GH Hypersecretion Research Articles

Functional and morphological changes in the adenohypophysis of dogs with induced primary hypothyroidism: Loss of TSH hypersecretion, hypersomatotropism, hypoprolactinemia, and pituitary enlargement with transdifferentiation

From case studies in humans it is known that primary hypothyroidism (PH) may be associated with morphological and functional changes of the pituitary. There is no insight into the time scale of these changes. In this study, seven beagle dogs were followed up for 3 years after the induction of primary hypothyroidism. Three of these dogs were followed up for another 1.5 years while receiving l-thyroxine. Adenohypophyseal function was investigated at 2-month intervals with the combined intravenous injection of CRH, GHRH, GnRH, and TRH, and measurement of the plasma concentrations of ACTH, GH, LH, PRL, and TSH. In addition, after 2 years of hypothyroidism a single TRH-stimulation test and a somatostatin test were performed, with measurements of the same pituitary hormones. Every 6 months the pituitary gland was visualized by computed tomography (CT). Induction of PH led to high plasma TSH concentrations for a few months, where after concentrations gradually declined to values no longer significantly different from pre-PH values. A blunted response to stimulation of TSH release preceded this decline. Basal plasma GH concentrations increased during PH and there was a paradoxical hyperresponsiveness to TRH stimulation. Basal GH concentrations remained elevated and returned only to low values during l-thyroxine treatment. Basal PRL concentrations decreased significantly during PH and normalized after several months of l-thyroxine treatment. The pituitary gland became enlarged in all dogs. Histomorphology and immunohistochemical studies in 4 dogs, after 3 years of PH, revealed thyrotroph hyperplasia, large vacuolated thyroid deficiency cells, and decreased numbers of mammotrophs. Several cells stained for both GH and TSH. In conclusion, with time PH led to a loss of the TSH response to low T 4 concentrations, hypersecretion of GH, and hyposecretion of PRL. The enlarged pituitaries were characterized by thyrotroph hyperplasia, large vacuolated thyroid deficiency cells, and double-staining cells, which are indicative of transdifferentiation.

Intrahypothalamic neurohormonal interactions in the control of growth hormone secretion.

The secretion of growth hormone (GH, somatotropin) is regulated by two neurohormones: one inhibitory, somatotropin release-inhibiting hormone (SRIH) or somatostatin, and one stimulatory, GH-releasing hormone (GHRH). There are several lines of evidence for reciprocal interactions between SRIH and GHRH neuronal networks. Anatomically, GHRH terminals contact SRIH-containing neurons in the periventricular nucleus and SRIH-containing fibres innervate GHRH-containing neurons in the arcuate nucleus. Physiologically, SRIH and GHRH are secreted into the portal blood in complementary oscillating patterns. Results from immunizations with anti-SRIH antisera suggest that endogenous SRIH blocks GHRH release from the median eminence. Intracerebroventricular injections of SRIH stimulate secretion of GHRH indirectly, probably via autoinhibition of SRIH neurons in the anterior periventricular region. High resolution autoradiography allowed us to visualize high affinity, specific [125]SRIH receptors on 30% of GHRH mRNA-containing cells in the ventrolateral portion of the arcuate nucleus. The functional importance of these receptors was demonstrated by blocking endogenous SRIH action with cysteamine, which resulted in an increase in GHRH mRNA levels and desaturation of SRIH receptors in the ventrolateral part of the arcuate nucleus. Alterations in GH production caused by hypophysectomy or acute and chronic GH hypersecretion have opposite effects on the synthesis of SRIH and GHRH, giving further evidence for reciprocal interactions between these two neurohormonal systems.

