Normal Insulin-like Growth Factor I Concentrations Research Articles

Discrepancy between the Growth Hormone and Insulin-like Growth Factor-I Concentrations in Patients with Acromegaly

Background: This study was performed to evaluate the frequency and clinical characteristics of patients with active acromegaly and who show discordance of the growth hormone (GH) level and the insulin-like growth factor-I (IGF-I) level. Methods: We reviewed the medical records of the patients who were diagnosed with acromegaly between 01/01/1995 and 6/30/2007 at Seoul National University Hospital. We selected only the patients whose basal GH and IGF-I levels were available. We investigated the pre- and post-operative clinical characteristics, as well as the blood concentrations of GH and IGF-I. The concordance rate between the two hormones was examined. The patients were considered to have active disease on the basis of their IGF-I levels above the normal range, after adjustment for age and gender, and their mean basal GH value was ≥ 2.5 μg/L. The hormone levels and the clinical parameters were compared between the hormone concordant and discordant groups. Results: We reviewed the preoperative records of 103 acromegalic patients, and these patients met the above-mentioned criteria. 53 postoperative patients who were not cured by operation were monitored without them receiving radiation or medical therapy. Both the basal GH and IGF-I levels were above normal in 103 patients preoperatively, and the discordant rate was 0% (0/103 cases). Postoperatively, the discordant rate between the two hormones was increased to 30.2% (16/53 cases). Age, gender, body mass index and tumor size were insignificantly different between the concordant and discordant groups. However, postoperative residual tumors were less frequently observed in the discordant group (P = 0.006). Conclusion: For the patients with acromegaly, unlike the 0% discordance preoperatively, 30.2% of patients showed a discrepancy between their GH and IGF-I levels postoperatively. The patients who had hormonal discrepancy were less likely to have residual tumors after operation. Considering the frequency of this hormonal discrepancy, both hormone levels should be measured to evaluate the disease activity after treatment. Further, oral glucose tolerance testing should be performed and especially for the patients with an increased GH level, but who have a normal IGF-I concentration. (J Korean Endocr Soc 23:395~403, 2008)

Prevalence of Thyroid Nodules Detected by Ultrasonography in Adults for Health Check-up and Analysis of Fine Needle Aspiration Cytology

Background: This study was performed to evaluate the frequency and clinical characteristics of patients with active acromegaly and who show discordance of the growth hormone (GH) level and the insulin-like growth factor-I (IGF-I) level. Methods: We reviewed the medical records of the patients who were diagnosed with acromegaly between 01/01/1995 and 6/30/2007 at Seoul National University Hospital. We selected only the patients whose basal GH and IGF-I levels were available. We investigated the pre- and post-operative clinical characteristics, as well as the blood concentrations of GH and IGF-I. The concordance rate between the two hormones was examined. The patients were considered to have active disease on the basis of their IGF-I levels above the normal range, after adjustment for age and gender, and their mean basal GH value was ≥ 2.5 μg/L. The hormone levels and the clinical parameters were compared between the hormone concordant and discordant groups. Results: We reviewed the preoperative records of 103 acromegalic patients, and these patients met the above-mentioned criteria. 53 postoperative patients who were not cured by operation were monitored without them receiving radiation or medical therapy. Both the basal GH and IGF-I levels were above normal in 103 patients preoperatively, and the discordant rate was 0% (0/103 cases). Postoperatively, the discordant rate between the two hormones was increased to 30.2% (16/53 cases). Age, gender, body mass index and tumor size were insignificantly different between the concordant and discordant groups. However, postoperative residual tumors were less frequently observed in the discordant group (P=0.006). Conclusion: For the patients with acromegaly, unlike the 0% discordance preoperatively, 30.2% of patients showed a discrepancy between their GH and IGF-I levels postoperatively. The patients who had hormonal discrepancy were less likely to have residual tumors after operation. Considering the frequency of this hormonal discrepancy, both hormone levels should be measured to evaluate the disease activity after treatment. Further, oral glucose tolerance testing should be performed and especially for the patients with an increased GH level, but who have a normal IGF-I concentration.

