Growth hormone release during insulin tolerance, clonidine, arginine and growth hormone releasing hormone tests in short normal children and adolescents.

This study was retrospectively performed in 574 short normal children and adolescents [328 underwent insulin tolerance test (ITT), 34 clonidine test (CLON), 64 arginine test (ARG), 19 GHRH test, 52 ITT+CLON, 30 GHRH+CLON, and 47 ITT+CLON+GHRH) in order to evaluate the effect of pubertal stage on GH response to different tests and to identify the most likely mechanism of action of different stimuli. GH peak was higher during GHRH than in all other tests. Sex or start of pubertal development did not cause any GH peak difference. Low-responder (GH peak less than 10 ng/ml) percentages were similar (ITT = 13.5%, CLON = 13.4%, ARG = 13.2%, GHRH = 10.6%) also when the subjects were divided according to sex and pubertal development. ITT+CLON showed discordant results in 42/99 subjects (30/42 = 71.4% were low-responders to ITT and 12/42 = 28.6% to CLON). GH peak appeared earlier during GHRH (85% less than 45 min) and later during CLON (78%: 60-120 min) than during all other tests; GH peak during ITT showed a wide variability of time. Negative correlations were found between GH peak during GHRH and chronological age, height and bone age and during CLON and chronological age. In conclusion our data show that these tests have similar GH secretagogue reliability.     

Use of growth hormone in children with short stature and normal growth hormone secretion a growing problem.

The ethical, economic, psychologic, social, and growth attainment outcome issues related to the use of GH therapy in normal children with short stature are discussed. Although some short children accelerate their growth velocity with GH treatment, the limited available data do not suggest a significant benefit in final height attainment. An international survey of 99 normal short children treated with GH for at least 3 years reported a net improvement in mean height gain of <1 cm/year. Only in one-third was the result considered very good or good; 40% stated that there was no benefit. Thus, it seems unlikely that GH will dramatically increase final height in short children. On this basis, the use of GH for the treatment of the normal child with short stature outside of carefully controlled clinical trials cannot be recommended at present.     

Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues

BACKGROUND AND OBJECTIVE Growth hormone treatment In children with Idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long-term effect of GH therapy in children with Idiopathic short stature. DESIGN We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m² body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n= 21) were compared to those of an untreated control group with ISS (ISS controls, n= 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n= 7). RESULTS In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from ?3.8±0.7 to ?2.3±0.9 (mean±standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from ?3.9±0.6 to ?1.8±0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated In the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was ?2.6±1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome. CONCLUSION rhGH treatment In this group of children with Idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.     

Growth hormone responsiveness in vivo and in vitro to growth hormone releasing factor in the spontaneously diabetic BB Wistar rat

In order to determine whether there is an abnormality in the pituitary responsiveness to GRF in the diabetic rat, we examined the in vivo and in vitro effects of hGRF-44 NH2 (hGRF) on growth hormone (GH) release in the spontaneously diabetic BB Wistar rat. Under pentobarbital anesthesia, hGRF was injected intravenously at a dose of 500 ng/kg in male diabetic BB Wistar rats (n = 11) and in male control Wistar rats matched for weight (n = 11). Basal serum GH concentrations were significantly lower in the diabetic group, (123 +/- 5 ng/ml, mean +/- SEM) than in the control group (362 +/- 15 ng/ml). However, the GH response to hGRF was significantly greater in the diabetic group (GH increment 873 +/- 153 ng/ml) than in the control group (268 +/- 91 ng/ml). The effect of hGRF was further tested in a perifusion system of freshly dispersed anterior pituitary cells of diabetic BB Wistar rats and control Wistar rats. Basal secretion rate of GH from cells of diabetic rats (0.85 +/- 0.06 microgram/2 pituitaries X 2 min) was lower than that from cells of control rats (1.60 +/- 0.18 micrograms/2 pituitaries X 2 min). The GH response to 2-min pulses of hGRF at concentrations of 1.56, 6.25, and 25 pM with and without somatostatin 10(-9) M was significantly greater in the diabetic group than in the control group. In conclusion, there is in the spontaneously diabetic rat an increased in vivo and in vitro GH responsiveness to exogenous hGRF suggesting an abnormality of GH regulation at the pituitary level.     

Secretion of growth hormone releasing hormone in obese children.

