortisolism decreases circulating growth hormone (GH) levels in acromegaly with respect to saline infusion. It has been hypothesized that in acromegalic patients, as well as in normal subjects, short-term increases in serum cortisol levels may be able to cause an enhancement of hypothalamic somatostatin secretion, which in turn may be responsible for the glucocorticoid mediated GH inhibition. The aim of our study was to investigate the acute effects of an intravenous infusion of hydrocortisone on the GH response to growth hormone-releasing hormone (GHRH) in acromegaly. We studied 6 adult patients with active acromegaly (3 M, 3 F; mean age 60.5 +/- 4.1 years; mean body mass index 27.1 +/- 0.6 kg/m2). All the patients underwent: (1) a bolus intravenous injection of 100 mg hydrocortisone succinate in 2 ml saline, at time -60 followed by a 120-min intravenous infusion of 250 mg hydrocortisone succinate in 250 ml saline, from -60 to 60 min; (2) a bolus intravenous injection of human GHRH 1-29NH2 100 micrograms in 1 ml saline, 60 min after initiation of a 2-hour hydrocortisone infusion; (3) a bolus intravenous GHRH injection 60 min after initiation of a 2-hour saline infusion. In all of the acromegalic patients during hydrocortisone succinate infusion, GH values clearly decreased with respect to basal levels (mean nadir 47 +/- 8.6%, p < 0.05 with respect to basal levels). After GHRH injection and saline infusion all the patients showed a significant increase in GH levels (mean peak 231.5 +/- 52.8%, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Acromegaly↗
Arginine blocks the inhibitory effect of hydrocortisone on circulating growth hormone levels in patients with acromegaly.
In patients with acromegaly, circulating growth hormone (GH) levels and GH responses to GH-releasing hormone (GHRH) are decreased by long-term administration of pharmacological doses of glucocorticoids. The aim of our study was to investigate the acute effects of intravenous (i.v.) infusion of hydrocortisone combined either with saline or arginine infusion on circulating GH levels in acromegaly. We studied five adult patients with acromegaly, two men and three women aged 54.6 +/- 4 years having a body mass index of 25.9 +/- 1.2 kg/m2. On two randomized occasions, patients underwent a bolus i.v. injection of 100 mg hydrocortisone succinate at time 0 followed by a 120-minute i.v. infusion of 250 mg hydrocortisone in 250 mL saline, combined with a 90-minute (from -15 to 75 minutes) i.v. infusion of (1) 60 g arginine hydrochloride in 200 mL saline, or (2) 200 mL saline. In all of the acromegalic patients during the infusion of hydrocortisone alone, serum GH levels clearly decreased (nadir range, 26.4% to 68.1%) with respect to GH levels before hydrocortisone administration (mean of time -15 and 0, basal level), with a nadir between 90 and 180 minutes after the beginning of the infusion. After arginine pretreatment, GH levels were significantly enhanced compared with levels attained with hydrocortisone saline, and they were also significantly increased (peak, 167.5% +/- 27.7%) with respect to basal levels. Our data show that arginine blocks the inhibitory effect of acute and sustained hypercortisolism on circulating GH levels in acromegaly.(ABSTRACT TRUNCATED AT 250 WORDS)
Acromegaly↗
Effects of metoclopramide on the growth hormone response to galanin in normal man.
One of the most prominent metabolic effects of the systemic administration of the synthetic neuropeptide galanin in man is the increase in growth hormone (GH) secretion. This stimulating action of galanin is thought to occur directly at the hypothalamic level through the release of GHRH. Recently, it has been shown that also dopaminergic drugs may elicit GH secretion through an increase in hypothalamic GHRH secretion. The aim of this study was to investigate if the action of galanin on GHRH and consequently on GH release may be mediated via dopaminergic pathways evaluating the effects of a potent central dopaminergic receptor blocker, metoclopramide (MCP), on the galanin-induced growth hormone (GH) secretion in normal subjects. We studied seven young non obese healthy subjects (three females and four males). GH secretion was evaluated after 45 min iv infusion of porcine galanin (0.5 mg in 100 ml of saline) from 0 to 45 min combined with a 60 min iv infusion of a) saline (100 ml) or b) MCP (10 mg in 100 ml of saline) from -15 to 45 min. In all the seven subjects, during galanin infusion, GH values increased with respect to baseline with peaks occurring between 30 and 60 min after the beginning of galanin infusion. Peak GH values ranged between 3.5 and 15.4 micrograms/l (mean 10.4 +/- 1.6 micrograms/l). During MCP infusion no significant differences in the GH response to galanin with respect to saline were observed both when absolute GH levels and GH AUC were examined.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effects of metoclopramide on the paradoxical growth hormone response to galanin in acromegaly.
Galanin is able to enhance growth hormone (GH)-releasing hormone stimulated GH secretion in normal man. In acromegaly circulating GH levels are elevated and the GH response to GHRH may be exaggerated. Galanin has been recently shown to decrease circulating GH levels in acromegaly. Dopaminergic drugs were the only previously known agents able to cause a paradoxical GH fall in acromegaly. Aim of our study was to investigate the effects of a potent central dopaminergic receptor blocker, metoclopramide (MCP), on the galanin-induced paradoxical GH secretion in acromegalic subjects. Two male and three female patients with active acromegaly (age range 44-66 years, body mass index range 24.6-28 Kg/m2) were studied after 45 min i.v. infusion of porcine galanin (0.5 mg in 100 ml of saline) from 0 to 45 min combined with a 60 min i.v. infusion of a) saline (100 ml) or b) MCP (10 mg in 100 ml of saline) from -15 to 45 min. After galanin, GH values fell from baseline (27.5 +/- 10 micrograms/L) to a mean nadir of 16.4 +/- 6.1 micrograms/L; after galanin + MCP, circulating GH levels were also decreased (mean nadir 17.3 +/- 8.1 micrograms/L) in all the patients with respect to baseline (23.6 +/- 9.7 micrograms/L). No significant differences were found in absolute or percent of baseline GH levels after galanin+saline vs galanin + MCP. Our results suggest that the paradoxical GH fall after galanin in acromegalic patients is not mediated through dopaminergic receptor. It can be hypothesized that galanin may interact at the pituitary level with its own receptors expressed by GH-secreting adenomatous cells.
Acromegaly↗