"Non-Classical" Indication for Provocative Testing of Growth Hormone: A Retrospective Cohort Study in Adult Patients Under Replacement Therapy.

BACKGROUND: Adult growth hormone deficiency (GHD) is considered a rare condition. Current guidelines state that GH provocative test is indicated in patients affected by organic hypothalamic/ pituitary disease or with a history of head injury, irradiation, hemorrhage or hypothalamic disease with multiple pituitary deficiencies. Nevertheless, the clinical picture related to GHD may be subtle. OBJECTIVE: We have retrospectively evaluated the indication to GHRH+arginine test in our monocentric cohort of patients treated with hrGH in order to assess whether other conditions had been considered as a rationale for provocative testing. METHODS: Ninety-six patients (51 females and 45 males), aged 19-67 years were included. The GHRH+arginine test had been performed in 29 patients with organic hypothalamic/pituitary disease and in 4 patients for Childhood onset-GHD (CoGHD). In other patients, the diagnosis was suspected for "non classical" reasons in the clinical picture suspected for GHD. RESULTS: Classical indications included previously known primary empty sella (n=15), pituitary surgery (n=14), pituitary cyst (n=1), non-secreting pituitary tumors (n=3) but more than half of the patients (57.3%) had been studied for "non classical" indications: metabolic syndrome (n=25), asthenia (n=13), heart failure (n=4), osteoporosis (n=6), unexplained hypoglycaemia (n=1) and infertility (n=6). The latter represented a significant percentage in the male subgroup under 45 ys. IGF-1 levels were lower than 50th percentile in 63% of patients. Finally, among non-classical reasons, organic pituitary disease was discovered in 22 patients. CONCLUSION: Idiopathic GHD may be unrecognized due to its subtle manifestations and that an extended use of dynamic GH tests may reveal such conditions. A potential field of investigation could be to identify subsets of patients with clinical conditions caused or worsened by underlying unrecognized GHD.

Dynamic GnRH and hCG testing: establishment of new diagnostic reference levels.

OBJECTIVE: Gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) stimulation tests may be used to evaluate the pituitary and testicular capacity. Our aim was to evaluate changes in follicular-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone after GnRH and hCG stimulation in healthy men and assess the impact of six single nucleotide polymorphisms on the responses. DESIGN: GnRH and hCG stimulation tests were performed on 77 healthy men, 18-40 years (reference group) at a specialized andrology referral center at a university hospital. The potential influence of the tests was illustrated by results from 45 patients suspected of disordered hypothalamic-pituitary-gonadal axis. METHODS: Baseline, stimulated, relative and absolute changes in serum FSH and LH were determined by ultrasensitive TRIFMA, and testosterone was determined by LC-MS/MS. RESULTS: For the reference group, LH and FSH increased almost 400% and 40% during GnRH testing, stimulated levels varied from 4.4 to 58.8 U/L and 0.2 to 11.8 U/L and FSH decreased in nine men. Testosterone increased approximately 110% (range: 18.7-67.6 nmol/L) during hCG testing. None of the polymorphisms had any major impact on the test results. Results from GnRH and hCG tests in patients compared with the reference group showed that the stimulated level and absolute increase in LH showed superior identification of patients compared with the relative increase, and the absolute change in testosterone was superior in identifying men with Leydig cell insufficiency, compared with the relative increase. CONCLUSIONS: We provide novel reference ranges for GnRH and hCG test in healthy men, which allows future diagnostic evaluation of hypothalamic-pituitary-gonadal disorders in men.

Comparison of two growth hormone stimulation tests and their cut-off limits in healthy adults at an outpatient clinic.

OBJECTIVE: A peak GH less than 3 µg/L to insulin tolerance test (ITT) is commonly used as a threshold indicating severe adult GH deficiency (GHD). This cut-off is based on results obtained by polyclonal radioimmunoassays preferably under standard conditions at hospital. Our aim was to evaluate the validity of this cut-off limit using two currently used immunometric GH assays and to compare GH responses in the ITT and the GH releasing hormone + arginine (GHRH + ARG) test in healthy adults at our outpatient endocrine unit. DESIGN: ITT was performed on 73 subjects and the GHRH + ARG test on those 28 who showed insufficient response to the ITT. METHODS: GH was measured by an immunofluorometric and immunochemiluminometric assay. RESULTS: GH peak above 3 µg/L was observed in 56% of the healthy volunteers with adequate hypoglycemia in the ITT. Among the 28 subjects with a peak GH below 3 µg/L, only two overweight men had a GH peak response below the commonly used cut-off limit of 9.1 µg/L in the GHRH + ARG test. CONCLUSIONS: Lean healthy adults could erroneously be classified as GH deficient by the ITT while their results in the GHRH + ARG test were normal. The GH results are highly dependent on the immunoassay used, but false positive results in the ITT are often obtained even if lower cutoff limits determined on the basis on the calibration of the GH assay are used. Confounding factors seemed to blunt the GH response to the ITT more than to the GHRH + ARG test at our outpatient clinic.

Cerebral ischaemia in pituitary apoplexy.