We have evaluated baseline and l-dopa-stimulated peripheral growth hormone releasing hormone (pGHRH) secretion in 6 obese pre-pubertal children and in 7 age-matched controls. Baseline pGHRH levels were no different between obese (36.6 +/- 9.8 pg/ml, mean +/- SE) and control children (40.6 +/- 10.1 pg/ml). Administration of l-dopa (500 mg po) caused a significant increase of pGHRH levels in both the obese (65.3 +/- 19.8 pg/ml, p less than 0.05) and the control children (84.1 +/- 10.0 pg/ml, p less than 0.003). Mean peak pGHRH levels after l-dopa were not significantly different between the two groups, whereas mean peak GH levels were significantly lower (p less than 0.05) in the obese (7.9 +/- 1.9 ng/ml) than in the control children (20.5 +/- 4.9 ng/ml). We conclude that despite reduced GH secretion, obese children have normal baseline and l-dopa stimulated pGHRH levels.     

Dynamics of growth hormone responsiveness to growth hormone releasing factor in aging rats: peripheral and central influences.

The in vivo and in vitro dynamics of somatotroph responsiveness to rGRF (1-29) NH2 (rat growth hormone releasing factor) were evaluated in 2-, 4-, 8-, 12-, and 20-month-old male rats. In vivo, using pentobarbital-anesthetized animals, we observed that the rGH (rat growth hormone) responsiveness to 0.4 and 1.6 micrograms/kg rGRF started to decline at the higher dose in 12-month-old rats and was completely blunted at both rGRF doses in 20-month-old animals. In vitro, using freshly dispersed perifused pituitary cells, we also documented a decrease of rGRF-induced rGH secretion in 12- and 20-month-old rats. Moreover, as the animals aged, the rGRF-induced rGH secretion was differentially affected by the inhibiting action of somatostatin (p less than 0.001), suggesting a loss of pituitary sensitivity to somatostatin in the presence of a high concentration of rGRF. The pituitary rGH content increased until rats reached 12 months of age, but was diminished in 20-month-old rats. In contrast, the pituitary somatostatin content increased twofold in 20-month-old rats as compared with younger rats. The hypothalamic somatostatin content was highest in 8-month-old rats and only slightly diminished in 20-month-old animals. Finally, plasma insulin-like growth factor I concentrations were highest in 8-month-old rats and lowest in 20-month-old animals. Altogether, these results indicate that the physiological loss of somatotroph responsiveness associated with the process of aging starts around 12 months of age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Corticotrophin releasing hormone levels in human plasma and amniotic fluid during gestation

OBJECTIVE Corticotrophin releasing hormone, a hypothalamic neuropeptide also made in placenta, may regulate fetal maturation in a stress-responsive manner. The objectives of this study were: (1) to determine if levels of corticotrophin releasing hormone in the amniotic fluid correlate with fetal lung maturation; (2) to confirm that third trimester plasma levels of corticotrophin releasing hormone are increased in patients with pregnancy-induced hypertension compared to normotensives, and (3) to increase the recovery of extracted corticotrophin releasing hormone from plasma and amniotic fluid. DESIGN (1) Levels of corticotrophin releasing hormone in amniotic fluid during the third trimester were compared with those of saturated phosphatidyl choline. (2) Corticotrophin releasing hormone levels were measured in a group of normotensive pregnant women during the entire gestation period. Corticotrophin releasing hormone levels during the third trimester were compared in normotensives and patients with pregnancy-induced hypertension. PATIENTS Twenty-one non-pregnant normal volunteers and 63 pregnant women. MEASUREMENTS Blood pressure, corticotrophin releasing hormone in plasma and amniotic fluid, and saturated phosphatidyl choline in amniotic fluid. RESULTS Corticotrophin releasing hormone levels in amniotic fluid samples during the third trimester ranged from 12 to 98 pmol/l and positively correlated with the saturated phosphatidyl choline levels, but not with gestational age. A significant difference existed in plasma corticotrophin releasing hormone concentration between gestational age-matched third trimester normotensive and hypertensive gravids: corticotrophin releasing hormone levels were significantly lower in normotensives (223 ± 65 pmol/l) than in patients with pregnancy-induced hypertension (544 ± 106 pmol/l, P= 0.001). Plasma corticotrophin releasing hormone increased with gestational age from 51 pmol/l (range 8.4–85) at 25–32 weeks to 375 pmol/l (range 35–1386) at 33–40 weeks. During the third trimester the rise in plasma corticotrophin releasing hormone conformed to an exponential mathematical model of a positive feedback loop between placental corticotrophin releasing hormone and fetal adrenal Cortisol. CONCLUSIONS During the third trimester of pregnancy there is a positive correlation between the level of amniotic fluid corticotrophin releasing hormone and that of saturated phosphatidyl choline. The positive correlation between amniotic fluid corticotrophin releasing hormone and saturated phosphatidyl choline, but not between amniotic fluid corticotrophin releasing hormone and gestational age, suggests that a factor(s), such as stress, may affect both amniotic fluid corticotrophin releasing hormone and saturated phosphatidyl choline in parallel. Furthermore, our data are consistent with the hypothesis that the rise in placental corticotrophin releasing hormone is coupled to an increase in fetal glucocorticoid and lung maturation, and that stresses such as pregnancy-induced hypertension may accelerate this process.     