Excess Mortality in Acromegaly

Background: Increased production of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in patients with acromegaly is associated with a twofold increase in mortality compared with the general population. The range of standardised mortality rates in various studies ranges from 1.2 to 3.6. Predictors of Mortality: Multivariate analysis has indicated that post-treatment serum GH levels and, in a number of studies, serum IGF-I levels are the most powerful predictors of outcome. Normal IGF-I concentrations and random GH levels <2.5 µg/l measured by polyclonal radioimmunoassay result in optimal outcome. Other factors adversely influencing mortality include hypertension and a long interval between onset of the disorder and diagnosis. Conclusions: Analysis of recent reports suggests that adoption of treatment guidelines with appropriate post-treatment target ranges for GH and IGF-I, together with the availability of newer methods to control GH oversecretion, has significantly improved patient outcomes.

Role of Medical Therapy in the Management of Acromegaly

Medical therapy plays an important role in the management of patients with acromegaly and is commonly used adjunctively after surgical resection of the pituitary tumor. Generally, surgery alone provides a 50 to 70% rate of cure; however, the outcome depends on the experience and ability of the surgeon and the characteristics of the tumor. The role of postsurgical medical therapy is to achieve long-term biochemical control of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. In some patients, medical therapies may be implemented sooner as primary or preoperative therapy. Somatostatin analogs have been the mainstay of medical therapy for acromegaly. The somatostatin analog octreotide produces normalization of IGF-I in approximately 50% of patients but is associated with gastrointestinal adverse effects, including the development of gallstones. Octreotide requires thrice-daily subcutaneous administration. Long-acting formulations of somatostatin analogs (octreotide LAR, lanreotide) are at least as effective and as well tolerated as short-acting octreotide. Unfortunately, some patients are suboptimally responsive to or become intolerant of these agents. Pegvisomant belongs to a new class of agents known as GH-receptor antagonists. This novel agent competitively binds to the GH receptor, blocking IGF-I production. Pegvisomant is highly effective in achieving normal IGF-I concentrations and in reducing signs and symptoms of acromegaly, even in patients resistant to previous treatments. Pegvisomant has been proved safe and well tolerated and has no effect on gallbladder motility. GH levels remain elevated. Transient elevations in liver enzyme levels require monitoring but rarely necessitate termination of therapy. Normalizing IGF-I concentrations with pegvisomant also may have a beneficial effect on carbohydrate metabolism and cardiovascular risk.

Ten-year follow-up results of transsphenoidal microsurgery in acromegaly.

Fifty-nine acromegalic patients, transsphenoidally operated by a single neurosurgeon (H.v.D.) were followed for at least 10 yr to assess the late outcome of surgery. Mean follow-up was 16 +/- 0.4 yr (range, 10-22). Criteria for remission were a serum GH concentration below 2.5 microg/L, a normal glucose-suppressed GH (oral glucose tolerance test), and a normal serum insulin-like growth factor I (IGF-I) concentration. Mean serum GH concentration decreased from 59 +/- 8.7 microg/L to 5.6 +/- 1.4 microg/L after surgery. Early postoperative remission rates were 61% (GH, <2.5 microg/L), 67% (suppressed GH), and 60% (both GH <2.5 microg/L and suppressed GH). Early postoperative remission was significantly related to preoperative serum GH concentration (P: = 0.023), but not to tumor size. Of 36 patients with postoperative remission (GH, <2.5 microg/L), 9 patients received (prophylactic) radiotherapy for persistent paradoxical reaction to TRH or probable invasive tumor growth. All nine patients are in remission at the end of follow-up. Of the other 27 patients with postoperative remission, 5 (19%) developed recurrence, becoming evident within 5 yr in 4 patients and after 10 yr in 1 patient. Of these 27 patients, surgical remission rates at the end of follow-up are 78% (random GH, <2.5 microg/L), 73% (normal glucose-suppressed GH), 74% (normal IGF-I), and 65% (normal IGF-I and GH suppression). Of the patients with postoperative persistent disease, 18 patients were irradiated and 5 patients were followed without further treatment. Two of five nontreated patients had spontaneous normalization of GH concentration at the 6 months visit and remained in remission by surgery only. The long-term efficacy of multimodality treatment was evaluated after exclusion of the prophylactically irradiated patients. At the end of follow-up, 48% of patients had not required adjuvant therapy and the rest received radiotherapy (34%), octreotide (10%), or both (8%). Remission rates of multimodality therapy were 96% (serum GH, <2.5 microg/L) and 94% (normal serum IGF-I concentration). Remission rates of transsphenoidal surgery alone were 46% (serum GH, <2.5 microg/L), 44% (normal IGF-I concentration), 41% (suppressed serum GH), and 37% (normal serum IGF-I and suppressed GH). In this first report on separate 10 or more years results of transsphenoidal surgery for acromegaly, using strict criteria for remission, 19% of patients with postoperative remission developed recurrence. Nevertheless, about 40% of patients remain in remission after only surgical intervention, even after a mean follow-up of 16 yr.