Pituitary apoplexy is a potentially fatal condition that can have serious consequences even after successful treatment. One of the potential complications of this syndrome is occlusion of the internal carotid arteries, which causes cerebral ischaemia. This can occur through one of two mechanisms--direct compression of the artery or vasospasm caused by factors released from haemorrhagic or necrotic material. We illustrate two examples of cerebral ischaemia with pituitary apoplexy, one with compression and one with vasospasm, both ending in a successful resolution. In both, magnetic resonance imaging, angiography, and hormonal studies allow diagnosis, and urgent surgical decompression should be the treatment of choice. We review the literature and discuss the mechanisms.

Oral clonidine provocative test in the diagnosis of growth hormone deficiency in childhood: should we make the timing uniform?

INTRODUCTION: Oral clonidine is one of the most frequent drugs used for the diagnosis of growth hormone deficiency (GHD), but the duration of the test, depending on which European centres use it, is not uniform and can vary from 120 to 150 min or even 180 min. SUBJECTS AND METHODS: To standardize this test, evaluating the possibility to shorten it to 90 min, we investigated the response of GH to the oral clonidine test in 291 children evaluated for short stature (height <-2 SD). Of these, 164 were diagnosed as idiopathic short stature (ISS) and 127 as GHD. In these patients, we calculated: (1) the frequency distribution of the GH peaks to clonidine in GHD and in ISS at various times; (2) the percentage of GH peaks to clonidine before and after 90 min in all and in ISS children; (3) the percentage of the first GH value >or=10 ng/ml before 90 min and after 90 min in ISS. RESULTS: GH peak distribution varied between 30 and 180 min, even though the vast majority of peaks occurred between 30 and 60 min. There was no significant difference (p > 0.05) in the peak distribution between ISS and GHD children. The percentages of GH peaks within 90 min were 92.1% in all children and 95.7% in ISS. If considering the first value of GH >or=10 ng/ml this last percentage reaches 96.3%. CONCLUSION: Our study suggests that the oral clonidine test can be administered for only 90 min without significantly changing its validity. This test should be standardized at 90 min in European protocols just as in those currently used in the USA in order to reduce the discomfort of patients and the cost of this diagnostic procedure.

Short procedure of GHRH plus arginine test in clinical practice.

Either in children or in adults, arginine (ARG) alone and combined with GHRH (GHRH+ARG) are reliable tests for the diagnosis of GH deficiency. The procedures of these tests generally include GH measurement every 15 min from baseline up to 90-120 min. Aim of our study was to verify if the procedure of these tests could be usefully shortened in clinical practice. To this goal we have studied 173 normally growing children and adolescents (C, 117 M and 56 F, age: 11.3 +/- 0.4 yr.) and 125 young and middle aged normal adults (A, 68 M and 57 F, age: 30.0 +/- 0.6 yr.). ARG alone test was performed by 81 C and 33 A (0.5 g/kg arginine, i.v., from 0 to +30 min, up to a maximum of 30 g) while GHRH (1 microg/kg i.v. bolus at 0 min) + ARG test was performed by 92 C and 92 A. After ARG alone, taking into account data from +15 to +105 min, GH values above the 3rd centile limit of arbitrary cut-off (7 or 10 microg/l in C and 5 microg/l in A) occurred in 85% or 64% and 94% subjects, respectively. After GHRH+ARG test, taking into account only data at +30, +45, +60 min GH values above the 3rd centile limit (20 microg/l in C and 16.5 microg/l in A) occurred in 99% of subjects in both groups. Taking into account only these 3 timing points, the percentage of GH peak above the third centile limits after ARG alone was never higher than 60% in C and 85% in A. In conclusion, this study shows that single GHRH+arginine test can be reliably performed in a shortened procedure which makes easier the clinical practice and further reduces costs.

Evaluation of the growth hormone exercise test in normal and growth hormone-deficient children.

A group of 168 short but otherwise normal children (group A) and 25 children deficient in growth hormone (GH) (group B) wwere studied with an exercise stimulation test to determine the expected error of this method. In group A, 125 (74.4%) had maximum GH responses greater than 15 ng/ml, 23 (13.7%) had responses between 10 and 15 ng/ml, and 20 (11.9%) had responses less than 10 ng/ml. The mean +/- SD values were 8.4 +/- 0.4 ng/ml at 0 time, 26.3 +/- 15.0 at 20 minutes, and 10.7 +/- 8.3 at 40 minutes. The mean maximum response was 27.7 +/- 14.3 ng/ml. In group B, 22 (88%) had maximum responses less than 10 ng/ml and 3 (12%) had responses between 10 and 15 ng/ml. Patients with maximum responses less than 10 ng/ml have a high probability of being GH-deficinet, whereas patients with responses between 10 and 15 ng/ml are less likely to be GH-deficient. No patients with responses greater than 15 ng/ml were GH-deficient.

Failure of insulin hypoglycemia to produce rise in serum prolactin.

Serum prolactin and growth hormone responses to insulin-induced hypoglycemia were measured in 5 normal individuals. While growth hormone rose appropriately in all subjects studied, serum prolactin levels did not significantly change despite the production of symptomatic hypoglycemia during testing. Prolactin response to insulin hypoglycemia is not a useful diagnostic test for prolactin secretion and cannot be used as such for assessment of pituitary reserve.