Growth hormone response to growth hormone releasing factor in Alzheimer's disease

Because of the well-established reduction in the concentration of somatostatin in several brain areas of patients with histologically verified Alzheimer's disease, we sought to determine if growth hormone (GH) secretion is altered in Alzheimer's disease. In order to study this, we assessed the GH response to growth hormone releasing factor (GRF) in 8 patients with Alzheimer's disease and 8 age-matched controls. Although there was no difference between the magnitude of the GRF-induced GH response (delta max GH response or area under the curve) between the Alzheimer's disease patients and the controls, the Alzheimer's patients exhibited a delayed GH response to GRF.     

Pulsatile growth hormone release in Turner's syndrome and short normal children

To determine whether the quantitative and qualitative aspects of GH secretion in girls with Turner's syndrome are similar to those of short-normal children we studied the 24-h GH secretion of 10 patients with Turner's syndrome and 9 short-normal children with comparable auxological features. GH profiles, obtained by 30-min sampling, were analysed by the Pulsar programme. The pulsatile GH release over the 24 h in Turner's syndrome was similar to that in normal children. However, when the GH release over the 12 day and night hours were separately analysed, only normal children showed a night-time increase in the sum of peak amplitudes. Moreover, patients with Turner's syndrome had significantly decreased number and frequency of peaks in the night-time compared with short children. In short-normal children but not in Turner's syndrome, height velocity was related to the 24-h integrated concentration of GH, area under the curve over zero-line and over baseline, sum of peak areas, and amplitudes. Night-time GH area over zero-line and over baseline, mean peak amplitude, height area, sum of peak area and amplitudes were positively correlated with height velocity in short children, whereas in Turner's syndrome height velocity was related to daytime parameters only. In conclusion, girls with Turner's syndrome have a discrete pattern of pulsatile GH release. However, the relation of GH secretion to growth in these patients, is uncertain.     

Growth hormone releasing hormone 1-44 NH2 and 1-40 OH levels in normal subjects during growth hormone stimulation tests

OBJECTIVE Little is known about the relative circulating concentrations of growth hormone releasing hormone (GHRH) 1-44 NH₂ and 1-40 OH in response to dynamic GH stimulation. We therefore studied the concentrations of growth hormone-releasing hormone (GHRH) 1-44 NH₂ and 1-40 OH in the peripheral plasma of normal male subjects during GH stimulation tests. DESIGN Tests were performed at 0900 h after an overnight fast. Stimulation tests, commenced at 0 minutes, included α-adrenergic activation with adrenaline (10 μg/min from 0 to 30 minutes) following β-blockade with propranolol (1.5 mg/min from -10 to 0 minutes), α2-adrenergic activation with clonidine 150 μg i.v., insulin hypoglycaemia (0.15 U/kg soluble insulin), l -arginine infusion (30 g from 0 to 30 minutes), l -dopa (500 mg orally) and oral glucose (100 g). SUBJECTS Groups of healthy male volunteers aged 20-42 years, all within 10% of ideal body weight. MEASUREMENTS Serum GH and plasma GHRH 1-44 NH2 and 1-40 OH were measured at intervals for between 60 and 390 minutes, depending on the stimulation test. RESULTS There were no significant changes in either GHRH 1-44 or 1-40 following a-adrenergic activation with propranolol/adrenaline infusion, a2-adrenergic activation with i.v. clonidine, insulin-induced hypoglycaemia or arginine infusion despite the expected rise in GH levels. After oral glucose, GH was initially suppressed with a late rise. There were no changes in GHRH 1-44 or 1-40 levels during either phase of this response. After l -dopa GH levels peaked at 90 minutes, 24.5 ± 11.0 mU/l (mean ± SEM). At 0 minutes GHRH 1-44 and 1-40 levels were 3.25 ± 0.89 and 4.93 ± 1.28 pmol/l respectively and rose in both cases, peaking at 60 minutes at 4.23 ± 1.01 and 7.55 ± 1.80 pmol/l (P < 0.05). At no time was there any evidence of differential secretion of GHRH 1-44 or 1-40. CONCLUSIONS We have confirmed previous studies demonstrating a small rise in GHRH before the GH response to l -dopa. However, in all other situations of pharmacological stimulation of GH release we were unable to detect any significant changes in GHRH 1-44 or 1-40 levels. It seems most likely that peripheral GHRH does not reflect hypothalamic secretion. As yet there is no evidence for differential release of GHRH 1-44 and 1-40.     