Recessive Robinow syndrome: With emphasis on endocrine functions

We present the characteristic features of 14 children with the recessive form of Robinow syndrome and the growth hormone (GH) response to provocation with clonidine and the serum insulin-like growth factor-I (IGF-I) concentration in 12 of these children. The gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) response to gonadotropin-releasing hormone (GnRH) was evaluated in early pubertal and pubertal patients, and the testosterone response to human chorionic gonadotropin (HCG) was evaluated in males. Children with Robinow syndrome, born at full-term, were short at birth (length, 41.4 ± 2.1 cm) and had markedly slow growth velocity (GV) during the first year (13.1 ± 2.1 cm/yr); consequently, they were significantly short at the end of the first year of life (length, 54.4 ± 2.9 cm). This intrauterine and early extrauterine growth delay reflected low growth potential. During childhood, the GV standard deviation score (GVSDS) remained low (− 2.17 ± 0.83). Despite the presence of empty sella in all of the patients, they had an adequate GH response to clonidine provocation (peak, 19.3 ± 5.8 μg/L) and a normal serum IGF-I concentration (309 ± 142 ng/mL) for their age. During childhood and early adolescence, boys with Robinow syndrome had low basal testosterone and a low testosterone response to HCG stimulation (3,000 IU/m 2/d intramuscularly [IM] for 3 days). However, their basal and GnRH-stimulated FSH concentrations were normal. Two girls (Tanner II breast development) had a normal serum estradiol (E2) concentration but high LH and FSH responses to GnRH stimulation. This suggested either defective feedback of E2 on the hypothalamic-pituitary axis or hyporesponsiveness of the ovaries to gonadotropin. Four weeks of HCG therapy (2,500 IU/m 2 IM twice weekly) in three boys with Robinow syndrome increased the penile length and testicular volume, denoting a significant Leydig cell response to prolonged HCG stimulation and the presence of functioning androgen receptors. It is suggested that HCG and/or testosterone therapy during infancy may improve the severe micropenis in these patients.

Cafeteria diet-induced obesity is associated with a low spontaneous growth hormone secretion and normal plasma insulin-like growth factor-I concentrations

Pituitary growth hormone (GH) secretion has been shown to be blunted in human and animal obesity. With respect to human obesity, cafeteria diet-induced obesity might be an appropriate model to study spontaneous GH secretion. In 6 cafeteria diet-overfed obese male Wistar rats and 6 control rats with chronically implanted catheters, GH levels were measured every 15 min over 6 h by standard RIA. A significantly lower GH secretion, reflected by the integrated GH concentration, was found in the obese rats (median 16.46, [range 10.55-19.13] ng/ml x 6 h vs 35.63 [range 21.90-41.50] ng/ml x 6 h, P < 0.05). The GH secretion in the obese rats was significantly negatively correlated with the body fat percentage, assessed by dual X-ray absorptiometry (Rho = -0.95, P < 0.05). Median plasma insulin-like growth factor-I (IGF-I) concentration was comparable between the two groups, while the median insulin concentration was significantly higher in the obese group (1.95 [range 1.76-3.55] ng/ml vs 1.21 [range 0.86-2.13] ng/ml, P < 0.05). No significant correlation existed between GH secretion and the plasma insulin concentration. In conclusion, cafeteria diet-induced obesity is associated with a low spontaneous GH secretion and normal plasma IGF-I concentration. The hyperinsulinemia present in this model probably explains the normal IGF-I concentrations, but not the GH hyposecretion.