Gamma knife stereotactic radiosurgery for acromegaly

Gamma knife radiosurgery (GKR) is an adjuvant treatment for acromegaly if surgery fails to normalize GH hypersecretion. To examine the effect of GKR on tumor growth and hypersecretion, and to characterize the adverse effect of this treatment. Cross-sectional follow-up study. First, retrospective data pre- and post-GKR were collected. PATIENTS then underwent a predefined survey including radiological, endocrinological, ophthalmological, and neurosurgical evaluation. Norwegian National Center for gamma knife treatment. Sixty-one patients treated with GKR for acromegaly. Out of 55, 53 living patients underwent a detailed survey. The mean follow-up was 5.5 years. No patient was lost to follow-up. Tumor growth was stopped in all patients. At 3, 5, and 10 years after GKR, 45, 58, and 86% of patients had normal IGF-I levels. Consecutive hormone value analysis showed that patients receiving GH-suppressive medication had a more rapid decline in hypersecretion than those who did not receive such medication. Evaluated by survey baseline values alone, non-elevated IGF-I and GH levels below 5 mIU/l were found in 38%. GH-suppressive medication was terminated in 16 out of 40 patients following GKR. Nine out of 53 surveyed patients (17%) had normal IGF-I and GH nadir below 2.6 mIU/l at glucose tolerance tests, while not on hormone-suppressive medication. Two patients developed minor visual field defects. Eight patients started hormone substitution therapy during the follow-up period. GKR is an effective adjuvant treatment for residual acromegaly, carrying few side effects.

Control of pituitary adenoma cell proliferation by somatostatin analogs, dopamine agonists and novel chimeric compounds

The antisecretory effects of somatostatin (SRIH) and its analogs are widely recognized and provide the basis for treatment of hormonal hypersecretion in patients with pituitary adenomas, especially in the settings of acromegaly. Dopamine (DA) agonists have also been used for medical treatment of prolactin and/or GH hypersecretion, and recent evidence points to an even greater antisecretory effect for a chimeric molecule, having high affinity for both SRIH and DA receptors. Evidence for an antiproliferative effect of these compounds has also been provided. This review focuses on the antiproliferative effects of SRIH and its analogs, of DA and chimeric compounds on pituitary adenomas, and on the clinical consequences on tumor volume of pharmacological treatment of pituitary adenomas with these drugs.

MRI finding of simultaneous coexistence of growth hormone-secreting pituitary adenoma with intracranial meningioma and carotid artery aneurysms: report of a case

Coexistence of pituitary adenoma, intracranial meningioma and cerebral aneurysm has never been described. We report on a patient with GH-secreting pituitary macroadenoma associated with a right frontal meningioma and with two intracavernous asymptomatic aneurisms. A 61-year-old woman was referred to our Endocrine Unit 13 years after a right frontal craniotomy for a pituitary tumour. Endocrine investigation showed high levels of IGF-1 (560 ng/ml) and increased basal serum GH (56 ng/ml) levels, not suppressed after OGTT. MRI showed persistence of a homogeneously enhancing intra- and suprasellar lesion, compressing the visual pathways, with bilateral intracavernous invasion and simultaneous coexistence of a right intracavernous internal carotid artery (ICA) aneurysm in direct contact with the pituitary tumour. Somatostatin analog treatment normalized GH and IGF-1 levels. Eight months later, the patient underwent a balloon ICA occlusion with disappearance of the right ICA aneurysm. One year later, a new MRI confirmed the presence of the pituitary mass showing also a right intracranial frontal meningioma and a new ICA aneurysm on the left side. Previous studies have suggested that prolonged GH hypersecretion could play a role in the genesis of intracranial aneurysms, inducing atherosclerotic and/or degenerative modification of the arterial walls. Other aetiological factors include a mechanical effect due to a direct contact between adenoma and aneurysm. Coexistence of pituitary adenoma and intracranial meningioma is a rare event, but also for this association it has been suggested that GH or other growth factors could play a role in appearance or in growth of meningioma. In our case, meningioma appeared and grew, despite the effective treatment of acromegaly.

Efficacy and safety of CyberKnife radiosurgery for acromegaly

Acromegaly is a disease characterized by GH hypersecretion, and is typically caused by a pituitary somatotroph adenoma. The primary mode of therapy is surgery, and radiotherapy is utilized as an adjuvant strategy to treat persistent disease. The aim of this study was to determine the efficacy and tolerability of CyberKnife stereotactic radiosurgery in acromegaly. A retrospective review of biochemical and imaging data for subjects with acromegaly treated with CyberKnife stereotactic radiosurgery between 1998 and 2005 at Stanford University Hospital. Nine patients with active acromegaly were treated with radiosurgery using the CyberKnife (CK). Biochemical response based on serum insulin-like growth factor-1 (IGF-1), anterior pituitary hormone function, and tumor size with MRI scans were analyzed. After a mean follow up of 25.4 months (range, 6-53 months), CK radiosurgery resulted in complete biochemical remission in 4 (44.4%) subjects, and in biochemical control with the concomitant use of a somatostatin analog in an additional subject. Smaller tumor size was predictive of treatment success: baseline tumor volume was 1.28 cc (+/- 0.81, SD) vs. 3.93 cc (+/- 1.54) in subjects with a normal IGF-1 vs. those with persistent, active disease, respectively (P = 0.02). The mean biologically effective dose (BED) was higher in subjects who achieved a normal IGF-1 vs. those with persistent, active disease, 172 Gy(3) (+/-28) vs. 94 Gy(3) (+/-17), respectively (P < 0.01). At least one new anterior pituitary hormone deficiency was observed after CK in 3 (33%) patients: two developed hypogonadism, and one developed panhypopituitarism. CK radiosurgery may be a valuable adjuvant therapy for the management of acromegaly.

