Interactions between glucocorticoids and the growth hormone-insulin-like growth factor axis

Glucocorticoids in pharmacological doses interfere with the integrity of the somatotropics hormone axis. However, the apparent discrepancies between the in vitro and in vivo studies, short-term vs. long-term exposure, and species-specific changes complicate a clear assessment of these interactions. The growth-depressing effects of glucocorticoids are multifactorial and involve suppression of pituitary GH release by stimulating hypothalamic somatostatin tone, down-regulation of hepatic GH receptors, inhibition of GH bioactivity by the induction of IGF inhibitors, complex alteration of the IGFBP serum profile, and a direct suppressive effect on tissue matrix production and synthesis of local growth factors.     

GHRH Treatment: Studies in an Animal Model

Shakatsui, S., Abe, H. and Chihara, K. (Division of Metabolism and Nutrition, International Centre for Medical Research, and the Third Division, Department of Medicine, Kobe University School of Medicine, Kobe, Japan). GHRH treatment: studies in an animal model. Acta Paediatr Scand [Suppl] 349 101, 1989.
This study examined the effects of chronic deletion of circulating growth hormone-releasing hormone (GHRH) and/or somatostatin (SRIF) on normal growing male rats, as well as the effects of exogenous GHRH (1–29)NH₂ and/or SMS 201–995 administration on the growth of rats with hypothalamic ablation. Passive immunization with anti-rat GHRH goat γ-globulin (GHRH-Ab) for 3 weeks caused a marked decrease in the levels of pituitary GH mRNA and severe growth failure. Treatment with anti-SRIF goat γ-globulin (SRIF-Ab) for 3 weeks produced a more modest decrease in GH mRNA levels in the pituitary and a slight hut significant inhibition of normal somatic growth. Hypothalamic ablation produced a marked decrease in the level of mRNA in the pituitary. Chronic continuous administration of GHRH (1–29)NH₂ stimulated pituitary GH synthesis, elevated serum levels of insulin-like growth factor I and increased body weight gain in rats with hypothalamic ahlation treated with replacement doses of cortisone, testosterone and L-thyroxine. Combined treatment with GHRH (1–29)NH₂ and SMS 201–995 appeared to promote the effect of GHRH on pituitary GH release and somatic growth in these animals. The results suggest that continuous administration of GHRH will be useful in the treatment of children with growth retardation resulting from hypothalamic disorders. In children with combined GHRH and somatostatin deficiencies, the addition of somatostatin to a GHRH treatment regimen may produce better results.     

Growth hormone / insulin-like growth factor-1 axis during puberty

Puberty is a dynamic, transitional period of life which is characterized by the acquisition of secondary sexual characteristics leading to the development of fertility. Puberty is accompanied by sexually dimorphic changes in linear growth, body proportions and body composition. The pubertal growth spurt is influenced by a number of factors such as hormones, nutrition, physical activity and general health, acting mostly in concert in order to modify a genetic potential for growth. Growth hormone (GH) is traditionally considered to be the main regulator of growth. During puberty, elevated sex steroid concentrations (especially oestrogens) stimulate GH production, leading to an activation of the whole GH/Insulinlike growth factor-1 (IGF-1) axis. This activation is mostly characterized by an increase in the amplitude of GH pulses rather than an increase in frequency or in duration. Interactions between GH and sex steroids (especially androgens) express an anabolic effect on muscle mass, bone mineralization and body proportion which constitutes the male and the female adult body composition.     

Management of puberty in growth hormone deficient children

The pubertal growth spurt accounts for approximately one-eighth of adult height and is regulated by complex hormonal interactions involving the somatotropic and gonadal axes. The observation that children with growth hormone deficiency (GHD) may fail to achieve an appropriate pubertal growth spurt led to the development of strategies to optimize GH therapy during puberty. In one strategy the dosage of GH is increased during puberty to support pubertal growth and in keeping with the physiological increase in serum levels of the hormone seen at that age. A different approach is to combine a GnRH analog (GnRHa) to GH to stop pubertal development, delaying epiphyseal fusion and prolonging peripubertal growth. Both strategies require caution. As regards the first strategy, too high doses of GH may shorten the pubertal time for growth; we found a small, nonsignificant, improvement in final height by increasing the dose by less than half. Preliminary results on the second strategy are more encouraging. However, manipulation of puberty should be limited to selected patients who show a statural height SDS for bone age unfavorable in terms of height prognosis.     

