Combined Stimulation Test Research Articles

Peak Growth Hormone Response to Combined Stimulation Test in 315 Children and Correlations with Metabolic Parameters

Background/Aims: Studies are lacking regarding the timing of peak growth hormone (PGH) response. We aim to elucidate the timing of PGH response to arginine and levodopa (A-LD) and evaluate the influence of body mass index (BMI) and other metabolic parameters on PGH. Methods: During growth hormone (GH) stimulation testing (ST) with A-LD, serum GH was measured at baseline and every 30 min up to 180 min. The PGH cut-off was defined as <10 ng/mL. IGF-1, IGF BP3, BMI, and metabolic parameters were obtained in a fasting state at baseline. Results: In the 315 tested children, stimulated PGH levels occurred at or before 120 min in 97.8% and at 180 min in 2.2%. GH area under the curve (AUC) positively correlated with PGH in all patients and with IGF-1 in pubertal males and females. BMI negatively correlated with PGH in all subjects. GH AUC negatively correlated with HOMA-IR and total cholesterol. Conclusion: We propose termination of the GH ST with A-LD at 120 min since omission of GH measurement at 180 min did not alter the diagnosis of GH deficiency based on a cut-off of < 10 ng/mL. BMI should be considered in the interpretation of GH ST with A-LD. The relationships between GH AUC and metabolic parameters need further study.

Das Kallmann-Syndrom – eine Form des hypogonadotropen Hypogonadismus

Two men (aged 44 and 47 years) were admitted with the diagnosis of Kallmann's syndrome, but they had widely different symptoms. The first patient (A) suffered from significant secondary symptoms, i.e. weight gain and skeletal pain, which had caused him to seek medical assistance. The second patient (B) had been admitted because of symptoms of depression, caused by separation from his female partner.Patient A showed major somatic symptoms characteristic of the syndrome: eunuchoidism (physique, boyish voice, gynecomastia, micropenis and absent secondary sex characteristics). Further diagnostic tests revealed low testosterone concentrations (0.958 ng/ml; reference range 1.8 - 7.58 ng/ml) and low luteinizing hormone (LH) concentrations (<0.7 IU/l; reference range 0.8 - 7.6 IU/l), as well as infertility. Radiology showed marked osteoporosis, providing the indication for total hip replacement. Magnetic resonance imaging (MRI) of the skull and chromosomal analysis gave normal results. The physical development of patient B had progressed ever since hormone substitution after a suspected diagnosis of mumps orchitis in early childhood. However infertility was still present. Abnormal laboratory findings at admission: LH 0.10 IU/l (reference range 0.8 - 7.6 IU/l), follicle stimulating hormone 0.10 IU/l (reference range 1.2 - 10.1 IU/l), testosterone 10.0 ng/ml (reference range 1.8 - 7.58 ng/ml). A hypoplastic olfactory sulcus was shown by MRI, but no olfactory bulb. Mineral density of the femur was slightly diminished. Combined stimulation test of the pituitary gland revealed hypogonadotropic hypogonadism and anosmia in both patients.In patient A administration of testosterone, calcium, colecalciferol and biphosphonates improved virilization and reduced skeletal pain. Continuation of testosterone, calcium and colecalciferol treatment, psychotherapy and antidepressive medication with paroxetine were initiated in patient B. His symptoms of depression were treated successfully, but personal and sexual relationships remained difficult and had many problems.Early diagnosis of Kallmann's syndrome and symptomatic treatment with hormone replacement prevent patients from developing pernicious sequelae. However, sexual identity will be difficult even for patients treated after early diagnosis.

Alterations in anterior pituitary function of dogs with pituitary-dependent hyperadrenocorticism.