Serum GH and IGF-I are significant determinants of bone turnover but not bone mineral density in active acromegaly: a prospective study of more than 70 consecutive patients

Acromegaly is characterized by a persistent hypersecretion of GH and provides information on long-term effects of GH on bone metabolism. The aim of this study was to examine the effect of gonadal status and disease activity on bone metabolism in active acromegaly. Seventy-three consecutive patients with active acromegaly: 40 women and 33 men (50 +/- 13 (mean +/- s.d.) and 49 +/- 10 years respectively) were evaluated and compared with age-, sex-, and body mass index (BMI)-matched controls by X-ray absorptiometry and biochemical analysis (markers of disease activity and bone turnover). We found that bone turnover, as evaluated by biochemical bone markers, is coupled and markedly increased in relation to disease activity in active acromegaly. Acromegalic women, but not men, were characterized by an increased bone area and slightly decreased bone mineral content resulting in significantly decreased bone mineral density (BMD) in the ultradistal radius, proximal radius, and total body. No differences in bone turnover or BMD were found between eu-and hypogonadal subjects. Multivariate analysis identified age, BMI, and gender as independent predictors of total BMD in acromegaly. Our study demonstrates a decreased total body BMD in women, not men, with active acromegaly, regardless of gonadal status or disease activity. Bone turnover is markedly increased in relation to disease activity, possibly counteracting the anabolic effects of excess GH/IGF-I in these subjects. We suggest more focus on biomechanical analyses when investigating endocrine disorders affecting bone size and distribution between compartments.

Short‐term suppression of elevated growth hormone concentrations following insulin‐like growth factor 1 administration in young adults with type 1 diabetes does not alter glomerular filtration or albumin excretion rates

Young adults with type 1 diabetes mellitus (T1DM) have increased glomerular filtration rate (GFR), which may mediate progressive renal disease and microalbuminuria. This may be secondary to low concentrations of insulin-like growth factor (IGF)-I and GH hypersecretion. We tested the hypothesis that restoration of circulating IGF-I concentrations in young adults with T1DM might suppress GH secretion, GFR and urinary albumin excretion. In a randomized double blind crossover study six young adults with T1DM (three men, 19-24 years) received 7 days treatment with rhIGF-I/insulin-like growth factor binding protein (IGFBP)-3 complex (SomatoKine) 0.4 mg/kg/day and placebo. Subjects underwent overnight insulin infusion for euglycaemia, followed by determination of GFR and albumin excretion rate. Following IGF-I/IGFBP-3 complex, overnight insulin requirements (0.15 vs placebo 0.21 mU/kg/min, P < 0.04), plasma insulin (77 vs placebo 152 pmol/l, P < 0.01) and mean overnight GH (2.6 vs placebo 4.8 mU/l, P < 0.04) fell. IGF-I (492 vs placebo 218 ng/ml, P < 0.01) and IGFBP-3 (4.5 vs placebo 3.9 microg/ml, P < 0.05) increased. GFR did not change (145.5 (23.9) ml/min/1.73 m(2) post-IGF-I/IGFBP-3 complex vs 152.2 (19.8) post placebo). Albumin excretion rate did not change 9.5 (5.5-16.6)mg/24 h pre- vs 11.5 (9.9-20.2) post-IGF-I/IGFBP-3 complex and 10.7 (8.1-21.2) pre- vs 11.5 (8.7-29.9) post placebo. Plasma creatinine levels were lower following IGF-I/IGFBP-3 complex (mean +/- SD, 56.2 +/- 16.8 micromol/l) vs placebo (61.5, 45.0, P < 0.02). Seven days treatment with IGF-I/IGFBP-3 complex enhanced overnight insulin sensitivity and reduced GH levels, but there was no effect on glomerular hyperfiltration or albumin excretion rates.