Differences of hexarelin-induced prolactin and cortisol responses between prepubertal and early pubertal short children and lack of correlation with gonadotropin-releasing hormone-induced gonadotropin response

Hexarelin (HEX), a synthetic hexapeptide with strong GH-stimulating activity, is known to induce the release of prolactin (PRL) and cortisol (F). The responses of GH and F vary according to age and pubertal development, correlating with serum levels of sex steroids, while the release of PRL does not. We evaluated GH, PRL and F responses to HEX (2 microg/kg i.v.) in 19 children with short stature, 12 prepubertal (Tanner stage I) and 7 early pubertal (stage II), and their correlation with those of FSH and LH to GnRH and with the serum levels of testosterone (T) or estradiol (E2). At baseline, the GH, PRL, F and sex steroid serum levels did not vary in the two groups of patients. HEX induced a strong GH and a slight PRL increase in prepubertal and early pubertal children, with no differences in the extent of the response, while F secretion was not affected in either group; these responses did not correlate with those of the gonadotropins to GnRH nor with basal T or E2.     

Gender and hormonal regulation of growth

Puberty is the transitional period between childhood and adulthood when substantial growth, sexual maturation, and reproductive capacity is attained. The onset of puberty is triggered by the combined action of the somatotropic (GH-IGF-I) and gonadotropic (GnRH-LH/FSH-sex steroid) hormone axes, the latter of which stimulates the former to produce the pubertal growth spurt. Studies of GH secretion in boys and girls, in Turner's syndrome, in hypogonadal girls, and in androgen-deficient boys have revealed estrogen-dependent mechanisms controlling GH production, age-dependent response to and control of GH, and gender-dependent differences in response to GH therapy. The interplay between the somatotropic and gonadotropic hormone axes during puberty has profound implications on the treatment of adolescent patients in need of hormone replacement therapy for growth deficiency or hypogonadism.     

Suppression of GH secretion in pituitary gigantism by continuous subcutaneous octreotide infusion in a pubertal boy

We describe a 12-y-old boy with excessive growth hormone and prolactin secretion presumably due to diffuse somatotroph hyperplasia. Until mid-puberty, his growth rate was under reasonable control, with high-dose octreotide injections every 8 h combined with a dopamine agonist. As his growth velocity started to increase, the efficacy of continuous s.c. octreotide infusion on GH secretion was tested. Similar total daily doses (600 microg) of octreotide were administered either by incremental s.c. injections at 8 h intervals, or by continuous s.c. infusion, two-thirds of the amount during night-time to control the presumed high nocturnal growth hormone (GH) peaks of the pubertal growth spurt. An overnight GH profile showed inadequate suppression of GH levels by incremental injections, while continuous s.c. infusion efficiently brought down the GH secretion. Another somatostatin analogue, lanreotide as a single depot injection was not effective. A 6-mo trial on the s.c. infusion regimen significantly reduced growth hormone secretion (as judged by IGF-I and IGFBP3 concentrations), and normalized growth velocity overcoming the pubertal growth spurt. It also caused a decrease in the pituitary size in magnetic resonance images. We conclude that the efficacy of octreotide infusion in suppressing GH secretion is superior to incremental injections with the same dose.     

Growth hormone releasing factor and somatostatin concentrations in the milk of lactating women

The concentrations of growth hormone releasing factor (GRF) and somatostatin, two hypothalamic neuropeptides involved in the regulation of growth hormone secretion, were measured in human milk samples. The study was performed in healthy women within 48 h of delivery or during established lactation (between 1 and 64 weeks post delivery). No statistically significant correlation was found between the levels in milk of either of the neuropeptides and the gestational age at birth. However, lower values of GRF (23±4.7 pg/ml vs. 40.5±4.9 pg/ml) were found in milk obtained during established lactation than in milk obtained close to delivery. A positive correlation was observed between somatostatin and GRF concentrations in milk. The possible involvement of milk neuropeptides in the control of growth hormone secretion in the neonate, as well as in the regulation of other physiological processes, are evaluated.Abbreviations BSA bovine serum albumin - EGF epidermal growth factor - GH growth hormone - GRF growth hormone releasing factor - HPLC high performance liquid chromatography - IR immunoreactive - LHRH luteinizing hormone releasing hormone - PBS phosphate buffered saline - RIA radioimmunoassay - SS somatostatin - TRH thyrotropin releasing hormone - VIP vasoactive intestinal peptide     

Correlation of sex steroids with IGF-1 and IGFBP-3 during different pubertal stages