For the purpose of obtaining an integral picture of anterior pituitary function in canine pituitary-dependent hyperadrenocorticism (PDH), 47 dogs with PDH and eight control dogs received combined administration of four hypophysiotropic hormones (CRH, GHRH, GnRH and TRH) and measurements were made of ACTH, cortisol, GH, LH, PRL and TSH. Basal plasma levels in 47 dogs with PDH were higher for ACTH, cortisol and PRL, lower for GH, and not different for LH (n = 25 noncastrated dogs) and TSH compared with controls (n = 8). In dogs with PDH the responses to combined hypophysiotropic stimulation, measured as increment and area under the curve (AUC), were not different for ACTH, lower for GH and TSH (increments and AUC) and higher for cortisol (increments), LH (AUC, n = 25 noncastrated dogs) and PRL (increments and AUC) than in controls. We conclude that pituitary function is altered in several respects in dogs with PDH. 1) In spite of persisting hypercortisolemia and the neoplastic transformation of the corticotropic cells, these cells usually remain responsive to combined hypophysiotropic stimulation. 2) Basal plasma GH concentrations and GH responsiveness in the combined stimulation test are decreased, probably as a result of the glucocorticoid-induced increase in somatostatin tone. 3) Plasma PRL concentrations and the PRL response to stimulation are increased, probably as a result of cosecretion with ACTH by the transformed corticotropic cells. 4) Despite the well known effect of glucocorticoids of decreasing circulating concentrations of gonadal steroids and thyroxine, the basal plasma concentrations of LH and TSH remain unchanged and there is a tendency to hyperresponsiveness to stimulation for LH and hyporesponsiveness for TSH. The most likely explanation for these changes is a dual effect of glucocorticoids: a direct effect on the gonads and thyroids and/or the transport and metabolism of their secretory products, and an influence on the sensitivity of the feedback control at the hypothalamic-pituitary level.

Pituitary size and function in children and adolescents with shunted hydrocephalus.

Most previous reports of endocrine disorders in children with shunted hydrocephalus have been case reports and there is a lack of systematic information on pituitary anatomy and function among these children. We have obtained these data in a large group of individuals with shunted hydrocephalus. A controlled cross-sectional study. Fifty-four children and adolescents with shunted hydrocephalus were studied for pituitary anatomy and function. They had 54 age- and sex-matched controls (group I). The mean age of the patients and controls was 12.6 years and the mean shunting period 10.6 years. There was a second control group (II) for the magnetic resonance imaging (MRI) and a third control group (III) for the radiography of the sella turcica. The anatomy was visualized by MRI of the pituitary gland and by radiography of the sella turcica. The functional evaluation included an arginine-insulin test and a combined stimulation test with corticotrophin releasing factor (CRF), GnRH and TRH. The patients were shorter (height 148.4 cm vs 153.7 cm, P < 0.05 and relative height -0.5 SDS vs 0.4 SDS, P < 0.05) and had a higher BMI than the control group I (20.6 kg/m2 vs 18.0 kg/m2, P < 0.001). They had also a greater pituitary height than the control group II (5.8 mm vs 5.1 mm, P < 0.01). The patients had significantly lower basal GH levels (P < 0.001) than controls I. Sixteen patients (30%) had a poor GH response (< 20 mU/l) in the arginine-insulin test. Pituitary height was significantly lower among these patients than in those with a normal response (4.7 mm vs 6.3 mm, P < 0.01), who had an increased pituitary height compared to controls II (5.1 mm, P < 0.01). The area under the curve (AUC) for GH correlated with the pituitary volume (r = 0.50, P < 0.001). The patients had higher basal FSH and LH concentrations than controls I (P < 0.001). The peak to basal ratios of FSH and LH were increased in the prepubertal patients and that of LH at Tanner pubertal stage II in the females. The basal FSH and LH levels correlated with the pituitary volume (r = 0.50 and r = 0.54, P < 0.001 for), as did FSH AUC and LH AUC (r = 0.48 and r = 0.75, P < 0.001 for both). These observations indicate that children with shunted hydrocephalus have an increased pituitary size on average. About one-third of these patients had signs of reduced GH secretion and significantly lower pituitary height, which probably contributes to their poor linear growth. Increased pituitary size was associated with enhanced gonadotrophin secretion, which may result in early puberty in children with shunted hydrocephalus.