Growth hormone: Historical notes

A brief review of important contributions to our present knowledge of growth hormone is given. In 1887 it had been noted that a pituitary tumor was present in most patients with acromegaly. Even at the beginning of the 20. Century relationship between growth disorders and the pituitary was contested. From 1908 pituitary surgery became established treatment in GH hypersecretion. In 1922 it was demonstrated that injection of pituitary extract to animals caused excessive growth and soon after the opposite: removal of the pituitary caused growth retardation. A huge number of studies on the effects of GH were subsequently reported as were trials with GH treatment. They were impeded by failure to recognize the impact of species specificity of GH. After this issue was clarified in 1957, treatment with human growth hormone proved effective. In 1985 it was realized that Creutzfeldt-Jakob's disease might be transmitted through human growth hormone. At this time recombinant GH had become available. In 1971 the structure of human GH was established. In the same period both GH releasing and inhibiting hormones were identified and an analogue of somatostatin had evolved into the first effective pharmacological treatment for acromegaly.

Treatment of growth hormone excess in dogs with the progesterone receptor antagonist aglépristone

Acromegaly or hypersomatotropism in dogs is almost always due to progestin-induced hypersecretion of GH originating from the mammary gland. The aim of this study was to investigate whether aglépristone, a progesterone receptor antagonist, can be used to treat this form of canine acromegaly. In five Beagle bitches hypersomatotropism was induced by administration of MPA for over 1 year. Subsequently, aglépristone was administered. Blood samples were collected before MPA administration, immediately before, during, and 3.5 and 5.5 weeks after the last administration of aglépristone for determination of the plasma concentrations of GH and IGF-I. In addition, blood samples for the determination of the 6-h plasma profile of GH were collected before MPA administration, before aglépristone administration, and 1 week after the last aglépristone treatment.MPA administration resulted in a significant increase of the mean plasma IGF-I concentration, whereas analysis of the pulsatile plasma profile demonstrated a trend (P=0.06) for a higher mean basal plasma GH concentration and a higher mean AUC0 for GH. Treatment with aglépristone resulted in a significant decrease of the mean plasma GH and IGF-I concentrations. Analysis of the pulsatile plasma profile showed a trend (P=0.06) for a lower mean basal plasma GH concentration and a lower mean AUC0 for GH 1 week after the last aglépristone treatment compared with these values before aglépristone administration. Three and a half and 5.5 weeks after the last aglépristone administration the mean plasma IGF-I concentration increased again.In conclusion, aglépristone can be used successfully to treat dogs with progestin-induced hypersomatotropism.

Resistance to somatostatin analogs in acromegaly: An evolving concept?

The aim of acromegaly treatment is to control the disease by suppressing GH hyperactivity and reducing the size or impeding the growth of the pituitary GH secreting mass. Over recent years, many studies have emphasized the role of SS analogs in the treatment of acromegaly. In fact, SS analogs have been demonstrated to be an effective tool not only in the control of GH hypersecretion but also more recently in the control of tumor growth, in a relevant number of acromegalic patients both as primary or adjunctive treatment. In this context, the therapeutic failure of medical treatment with SS analogs needs to be accurately defined particularly when they are used as primary treatment but also when they are given to patients previously operated upon, since other effective therapeutic options are nowadays available. Current definition of resistance to SS analogs is based on their efficacy to control GH and IGF-I. However, due to the emerging significance of the shrinkage effect of SS analogs on pituitary adenomas as well as to the apparent dissociation between this effect and the biochemical effects of treatment with these analogs, an evolution in the concept of SS resistance is likely to be occurring. In this review, we will discuss the biological basis of the discordance between biochemical and volumetric effects of SS analogs, and we will address the intriguing clinical and therapeutic aspects related to a possible redefinition of the resistance to SS analogs.