Insulin-like growth factor 1 (IGF-1) is the major factor that affects linear bone growth. Also, androgens and estrogens are necessary for increasing longitudinal bone growth during sexual maturation. The aim of this study was to investigate the relationships among IGF-1 axis and sex steroids during pubertal development in healthy adolescents. In this cross-sectional study, IGF-1, IGF binding protein-3 (IGFBP-3) and sex steroid levels (estradiol in girls, testosterone in boys) of 205 healthy adolescents (101 female, 104 male) aged 9-17 years were measured. All subjects were apparently healthy, with no growth retardation and with skeletal ages appropriate for chronological ages, and none were taking medications known to influence calcium homeostasis. Greulich and Pyle's Radiographic Atlas of Skeletal Development of the Hand and Wrist was used for determination of skeletal ages. Tanner's classification was used to determine the pubertal developmental stage. Fasting blood samples were obtained from subjects between 09:00-10:00 h. Serum IGF-1 and IGFBP-3 levels differed significantly between pubertal developmental stages. Serum IGF-1 levels and IGF-1/IGFBP-3 ratios increased with proceeding stages and maximum mean values were found at stages III-IV in girls and at stage IV in boys. Estradiol levels of girls and testosterone levels of boys differed significantly between stages, and in both sexes, serum IGF-1 levels and IGF-1/IGFBP-3 ratios were significantly correlated with sex steroid levels. Increase in growth hormone secretion increases IGF-1 levels. Furthermore, increasing sex steroids with pubertal development increase the IGF-1 levels and IGF-1/IGFBP-3 ratios that affect bone growth.     

Comparison of low‐dose and high‐dose cosyntropin stimulation testing in children

Background: There is no consensus among pediatric endocrinologists in using low‐dose (LD) versus high‐dose (HD) cosyntropin to test for secondary/tertiary adrenal insufficiency. This paper compares LD and HD cosyntropin stimulation testing in children for evaluation of hypothalamic‐pituitary‐adrenal axis (HPAA) and suggests a new peak cortisol cut‐off value for LD stimulation testing to avoid false positivity. Methods: Data of 36 children receiving LD (1 µg) and HD (249 µg) cosyntropin consecutively during growth hormone (GH) stimulation testing were analyzed in two groups. Group A were patients who passed GH stimulation testing and were not on oral, inhaled or intranasal steroids (intact hypothalamic‐pituitary axis, n= 19). Group B were patients who failed GH stimulation testing and/or were on oral, inhaled or intranasal steroids (impaired hypothalamic‐pituitary axis, n= 17). Results: In group A, the mean peak cortisol response in LD cosyntropin was 18.5 ± 2.4 µg/dL and that for the HD cosyntropin was 24.8 ± 3.1 µg/dL (r: 0.76, P≤ 0.05). In group B, the mean peak cortisol response in LD cosyntropin was 15.7 ± 6.1 µg/dL and that for HD cosyntropin was 21.7 ± 7.9 µg/dL (r: 0.98, P≤ 0.05). When a standard cut‐off of 18 µg/dL was used, 37% of the patients with intact HPAA failed LD cosyntropin testing, but a cut‐off of 14 µg/dL eliminated false positive results. Conclusions: LD cosyntropin stimulation testing results should be interpreted cautiously when used alone to prevent unnecessary long‐term treatment. Using a lower cut‐off for LD (≥14 µg/dL) seems to avoid false positive results and still detects most cases of impaired HPAA.     

Androgen and estrogen treatment, alone or in combination, differentially influences bone maturation and hypothalamic mechanisms that time puberty in the male rhesus monkey (Macaca mulatta)

In higher primates, the mechanisms that govern the ontogeny of gonadotropin-releasing hormone pulse generator activity and that, therefore, dictate the timing of the onset of puberty remain intriguingly elusive. Groups of three infant agonadal male monkeys were treated with sex steroids [17beta-estradiol (E(2)), testosterone (T), or dihydrotestosterone (DHT)] for the first year of life to advance bone age (BA). E(2) and T resulted in a significant advancement of BA, and a pubertal BA of 130 wk was attained at a mean chronological age of 64 and 67 wk, respectively. In contrast, DHT failed to advance BA during treatment but stimulated linear growth. All animals exhibited a pubertal resurgence in LH secretion, but the timing of this developmental event did not differ between treatment and control groups (the mean for all animals was 117.7 +/- 8.9 wk). Two of the three T-treated animals, however, displayed a pubertal LH resurgence at a remarkably young age (70 and 76 wk of age) that coincided with T withdrawal. During the period of steroid treatment, all three groups were significantly heavier than the controls. The rate of body weight gain was most rapid in the DHT-treated group. Steroid treatments also resulted in accelerated linear growth. Body weight gain and linear growth continued at the same rate as controls after withdrawal of treatment. These data indicate that attainment of a pubertal BA may be a necessary but not a sufficient factor to trigger the onset of puberty. The results not only are consistent with the view that androgen-induced skeletal maturation in males is mediated by estrogen receptor activity but also indicate that androgen receptor activity contributes to the pubertal growth spurt in males.     