Clinical significance of multiple hypothalamic-pituitary functions assessment in patients with Turner's syndrome.

Hypothalamic-pituitary functions in 26 cases of Turner syndrome were assessed with a combined stimulation test. The results showed that the peak GH levels of 12 cases were less than 10 micrograms/L; 3 patients were demonstrated as having an even TSH response, while another one with a delayed TSH peak, and other 4 had high basal values and consistent exaggerated TSH responses to TRH; all patients showed increased basal and peak LH and FSH levels but 5, whose LH and FSH secretion patterns were similar to normal. 12 cases have been treated with individualized protocols and followed up for 12 months or more, of them the growth velocity all increased, especially those with hypothyroidism or with a BA less than 13. It is suggested that multiple functions of hypothalamic-pituitary axis in Turner patients be evaluated as early as possible, in order that proper treatment could be adopted and their growth and development improved.

Hypothalamic-pituitary function assessment in children by a combined stimulation test.

We utilized a combined stimulation test using insulin, thyrotropin-releasing hormone, gonadotropin-releasing hormone and levodopa to assess multiple pituitary hormones including growth hormone, thyrotropin, prolactin and gonadotropins in 32 children of short stature and 18 girls with early appearance of puberty. It was found that this combined stimulation test can assess multiple hormone responses with satisfactory results in a single 90-min test. Compared with any of those laborious classic stimulation tests alone, it is easier to be carried out and willingly accepted by children.

Hormone load tests in infertile male patients.

The recognition that discreet hormonal abnormalities may cause ovulation disorders in women suggested that the male partner of infertile women might also suffer from unrecognized hormonal dysfunction amendable to substitution therapy. We obtained a combined stimulation test with gonadotropin-releasing hormone (GnRH), thyreotropin-releasing hormone (TRH), and ACTH in 225 males with childless spouses, when the couple sought to have children for at least one year. The following hormone levels were determined: estradiol (E), thyroid-stimulating hormone (TSH), prolactin, testosterone (T), dihydrotestosterone (DHT), androstenedione(A), 17-OH-pregnenolone (17-OH-Preg), 17-OH-progesterone (17-OHP), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), cortisone (F), and 21-desoxycortisone (21DF). Basal and stimulated, and adrenal-testicular steroids with and without ACTH stimulation failed to demonstrate a relevant relationship to semen parameters. Gonadotropin levels had a significant negative correlation to all important semen parameters (testicular volume, sperm count, motility, morphology, and vitality) and were positively correlated to spermiogenetic defects. Stimulated LH values were more clearly associated with spermiogenetic defects than basal LH. Nonetheless, basal FSH concentrations were more informative than LH. Stimulated prolactin values were positively correlated with both gonadotropin and with sperm morphology. E concentrations had a significant positive correlation with both basal and poststimulation DHEAS values, and showed a highly negative correlation with sperm count, morphology, and vitality. In comparison, good sperm parameters were associated with high poststimulation T concentrations. The results of this study suggest that basal FSH and E concentrations, as well as the stimulated LH, T, and prolactin determinations, should be included in the evaluation of male sterility.

Morning to evening changes of human pituitary and adrenal responses to specific stimuli

We performed a combined stimulation test with the simultaneous application of GnRH (100 micrograms), TRH (200 micrograms) and ACTH (10 micrograms) in 10 healthy adult males at two opposite clock timing, i.e. at 09:00 and 21:00 h. Pituitary (gonadotropins, PRL, TSH) and adrenal (cortisol, aldosterone, progesterone) hormones showed a common trend of enhanced responsiveness to the evening challenge. Differences reached statistical significance in the case of cortisol, aldosterone, PRL and FSH. These findings suggest that the responsiveness of some pituitary and adrenocortical hormones to specific stimuli is physiologically different in humans as a function of the clock timing, being higher in the evening than in the morning. From the clinical standpoint, however, differences in the magnitude of responses were not enough to recommend provocative testing at a particular clock time, at least for routine diagnostic purposes.