Outcome of Gamma Knife Radiosurgery in 82 Patients with Acromegaly: Correlation with Initial Hypersecretion

Because surgical and medical therapies of acromegaly all have specific limitations, radiotherapy has been used as an adjunctive strategy. Stereotactic radiosurgery has not yet been widely evaluated. The objective was to perform an analysis of long-term hormonal effects and tolerance of gamma knife radiosurgery. Eighty-two patients were prospectively studied over a decade, with a mean follow-up of 49.5 months. All patients were treated at the Department of Functional Neurosurgery of Marseille, France. The patients included 82 with active acromegaly, of whom 63 had previous transsphenoidal surgery. Intervention included radiosurgery using the Leksell Gamma Unit B model. Remission was diagnosed when mean GH levels were less than 2 ng/ml and IGF-I was normal for age off somatostatin agonists (at least 3 months). Seventeen percent of the patients were in remission without any treatment. Twenty-three percent previously uncontrolled on somatostatin agonists fulfilled the same criteria after gamma knife while maintained on medical treatment. Initial GH and IGF-I levels off somatostatin agonists were significantly higher in uncured than in remission group (P = 0.01 and 0.047, respectively). Withdrawal of somatostatin agonists at the time of radiosurgery had no incidence on the outcome. No significant difference was found in success rate whether patients had previously been treated or not. Long-term side effects included complete (n = 2) or partial (n = 12) hypopituitarism diagnosed 1-7 yr after gamma knife. Gamma knife radiosurgery may represent a therapeutic approach in patients with moderate initial or residual GH hypersecretion.

Acromegaly due to a growth hormone-releasing hormone-secreting intracranial gangliocytoma

In more than 95% of cases acromegaly is due to GH hypersecretion by a pituitary adenoma. GHRH hypersecretion accounts for about 0.5% of cases of acromegaly. Intracranial GHRH-secreting tumors are extremely rare and only a few well-documented cases have been reported. The clinical features of acromegaly due to intracranial GHRH-secreting tumor are indistinguishable from those of other patients with "classical acromegaly". In cases of intrasellar gangliocytomas, not even radiological findings help to make the correct diagnosis, which can only be made with the hystological study. We present the case of a woman with acromegaly; the magnetic resonance demonstrated a 2x1.8x1.2 cm mass in the jugum sphenoidalis region, associated with a partial empty sella. There was a partial response to high-dose lanreotide therapy, so surgical treatment was decided, although only part of the tumor could be removed. Histopathological diagnosis was consistent with gangliocytoma, and immunostaining in the ganglionic cells was positive for GHRH. After surgery, hormone hypersecretion persisted, so medical treatment was reintroduced. In summary, we report a well-documented case of an intracranial GHRH-secreting gangliocytoma, an exceedingly rare cause of acromegaly. Clinical and biochemical data did not allow to make the correct diagnosis, which was only made on the pathological study. This case underscores that acromegaly can be due to causes other than a GH-secreting adenoma, and underlines that finding an image not typical of a pituitary adenoma should raise the suspicion that an unusual cause subsides the acromegaly.

The Antitumoral Effects of Somatostatin Analog Therapy in Acromegaly

Somatostatin analogs are the mainstay of medical therapy for acromegaly. Suppression of GH hypersecretion, lowering of IGF-I production, and control of symptoms are established benefits of therapy. In addition, clinically significant tumor shrinkage has been seen in a number of studies, particularly in patients undergoing primary medical therapy. This review summarizes current knowledge of the effects of somatostatin analogs on tumor size and cellular morphology and examines the available data on predictors of tumor shrinkage.

The efficacy of octreotide LAR (long acting release) treatment in patients with somatotropinoma, and mixed pituitary tumours

The efficacy of somatostatin analogues in the treatment of acromegaly is not always equal and therefore we wanted to evaluate the efficacy of therapy with octreotide long acting release (LAR) in patients with monohormonal tumours (somatotropinomas) in comparison to individuals with mixed pituitary tumours secreting alpha-subunit. The 35 acromegalic patients (18 males and 17 females), aged 41.8 +/- 8.8 years, were divided into 2 groups according to the secreted hormones: 1 with mixed pituitary tumours with elevated growth hormone and alpha-subunit concentrations, the other with isolated growth hormone hypersecretion and normal alpha-subunit levels. The groups included 19 patients (9 males and 10 females), aged 40.1 +/- 7.1 years (mean +/- SD), and 16 patients (9 males and 7 females) aged 43.8 +/- 8.8 years (mean +/- SD), respectively. The decrease of GH and IGF-I levels after octreotide LAR treatment were observed in both groups. However, the reduction of GH and IGF-I concentrations was not equal in both groups and the differences between both groups were statistically significant (P = 0.01 for GH levels, and P = 0.047 for IGF-I levels). After octreotide LAR treatment, the decrease of GH level and of mean IGF-I values was greater in patients with mixed pituitary tumours and high alpha-subunit concentrations than in patients with isolated GH hypersecretion and normal alpha-subunit levels.