Confirming the diagnosis of growth hormone deficiency (GHD) and transitioning the care of patients with childhood-onset GHD

Growth hormone deficiency (GHD) diagnosed in childhood may persist into adult life. After attainment of final height, retesting of the patient's growth hormone-insulin-like growth factor (GH-IGF) axis using the adult GHD diagnostic criteria should be performed after an appropriate interval of 1-3 months off GH therapy. At the time of retesting, other pituitary hormones and serum IGF-I levels should also be measured. The opportunity should be taken to assess body composition, bone mineral density, and fasting lipid and insulin levels. Patients with severe, long-standing, multiple pituitary hormone deficiency, genetic defects, or severe organic GHD can be excluded from GH retesting. When the diagnosis of adult GHD is established, continuation of GH therapy can be recommended unless there is a known risk of diabetes mellitus or malignancy. The patient's transition to GH replacement in adulthood should be arranged as a close collaboration between the pediatric and adult endocrinologists, who should discuss the reinitiation of treatment with the patient.     

Pre- and postnatal developmental changes in hypothalamic and pituitary content of alpha-melanocyte-stimulating hormone and somatostatin in the rat

The developmental pattern of hypothalamic and pituitary somatostatin and alpha-melanocyte-stimulating hormone (alpha-MSH) was studied in the rat by radioimmunoassay (RIA). Prenatally hypothalamic somatostatin was low and the first increase in content occurred on day 5 of the postnatal period. Pituitary somatostatin was undetectable prenatally and was first detected on day 6 postnatally. Pituitary somatostatin showed the same development pattern as hypothalamic somatostatin. Whole pituitaries were analyzed from the fetuses and neonates. Analysis of anterior and posterior lobes from adults revealed that all the somatostatin was in the posterior lobe. Therefore, it is believed that the somatostatin found in the glands of the younger animals was in the neural lobe. alpha-MSH was detected in the fetal hypothalamus as early as day 16, with a marked increase occurring on day 19 prenatally and a further increase on day 10 postnatally. Pituitary alpha-MSH content, readily detectable on the first day examined, i.e. day 16 of the fetal period, increased throughout development. The effect of alpha-MSH on the release of growth hormone in vitro from pituitaries of rats of various ages was tested. alpha-MSH had no effect on growth hormone release.     

When should hydrocortisone therapy be instituted in children with hypopituitarism?

The records of 72 pediatric and adolescent patients with multiple hypothalamic and/or pituitary hormone deficiencies of nontumoral origin who were followed up for years and receiving somatotropin, thyroxine, and sex hormones at the appropriate age have been reviewed. According to their corticotropin-releasing factor-corticotropin-cortisol (CAC) axis function as evaluated by basal plasma cortisol levels and the response of cortisol to insulin hypoglycemia and to corticotropin-releasing factor, the patients were divided into three groups: group 1 (n = 25), patients with multiple hypothalamic and/or pituitary hormone deficiencies with normal CAC axis; group 2 (n = 38), patients with partial CAC deficiency without cortisol replacement therapy (hydrocortisone); and group 3 (n = 9), patients with CAC deficiency receiving hydrocortisone therapy (5 to 10 mg/d). Repeated CAC axis evaluation in patients of group 2 over years revealed a progressive decrease in the basal and stimulated cortisol levels with age and pubertal advancement. Despite the low cortisol levels and the low cortisol response to insulin hypoglycemia, these patients did not have clinical symptoms until the end of puberty when nine of 24 patients complained of abdominal pain, weakness, or anorexia. Linear growth, which was followed up in all patients at regular intervals, showed a lower growth velocity and irregular growth in response to somatotropin treatment in the patients receiving low doses of hydrocortisone (group 3 patients when compared with group 2 patients not receiving hydrocortisone).     

Interactions between GH,IGF-I,glucocorticoids, and thyroid hormones during skeletal growth

Linear growth occurs during development and the childhood years until epiphyseal fusion occurs. This process results from endochondral ossification in the growth plates of long bones and is regulated by systemic hormones and paracrine or autocrine factors. The major regulators of developmental and childhood growth are GH, IGF-I, glucocorticoids, and thyroid hormone. Sex steroids are responsible for the pubertal growth spurt and epiphyseal fusion. This review will consider interactions between GH, IGF-I, glucocorticoids, and thyroid hormone during linear growth. It is well known from physiologic and clinical studies that these hormones interact at the level of the hypothalamus and pituitary. Interacting effects on peripheral tissues such as liver are also well understood, but we concentrate here on the epiphyseal growth plate as an important and newly appreciated target organ for convergent hormone action.     