Reduction of plasma insulin levels does not restore integrated concentration of growth hormone to normal in obese children.

Obesity in childhood is characterized by subnormal integrated concentrations of growth hormone (IC-GH) and elevated integrated concentrations of insulin (IC-I). We tested whether a reduction of IC-I induced by a low calorie diet would lead to a rise of IC-GH into the normal range for age. Six obese children (body mass index (BMI) 39.1 +/- 9.2 kg/m2) underwent integrated concentration (IC) studies by continuous withdrawal before and again 5-8 weeks after being on a low calorie diet. In response to the diet BMI was lower 34.7 +/- 9.4 kg/m2 (P less than 0.003), and IC-I was considerably reduced, 479 +/- 255 pM initially vs. 109 +/- 109 pM on the diet, P less than 0.0008. IC-GH increased modestly from 1.6 +/- 0.6 micrograms/l initially to 2.4 +/- 0.6 micrograms/l, P less than 0.01 on the diet. None of the patients had repeat IC-GH levels which were above the lower limit of normal for lean children of normal stature (3.2 micrograms/l). Single sample insulin-like growth factor 1 (IGF-1) levels were unchanged: 40.9 +/- 23.1 nM initially vs. 49.7 +/- 25.7 nM (314.6 +/- 197.7 vs. 382.5 +/- 217.0 ng/ml, n.s.). Thus reduction of high insulin concentrations during 5-8 weeks of a low calorie diet has only a small effect on IC-GH in obese children. Factors other than circulating insulin levels are likely to play the major role in mediating the reduced levels of GH observed in obesity.     

Theophylline blunts the GH-response to growth hormone releasing hormone in normal subjects

Theophylline enhances GH-secretion in vitro, whereas in vivo a slight decrease of basal GH-levels has been observed. In the present study the effect of theophylline on the GH-responsiveness to acute and continuous administration of growth hormone releasing hormone (GHRH) was investigated. The following protocol was performed. GHRH study. Fifty micrograms GHRH was given as an iv bolus followed by constant GHRH-infusion (100 micrograms/h) over 2 h after which another GHRH bolus of 50 micrograms was given. GHRH plus theophylline study. GHRH was administered as in the first study and theophylline was infused at a constant rate of 3.56 mg/min over 3 h, starting one h before the GHRH bolus. Theophylline study. Only saline and theophylline were infused. GHRH alone led to a GH-rise within 30 min with a maximum of 22.8 +/- 7.2 ng/ml (mean +/- SE) after which GH-levels decreased despite continuous GHRH-infusion to a nadir of 12.1 +/- 4.4 ng/ml at 105 min. The second GHRH bolus led to a minimal GH-increase (13.3 +/- 6.4 ng/ml at 135 min). Theophylline administration resulted in blunting of the GH-response to GHRH in all volunteers, with GH levels fluctuating between 4-6 ng/ml throughout GHRH-administration. Theophylline alone did not affect GH-levels in three subjects studied, whereas in the other one a GH secretory episode 90 min after administration of the drug was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Growth hormone treatment in short children: relationship between growth and serum insulin-like growth factor I and II levels

Thirty-one children who were short but not GH deficient, whose serum GH responses to provocative tests were normal, and whose spontaneous GH secretion was low received daily sc injections of human GH (Crescormon; 0.1 IU/kg BW) for 1 yr. Their initial serum insulin-like growth factor I (IGF-I) and IGF-II responses to GH were compared with their 1-yr growth response to therapy. In the prepubertal group (n = 18) the growth rate of all but two children increased 3.4 +/- 0.2 (+/- SEM) cm (from 4.1 +/- 0.2 to 7.5 +/- 0.3 cm/yr). The mean increment in the growth rate of the pubertal group was 5.2 +/- 0.5 cm. In both groups the growth increase was strongly correlated with both the percent increase in serum IGF-I and the percent increase in serum IGF-II during the first 10 days of treatment. No correlation was found between the basal growth rate and basal serum IGF-I or IGF-II levels. In the prepubertal group of children, both the percent increase in serum IGF-I levels in response to GH and the age at start of treatment were predictors of long term growth. We conclude that this subgroup of normal short children with low spontaneous GH secretion and high percent increase in serum IGF values benefits from GH treatment with an increased growth rate.     