Long-Term Outcome of Patients with Acromegaly and Congestive Heart Failure

Cardiovascular complications are a major cause of morbidity and mortality in patients with acromegaly. Normalization of GH secretion is associated with an improvement in structural and functional cardiac abnormalities. However, the long-term cardiac effects of treatment for acromegaly have not been studied in patients who have already developed chronic congestive heart failure (CHF). We reviewed the charts of 330 consecutive patients with acromegaly treated in two French and Belgian centers since 1985. Ten patients with both acromegaly and CHF (eight men, two women, mean age 49.7 yr) were studied retrospectively. One of them was excluded because CHF was due to severe aortic stenosis.CHF (New York Heart Association stages III-IV and echocardiography showing dilated hypokinetic cardiomyopathy with left ventricular systolic dysfunction and a left ventricular ejection fraction less than 45%) was diagnosed before, concomitantly, or after acromegaly in, respectively, two, five, and two patients. Three patients were referred with terminal heart failure requiring transplantation.One patient had transient CHF associated with a hypertensive crisis. The other eight patients had symptomatic chronic CHF. Control of GH hypersecretion failed, totally or partially, in three patients: one had a long-term survival, and the two others died at 1 and 5 yr. Good GH control was achieved in five patients: four of these are still alive 2-16 yr after diagnosis of CHF, their clinical status is stable or improved, and their quality of life is good. Overall, the 1- and 5-yr mortality (or transplantation) rates for patients with chronic symptomatic CHF were 25% (2 of 8 patients) and 37.5% (3 of 8 patients), respectively. In conclusion, less than 3% of acromegalic patients developed CHF in this study. Although effective treatment of acromegaly improved short-term cardiovascular status, its impact on long-term survival is questionable.

Signes buccaux de la pathologie endocrinienne

Oral manifestations of endocrine dysfunction often may be observed initially by the dentist. Objective manifestations, such as ophtalmos in hyperthyroidism, signs of hypersecretion of GH in acromegaly, are easily recognized. Dentists should have some knowledge of many other diseases in this category that occasionally come in our attention. The present article will discuss the effects of over and under-secretion of each endocrine gland separately, showing its influence on the development and maintenance of the health of the teeth and supporting structures. Diabetes mellitus is the most common endocrinological disease, with an incidence of 3%. Periodontitis risk is three time greater in diabetic patients than in general population and it may worsen the diabetes evolution. Periodontitis in diabetic patients needs an rapid diagnosis and treatment. We also presents the oral aspects of thyroid, parathyroid, suprarenalian, growth hormone and female hormones pathology. The incidence of these troubles is less important, but oral manifestations may reveal an endocrine disfunction.

Combined evaluation of resting IGF-I, N-terminal propeptide of type III procollagen (PIIINP) and C-terminal cross-linked telopeptide of type I collagen (ICTP) levels might be useful for detecting inappropriate GH administration in athletes: a preliminary report.

To verify whether combined measurements of GH-dependent parameters might be useful in detecting exogenous recombinant GH (rGH) administration in male athletes from different disciplines. Sixty-six athletes (control group) were sampled for the evaluation of resting IGF-I, N-terminal propeptide of type III procollagen (PIIINP) and telopeptide type I collagen (ICTP). Cut-off values (mean + 2 SD) for IGF-I, PIIINP and ICTP were calculated and arbitrary scores (1.5, 2.0) were assigned to abnormal parameters. By using the sum of individual parameter scores, positive (> or = 3) or negative (< 3) scores were obtained. In addition, a subgroup of six athletes was treated for 3 weeks with rGH (0.09 IU/kg body weight, 6 days/week) and was similarly evaluated at the end of the 1st, 2nd and 3rd week (i.e. 18 samples). Abnormal IGF-I, or PIIINP or ICTP levels were found, respectively, in one, two and four subjects (1.5-6.1%) of the control group (in the younger athletes); only one 19-year-old subject of this group obtained a positive score. Abnormal IGF-I, PIIINP and ICTP levels were found in 61.1-66.7% samples of the treated group. Positive cases were 3/6 at the 1st and 2nd week and 6/6 at the 3rd week. The sensitivity of the screening approach was 50-100% (at the 1st-2nd and 3rd week, respectively) and specificity was 98.5%. This 'first level' screening test is safe, acceptable and relatively inexpensive. Further additional investigations of 'second level' (i.e. GH secretory profile, GH response to a GH-releasing peptide) can be retained to validate or exclude rGH administration or for the early diagnosis of infrequent endogenous GH hypersecretion.