Studies on the Influence of Selective Adenomectomy on Hormone Secretion from Normal Anterior Pituitary Gland

In 70 patients with pituitary adenomas combined stimulation tests using releasing factors were performed before and 10 to 20 days after pituitary surgery. Qualitatively, the dynamics of hormone secretion were mostly unaltered after surgery. Quantitatively, the mean amounts of secreted hormones were found lowered after surgery. In some individual patients, however, a postoperative improvement was also observed. Pituitary testing early after surgery proved to be helpful for assessing the definite need for a hormonal replacement therapy.

Assessment of definitive residual pituitary-adrenal function and of hydrocortisone replacement therapy 10 to 14 days after microsurgery for pituitary adenomas.

Anterior pituitary function was evaluated by a combined stimulation test 10-14 days and again 6-8 months after micro-surgery for pituitary tumors. It was found that definite residual pituitary-adrenal function could accurately be assessed already 10-14 days after operation, as judged by the subsequent testing. By this means, hydrocortisone replacement therapy necessary one year after operation could be predicted.

Thyroid function and thyroid hormone metabolism in elderly people. Low T3-syndrome in old age?

T4-, T3- and reverse-T3 concentrations were measured in the sera of 365 subjects beyond the age of 65 in order to evaluate if the decrease of serum T3 frequently observed in old age can be attributed to old age per se or to concomitant nonthyroidal disease. The results obtained from a carefully selected healthy group of elderly people show that 1) total and free T3 levels are lower in senescence but well within the range for euthyroidism in younger healty controls;2) the decrease of serum T3 is more pronounced and occurs earlier in healthy old males than in females, so that for subjects over the age of 75, the upper limit for euthyroidism has to be adjusted by 10% in women and by 20% in men; and 3) there is no low T3 syndrome characterized by decreased serum T3 and increased serum reverse T3, solely due to old age. Turnover kinetics have shown the daily production of T4 and T3 in old age to decrease by 20 micrograms and 10 micrograms, respectively, and an increased T3 metabolic clearance not to account for the reduction of serum T3 concentrations. Combined stimulation tests with TSH and TRH showed that the functional reserve of the thyroid gland to produce T3 is maintained in old age. The first step in the sequence of events may be seen in an impairment of TSH secretion leading to an adaptation of the amount of thyroid hormones to a reduced mass of metabolically active body tissue in old age.

COMBINED TEST OF HYPOTHALAMIC‐PITUITARY FUNCTION IN GROWTH RETARDED CHILDREN TREATED WITH GROWTH HORMONE I. Secretion of Growth Hormone and Somatomedin before and after Treatment

In 23 growth retarded children two consecutive insulin tolerance tests (ITT) were performed to establish a diagnosis of growth hormone (GH) deficiency. Nine children did not respond (GH peak value less than 8 mU/1), whereas 14 were classified as having partial GH deficiency (GH peak value less than 20 mU/1). All were treated for an average period of 40 months with human growth hormone (HGH). In a combined stimulation test at the end of the treatment period 9 children demonstrated a persistent GH deficiency, whereas a normal response was found in 14 of the previous partial GH deficient children. During treatment the monthly growth rate rose from 0.21 cm 0.58 cm in the GH deficient children and from 0.31 cm to 0.70 cm in the partial deficient children, in most of whom spontaneous pubertal development occurred during treatment. Somatomedin (SM) values were decreased in the GH deficient children before and after treatment but increased to normal levels during treatment. Growth velocity in these children during treatment was correlated to SM values before treatment. In the partial GH deficient children SM values were subnormal before but normal after treatment. This supports the assumption that in some children with constitutional delay in puberty a reversible functional hypopituitarism exists, which is normalized after the onset of puberty, due to androgens sensitizing growth hormone releasing mechanisms. Treatment with HGH may induce increased growth velocity in some of these patients.