Growth hormone releasing factor induces prolactin secretion in acromegalic patients but not in normal subjects

The effect of an iv injection of growth hormone releasing factor (GRF) on Prl secretion in healthy volunteers and patients with active acromegaly was investigated. Thirteen normal subjects received 100 micrograms GRF 1-44, and 19 acromegalics received 100 micrograms GRF 1-44. Nine normals and 9 patients were given the diluent only and served as placebo control. In healthy volunteers GRF did not affect Prl secretion significantly when compared to placebo, whereas in acromegalics Prl levels after GRF were higher than after placebo. We have divided acromegalics in Prl-responders to GRF (n = 11) and Prl-non-responders (n = 8) using the criterion of strict parallelism between GH and Prl secretion after GRF. In cases with no GH response to GRF a clear increase of Prl levels with the maximum 15-30 min after GRF was also regarded as a Prl response. Acromegalic Prl-responders and Prl-non-responders did not significantly differ in age, sex, previous therapy, and basal GH and Prl levels. However, Prl-non-responders had a significantly reduced response of both GH and Prl to TRH (GH: 147.3 +/- 16.0 vs 590.1 +/- 127.8%; mean +/- SE; Prl: 159.4 +/- 32.6 vs 504.9 +/- 109.3%). It is concluded that 50 or 100 micrograms GRF does not affect Prl secretion in normal subjects. In contrast, in acromegaly GRF leads to Prl secretion in more than half of all patients.     

Recombinant human growth hormone therapy does not increase microalbuminuria in children with short stature

OBJECTIVE Concerns have been raised about possible adverse effects of growth hormone on renal function. We measured microalbuminuria as a sensitive index of early glomerular damage in children being treated with recombinant human growth hormone. DESIGN AND PATIENTS Microalbuminuria was measured in a group of 17 children with short stature being treated with recombinant human growth hormone and in a group of 13 patients with idiopathic short stature not receiving therapy. MEASUREMENTS Microalbuminuria was measured by a commercially available ELISA and urinary creatinines were determined using a Beckman creatinine analyser. RESULTS The level of microalbuminuria was 0 484 ± 0 275 g albumin/mol creatinine (mean ± SD) in the patients receiving growth hormone and 0 681 ±0 574 g albumin/mol creatinine in the untreated controls. There was no statistically significant difference between these values. CONCLUSIONS Treatment with recombinant human growth hormone does not cause an increase in microalbuminuria in children with normal renal function. This supports the safety of this medication in growth hormone deficient children with normal renal function.     

The corticotropin-releasing hormone test in normal short children: comparison of plasma adrenocorticotropin and cortisol responses to human corticotropin-releasing hormone and insulin-induced hypoglycemia

The human corticotropin-releasing hormone (hCRH) tests were performed in twelve normal short children, and the responses of plasma ACTH and cortisol to iv administration of 1 micrograms/kg hCRH were compared with those to insulin-induced hypoglycemia. After administration of hCRH, the mean plasma ACTH level rose from a basal value of 3.3 +/- 0.4 pmol/l (mean +/- SEM) to a peak value of 9.2 +/- 0.8 pmol/l at 30 min, and the mean plasma cortisol level rose from a basal value of 231 +/- 25 nmol/l to a peak value of 546 +/- 30 nmol/l at 30 min. The ACTH response after insulin-induced hypoglycemia was greater than that after hCRH administration; the mean peak level (P less than 0.01), the percent maximum increment (P less than 0.01), and the area under the ACTH response curve (P less than 0.01) were all significantly greater after insulin-induced hypoglycemia than those after hCRH administration. Although the mean peak cortisol level after insulin-induced hypoglycemia was about 1.3-fold higher than that after hCRH administration (P less than 0.01), neither the percent maximum increment in plasma cortisol nor the area under the cortisol response curve after insulin-induced hypoglycemia was significantly different from that after hCRH administration. Consequently, the acute increases in plasma ACTH after the administration of 1 microgram/kg hCRH stimulated the adrenal gland to almost the same cortisol response as that obtained with a much greater increase in plasma ACTH after insulin-induced hypoglycemia. These results suggest that a plasma ACTH peak of 9-11 pmol/l produces near maximum acute stimulation of adrenal steroidogenesis.     