The new somatostatin analog SOM230 in the treatment of acromegaly

Most GH-secreting pituitary adenomas predominantly express sst2 and sst5, while sst1 and sst3 are moderately and sst4 almost not expressed. The clinically available SS-analogs octreotide and lanreotide display a high, low and moderate affinity to sst2, sst1+3 and sst5 respectively. Saveanu et al. reported that due to the heterogeneous expression of sst2 and sst5 subtypes in GH-secreting adenomas, a bispecific analog, such as BIM-23244 that can activate both receptors, and may achieve a better control of GH hypersecretion of acromegalic tumors. Bruns et al synthesized SOM230, a new cyclic hexapeptide somatostatin (SRIF) analog which binds with nanomolar affinity to sst1, 2, 3 and 5 receptors. In short term (1h) rat experiments, SOM230 and SMS 201–995 inhibit GH release with similar potency, but the effect of SOM230 was longer lasting, due to its increased metabolic stability. The plasma half-life of SOM230 in rats is 23h, as compared to 2h for SMS 201–995. The improved metabolic stability of SOM230 was confirmed in monkeys and humans. Continuous treatment of rats with SOM230 at 10µg/kg/h, decreased IGF-1 plasma levels on day 2 by 90% while under SMS 201–995 treatment plasma IGF-1 levels decreased only by 49%. After a 2-week infusion of somatostatin analogues in rats the suppression of GH and IGF-1 levels by SOM230 was still pronounced, while the response to SMS 201–995 was largely lost. Similar results were obtained in dogs and monkeys. Normalization of GH values was obtained recently in a first clinical study in acromegalic patients acutely treated with SOM230. Most importantly, SOM230 reduced plasma GH level in a patient unresponsive to octreotide and this patient showed a high expression of sst5. Similarly, sst5 receptors were found to be heavily expressed in ACTH secreting pituitary cells from Cushing's patients (Hofland et al.,) and SOM230 is shown strongly inhibiting ACTH release in vitro, in contrast to octreotide. In conclusion, SOM230 might be more efficacious than octreotide in established indications and has the potential for the treatment of additional endocrine indications, such as Cushing's disease, as well as non-endocrine indications, due to its multiligand binding properties. Studies evaluating effects of SOM230 in patients with Cushing's disease and somatostatin refractory carcinoid syndrome are ongoing.

Circulating ghrelin levels in the newborn are positively associated with gestational age.

Ghrelin exerts potent GH-releasing activity and stimulates food intake. Circulating ghrelin levels are increased in anorexia and cachexia, reduced in obesity and restored by weight recovery. Newborns are characterized by GH hypersecretion associated with low IGF-I levels reflecting peripheral GH resistance. The aim of our study was to measure cord ghrelin levels in 117 newborns appropriate for gestational age, born either at term or preterm. Ghrelin levels in cord blood (median; 25th-75th centile: 327.6; 206.0-413.0 pg/ml) were higher (P < 0.0001) than those in maternal blood at delivery (133.0; 89.0-173.7 pg/ml), without gender differences. A positive correlation between ghrelin levels in mothers and newborns (r = 0.26, P < 0.01) was observed. Ghrelin levels in newborns born at term (399.0; 229.0-438.0 pg/ml) were remarkably higher (P < 0.0001) than those in born preterm (208.0; 144.5-278.9 pg/ml). A clear positive association was present between ghrelin levels and gestational age. No association between ghrelin and GH, IGF-I, insulin, glucose and leptin levels were found. Cord ghrelin levels show clear gestational age-related dependency. The lack of any direct relationship between ghrelin and anthropometric or biochemical parameters in adequate for gestational age newborns does not support the hypothesis that ghrelin has major role in foetal GH secretion and growth.