Disturbed release of growth hormone in mature dogs: a comparison with congenital growth hormone deficiency

An acquired defect in growth hormone secretion in mature dogs has been associated with some forms of generalised alopecia. In an attempt to elucidate the pathogenesis of the disturbance in growth hormone release, the plasma concentrations of growth hormone and insulin-like growth factor I (IGF-I) were measured in two seven-year-old poodles with alopecia and, for comparison, in two young German sheperd dogs with congenital hyposomatotropism (pituitary dwarfism). In the poodles the basal concentrations of growth hormone were low, although often above the detection limit of the assay. The concentrations of IGF-I were in the reference range for healthy poodles. No growth hormone could be detected in the plasma of the German sheperd dogs and the concentrations of IGF-I were very low. Stimulation with clonidine and growth hormone releasing hormone (GHRH) before and after repeated injections of GHRH did not result in significant increases in growth hormone concentrations in plasma. The concentrations of growth hormone in the poodles fluctuated at low levels during the test period. In the German sheperd dogs the levels of growth hormone remained unmeasurable during the stimulation tests. It was concluded that in the two poodles the basal concentrations of growth hormone were sufficient to maintain normal IGF-I concentrations, and thus the release of growth hormone was considered appropriate. Based upon measurements of urinary corticoids and a review of the literature it is suggested that the lack of a growth hormone response to stimulation was due to the enhanced release of somatostatin as a result of mild and fluctuating hyperadrenocorticism.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of Insulin-Like Growth Factor-I (IGF-I) Infusion to Promote Growth in Protein-Restricted Rats Despite Normalization of Serum IGF-I Concentrations*

Dietary protein restriction in young rats induces GH resistance characterized by growth arrest and low serum insulin-like growth factor-I (IGF-I) concentrations. To determine whether the low serum IGF-I concentrations are responsible for the stunted growth, we infused 4-week-old protein-restricted rats with recombinant human IGF-I (300 micrograms/day) or rat GH (200 micrograms/100 g body wt/day) by osmotic minipump for 1 week. Despite the normalization of serum IGF-I concentrations by IGF-I infusion, carcass growth was not stimulated. In contrast, growth of the spleen and kidney was enhanced (+45% and +28%, respectively). Serum IGF-binding protein 3 (IGFBP-3), the principal carrier of IGF-I in the serum at this age, is decreased by 34% in protein-restricted animals and restored to normal by IGF-I infusion. Contrary to the selective effects of IGF-I on growth of protein-restricted rats, well nourished hypophysectomized rats infused with 150 micrograms/day recombinant human IGF-I showed a significant growth response, including carcass and organ growth and normalization of IGFBP-3 values. These responses indicate that our IGF-I preparation and mode of delivery were effective. We conclude that: 1) dietary protein restriction causes organ-specific resistance to the growth-promoting properties of exogenous IGF-I; 2) IGF-I mediates the stimulatory effects of growth hormone on IGFBP-3 synthesis; and 3) the absence of carcass growth in the presence of normal serum IGF-I concentrations during infusion of IGF-I suggests that the growth arrest that accompanies protein restriction is mediated in part by resistance to IGF-I.