Growth hormone release in response to human pancreatic tumor growth hormone-releasing hormone-40 in children with short stature

Forty children with short stature were evaluated for GH reserve after pharmacological tests and after a single iv injection of human pancreatic tumor GH-releasing hormone [hpGRH-40). These children were grouped into four diagnostic categories: 1) idiopathic GH deficiency (n = 10); 2) organic hypopituitarism (n = 7); 3) intrauterine growth retardation (n = 5); and 4) constitutional delay of growth and/or familial short stature (n = 18), by standard clinical criteria and physiological and pharmacological tests of GH reserve. Venous blood was sampled for GH concentrations on 2 consecutive days: on day 1, after the iv administration of L-arginine (0.5 g/kg for 30 min) and oral administration of L-dopa (9 mg/kg), and on day 2, after the administration of hpGRH-40, 3.3 micrograms/kg, as an iv bolus. No GH-deficient patient in categories 1 or 2 increased his/her circulating GH concentration to more than 7 ng/ml after the arginine-L-dopa test; however, six children had marked GH responses after hpGRH-40 administration. As a group the lowest peak responses (mean +/- SE) to GRH were found in the organic hypopituitary (3.4 +/- 1.1 ng/ml) and in the idiopathic GH deficiency (8.2 +/- 2.4 ng/ml) categories. All children in the intrauterine growth retardation and constitutional delay of growth (controls for the GH-deficient children) responded briskly to hpGRH-40, although there was wide variation of the peak GH levels (5-51 ng/ml). Circulating concentrations of somatomedin-C did not differ in subjects in any category 24 h after hpGRH-40 injection when compared to basal values. These data indicate that hpGRH-40 can be employed to evaluate GH reseve in short children and may be useful in the diagnosis of hypothalamic-pituitary disorders.     

Hypothalamic luteinizing hormone releasing factor and corticotrophin releasing activity in relation to pituitary and plasma hormone levels in male and female rats.

Hypothalamic corticotrophin releasing (CR) activity and LH-releasing factor (RF) content, and pituitary and plasma LH, FSH and ACTH were measured in adult male and female Wistar rats maintained under 14 h light per day. Hypothalamic LH-RF and pituitary and plasma hormones were estimated by radioimmunoassay while CR-activity was assessed by the amount of ACTH released from hemipituitaries in vitro. Two experiments were carried out on male animals. In the first, some of the animals were kept in a room, distant from the animal house, in which the lighting was reversed with respect to the external environment. In animals exposed to the reversed lighting regime, hypothalamic LH-RF content and pituitary gonadotrophin concentrations were significantly lower than the values in male rats kept in the animal house where they were in close proximity to female rats. In the second experiment, which was carried out on animals which had all been kept in the animal house, there was no significant differences between the LH-RF contents measured at 3-4 h intervals throughout the day. Pituitary LH and FSH contents, but not concentrations, were significantly increased at 12.00 h. There was little differences between the experiments in CR-activity, plasma ACTH concentrations and profiles of pituitary ACTH content and concentration. As expected there was a diurnal rhythm in plasma corticosterone concentrations (determined by competitive protein-binding assay) with the peak occurring between 15.00 and 18.00 h. The profiles of plasma and pituitary ACTH were similar to that of plasma corticosterone. Corticotrophin releasing activity dropped significantly between 12.00 and 16.00 h, but remained steady at the other times. In female rats there were no significant differences between hypothalamic LH-RF content throughout the 4-day cycle. During pro-oestrus the mean LH-RF content rose to teach a high level at 18.00 h at which time plasma LH concentration had risen sharply to a level consistent with the peak of the preovulatory surge. Plasma FSH concentration also rose significantly between 15.00 and 18.00 h of pro-oestrus. At metoestrus and dioestrus, plasma FSH levels were lower in the morning than in the evening. These results suggest that (1) there is no diurnal rhythm in hypothalamic LH-RF, (2) there may be a diurnal rhythm in pituitary gonadotrophin content in the male and in plasma FSH concentration on the days of metoestrus and dioestrus in the female, (3) if a surge of LH-RF does occur on the afternoon of pro-oestrus, the rate of LH-RF synthesis exceeds its release, and (4) the mechanism which regulates gonadotrophin secretion in the male may be affected by factors in the environment other than daylength. The results provide further evidence for the view that the diurnal rhythm of corticosterone secretion is under hypothalamo-hypophysial control.