Three-peptide control of pulsatile and entropic feedback-sensitive modes of growth hormone secretion: modulation by estrogen and aromatizable androgen

The present review highlights a simplified perspective of growth hormone (GH) secretory control, which incorporates the individual and joint effects of final-common signals that converge on somatotrope cells. Critical peptidyl effectors are GH-releasing hormone (GHRH), GH-releasing peptide (GHRP, ghrelin), and somatostatin. The latter three-peptide ensemble mediates stimulation, inhibition, and feedback suppression of GH secretion via homologous and heterologous interactions. Pubertal sex steroids putatively act via post-aromatized estrogen (e.g., testosterone converted to estradiol by aromatase) to augment sensitivity to GHRH, potentiate GHRP action, and mute somatostatin restraint. The dynamic interactions in this three-peptide network, rather than the activity of any single effector, subserve core adaptations in GH secretion across development.     

Clinical value of the gonadotropic hormone releasing hormone (GHRH) test in the diagnosis of growth deficiency

Many stimulation tests are available for the assessment of growth hormone release from the pituitary in clinical practice. Three of the most common tests are insulin-hypoglycaemia, arginine stimulation and spontaneous hGH nocturnal peaks and profiles. In this study we compared the Growth hormone releasing-hormone (GHRH)-test in a dose of 1 microgram/kg b.w. with these three other tests for evaluation of the somatotropic function of the pituitary. Each of these four tests was performed in 29 children with short stature due to growth failure of various etiologies and height-deficits (-SDS) of -3.0 +/- 0.5 SE. The peak plasma hGH levels of all patients after GHRH stimulation did not correlate with the respective peak values during insulin (r = 0.02) and arginine (r = 0.28) stimulation and with peak levels during the spontaneous nocturnal hGH profile (r = 0.18). The diagnostic value of the GHRH test alone is thus still questionable in establishing the diagnosis of a hypothalamic GHRH/GH defect, because some of these patients do not react to the first GHRH dose as one might expect, but only after a few days of repeated injections of GHRH (priming). The tolerance of intravenous injections of GHRH was excellent. The mean plasma GH response to GHRH was higher (p less than 0.05) in the group of children with constitutional short stature than in GH deficient patients, but there were overlaps in this group with normal volunteers and other groups of patients with growth failure.     

Evidence for decreased growth hormone in patients with hypothalamic hamartoma due to Pallister-Hall syndrome

Pallister-Hall syndrome (PHS) is characterized by hypothalamic hamartoma, bifid epiglottis, and central or postaxial polydactyly. Familial transmission is autosomal dominant; isolated cases also occur. To screen for hypothalamic-pituitary dysfunction in PHS, we studied a 12 year-old boy (patient #1), and 14 additional patients (patients #2-14: 7M, 7F; ages 4-72 yr). We performed serial sampling of GH, LH/FSH, TSH, and cortisol from 20.00-08 00 h. At 08.00 h, we measured IGF-I, peak responses of LH and FSH after GnRH, and cortisol after ACTH. We found that 6/7 children, including patient #1, and 6/8 adults had low or absent spontaneous GH secretion and/or low levels of IGF-I. Patient #1 also had accelerated pubertal development, but no other patient had abnormalities of the pituitary-gonadal axis, and none of the 14 patients had an abnormal thyroid or adrenal axis. We conclude that decreased pituitary GH secretion is common in PHS, and may exist in the absence of other forms of endocrine dysfunction.     

Effects of human growth hormone on very short children with intermediate responses to somatotropic stimulation tests

The effects of treatment with human growth hormone (hGH) were studied in 29 patients aged 2 to 16 years with growth retardation between 2.2 and 6 standard deviations and insufficient growth velocity in whom repeated pharmacologic somatotropic stimulation tests had shown discordant responses either above 7 ng/ml, or lower than 6 ng/ml. An important acceleration of growth was obtained in 10 of 16 patients before puberty and in all the 13 cases treated at the beginning of puberty. No correlation was observed between the GH levels observed during the stimulation tests and the clinical results of treatment. These data lead to discuss partial GH deficiency and to propose a trial of treatment in very short children with low and/or dissociated responses to repeated tests of pituitary somatotropic secretion.