Dose-Response Study and Long Term Effect of the Somatostatin Analog Octreotide in Patients with Therapy-Resistant Acromegaly*

Twelve acromegalic patients in whom standard therapy was unsuccessful were evaluated with 24-h serum GH profiles (hourly sampling) and oral glucose tests (oGTT) while being treated with octreotide, a long-acting somatostatin analog. During a dose-response study (300, 600, and 1500 micrograms/day sc, for 4 weeks), serum GH decreased significantly after 300 micrograms/day in 8 of 12 patients [from 14.5 +/- 6.2 (+/- SE) to 4.9 +/- 1.9 micrograms/L]. Higher doses further reduced serum GH concentrations in 3 (600 micrograms/day) and 1 (1500 micrograms/day) patients, respectively. Four patients did not respond to any dose. Serum GH concentrations declined normally (GH nadir, less than 2 micrograms/L) after glucose ingestion in 4 of the 10 nondiabetic acromegalic patients. In 4 patients, including 2 of the initial nonresponders, serum GH further declined during long term treatment (12 and 18 months). In the latter 2 patients, serum insulin-like growth factor I (IGF-I) concentrations had decreased during the dose-response study despite the absence of measurable GH suppression. Eight patients attained normal serum IGF-I concentrations during treatment. Serum IGF-I and GH correlated significantly before, but not during, treatment. Retrospective comparison suggested that in 5 of 6 patients, serum GH was more effectively suppressed by octreotide than by bromocriptine. The 24-h serum octreotide concentration varied greatly among the patients. Although the 24-h serum octreotide and GH concentrations did not correlate with one another, the serum octreotide and IGF-I concentrations when the patients were receiving 300 micrograms/day tended to be negatively correlated (r = -0.496; P = 0.118). The 24-h serum insulin values decreased and those of glucose increased during treatment; after oral glucose, serum insulin was lower and glucose was higher. However, after 12 months of treatment, the 8-h serum insulin profile and peak serum insulin after oral glucose administration had returned to pretreatment values, while serum glucose remained abnormal. We conclude that 1) octreotide lowers serum GH in many, but not all, acromegalic patients resistant to other forms of treatment; 2) doses in excess of 300 micrograms/day should be tested in those patients in whom lower doses are ineffective; 3) serum IGF-I measurement may be a better indicator of treatment success than GH measurement; 4) octreotide concentrations do not correlate with GH suppression; and 5) deterioration of carbohydrate tolerance does occur but tends to improve during chronic treatment.

The measurement of insulin-like growth factor I: clinical applications and significance.

Of the somatomedins so far measured, the selective quantitation of insulin-like growth factor I (IGF-I) appears to have the greatest potential in clinical diagnosis. There have been two approaches to the development of immunoassay systems. One type uses antibodies raised against synthetic fragments of IGF-I which exhibit cross-reactivity with the whole hormone. Such assay systems may be adequate for measuring normal adult plasma IGF-I levels, but the potential for the higher sensitivity required for detecting sub-normal plasma levels in young children is apparent only in methods using antibodies raised against the complete hormone. IGF-I in plasma exists as part of a high molecular weight complex in which it is bound to carrier proteins. The binding proteins may interfere with plasma IGF-I measurements by radioligand assays. Direct analysis of untreated plasma samples is claimed to be possible using disequilibrium assay conditions but in order to maximise assay sensitivity it is necessary to employ an initial extraction stage in order to eliminate binding protein interference. Whether the measurement of plasma IGF-I can or should be used in addition to, or as a replacement for, plasma growth hormone (GH) measurement in the clinical assessment of growth disorders remains a controversial issue. Available evidence indicates that a single, random plasma IGF-I level provides an accurate reflection of GH secretion. Adequate discrimination between the elevated levels in acromegaly and normal reference values has been demonstrated. However, in the investigation of growth-retarded children available radioimmunoassay (RIA) methods have proved only partially successful because of the age-related nature of normal plasma IGF-I concentrations. Existing assays appear capable of identifying sub-normal plasma levels after the age of approximately 4 years. In younger subjects an improvement in assay sensitivity is required in order to establish with greater accuracy the relevant normal ranges. Improvements in the identification of the particular lesion responsible for retarded growth in a child can be achieved by measurement of both plasma GH and IGF-I concentrations. The predictive value of the acute plasma IGF-I response to single-dose GH therapy may identify patients who will respond to long-term GH therapy. Better, more informed decisions on subsequent treatment may therefore be made. Apart from GH control, several other factors influence circulating IGF-I levels. Nutritional status can be assessed through reference to IGF-I analysis, overall catabolic or anabolic processes being associated with decreasing or increasing plasma IGF-I levels respectively.