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ABSTRACT

This study was carried out in order to determine whether children with a transitory type of growth hormone deficiency showed an accelerated growth in height velocity on treatment with human growth hormone (HGH).

Following careful diagnostic routine procedures 13 extremely short children were diagnosed as having isolated growth hormone deficiency, and were successfully treated with HGH. A true isolated growth hormone deficiency was present in 5 of the children, whereas 8 showed a normal increase in serum growth hormone on repeated growth hormone stimulation tests after their development of puberty and termination of HGH treatment. Three boys with bone ages of 5.5, 8.0 and 9.5 years showed an undisputable effect following HGH administration. They showed an initial growth at the start of treatment, and a second growth spurt during development of puberty. Two of the boys reached final statures of 14 cm taller than the predicted heights. The other patients, including the children with true isolated growth hormone deficiency showed an initial spurt of growth at the start of the HGH treatment immediately followed by a pubertal growth spurt. The mean acceleration of height velocity for the children with true isolated growth hormone deficiency was from 3.4 cm during the year before treatment to 7.0 cm during the first year on treatment, as compared to 2.8 and 7.4 cm, respectively, for the children with transitory growth hormone deficiency. A girl with severe anorexia nervosa who had a transitory growth hormone deficiency, showed an accelerated high velocity from 1.1 cm to 7.6 cm during the first year following treatment with HGH.

The question whether HGH treatment should be made available to all short children with no known syndrome, and presenting a height less than −3.5 sds, a bone age/chronological age ratio of less than ⅔, and a height velocity less than −2 sds is discussed. The only way to know if a child will respond to HGH treatment is to give it for a trial period of at least six months. At least a physiological stimulus to growth hormone secretion should be decisive in the selection of growth retarded children for HGH treatment. Different mechanisms seem to be responsible for physiological growth hormone secretion to sleep or exercise, and the secretion obtained with pharmacological stimuli.

ABSTRACT

An inhomogeneous human pituitary lipid-mobilizing factor (LMF) different from somatotrophin and adrenocorticotrophin has previously been prepared. The extraction of LMF deprived fat-mobilizing effect of the simultaneously prepared growth hormone. Subcutaneous injection of LMF in rabbits caused hypocalcaemia and hyperglycaemia in addition to the adipokinesis.

The preparation procedure which resulted in a homogeneous LMF is reported. When examined for purity by electrophoresis in polyacrylamide gel the material migrated as a single band. The LMF is probably a polypeptide with a molecular weight in the range of 2100 determined by ultracentrifugation. It is a potent adipotrophin in rabbits, and a concentration of 0.001 μg/1.1 ml gave a significant release of nonesterified fatty acids (NEFA) from human subcutaneous fat pads also. No in vitro lipolysis occurred in normal albino mouse or rat fat, whereas concentrations of 0.01–0.1 μg/1.1 ml had lipolytic effect on fat pads from obese yellow mice and from hypophysectomized rats. In addition to the increase of serum NEFA in rabbits, the purified LMF gave a prolonged hyperglycaemia which persisted for nine days following a single subcutaneous injection of 0.5 mg, but it had no influence on the serum calcium level.

Evidence is presented suggesting that the lipolytic mechanism for LMF resembles more closely that of adrenocorticotrophin than of somatotrophin. The LMF may be of physiological importance and is perhaps related to a human pituitary diabetogenic adipotrophin. A possible mechanism for the acute and prolonged hyperglycaemia in rabbits is discussed.

ABSTRACT

Lipid-mobilizing effect has been observed for nearly all the accepted pituitary hormones and for several suggested pituitary 'lipotrophins'. Pituitary hormone preparations are usually not homogeneous, and even a highly purified ACTH (p.ACTH) contains less than 30 per cent pure adrenocorticotrophin.

Crude ACTH (c.ACTH) was found to be 250 times more adipokinetic in rabbits than p.ACTH, indicating that this effect was mainly due to impurities.

A lipid-mobilizing fraction (LMFr) was precipitated from a human pituitary gland extract before the preparation of growth hormone and crude gonadotrophins, whereby the adipokinetic effect of these preparations in the rabbit became negligible. Removal of LMFr gave an electrophoretically purified growth hormone with reduced molecular weight and an increased somatotrophic potency per unit weight in a radioimmunoassay system.

Injection of the lipotrophic preparations into rabbits lowered the serum calcium level, and concentrations below 3 meq./l were observed, often accompanied by convulsions and in some instances by death.

It is concluded that the adipokinetic and hypocalcaemic effects of c.ACTH, p.ACTH and the employed human growth hormone preparations in rabbits may be due to contaminations. It is suggested that the LMFr contains a human pituitary lipotrophic factor which may also be responsible for the hypocalcaemia observed in the rabbit.

ABSTRACT

Clinical observations and endocrinological research have provided evidence of the existence of a specific pituitary regulation of triglycerideolysis in depot fat.

A lipid-mobilizing fraction was prepared from deep-frozen human pituitary glands by slightly alkaline extraction followed by acetone precipitation at a pH below the isoelectric point for growth hormone. This crude fraction was purified by Sephadex gel filtration and DEAE-cellulose chromatography. Preparation of this lipid-mobilizing fraction failed when acetone-dried pituitary glands were used.

The obtained lipid-mobilizing factor (LMF) had two bands on polyacrylamide gel disc electrophoresis, and the molecular weight was determined to be in the range of 5000. There was loss of lipolytic activity when partly purified LMF was incubated in physiological saline at 37° C.

No somatotrophic or thyrotrophic activity was observed in LMF and only traces of prolactin, ACTH- and MSH-like activities. The LMF was lipolytic both in vivo and in vitro on rabbit and human adipose tissue. The effect on mouse and rat was questionable. In rabbits LMF also caused ketonaemia, hyperlipaemia, increased liver fat, decrease of liver glycogen, prolonged hyperglycaemia and decrease of serum calcium and inorganic phosphorus. High doses of LMF induced a hypermetabolic state in the rabbit with marked hypocalcaemia usually accompanied by convulsions and death.

It is concluded that the prepared LMF is probably an aggregation of a lipotrophic and a rabbit serum-calcium-lowering factor. The lipotrophic factor may be a specific pituitary 'adipotrophin' or a denaturation product from a previously accepted pituitary hormone. A possible relationship between LMF and a diabetogenic-adipokinetic core of growth hormone is discussed.

Abstract

In 1980-1985 680 preadolescent tall girls were treated with pharmacological doses of oestrogen to reduce final height. Indications for the therapy were predicted final height >+2.5 SD (180.75 cm), idiopathic scoliosis, and psychosocial problems. Until 1976 141 girls were given diethyl stilboestrol 5 mg daily. By advice of Prader this was then replaced by ethinyl oestradiol and a progestin was given on days 5-10 each month. The mean duration of therapy was close to 2 years. The observed short-term unwanted effects were due to the pharmacological actions of the drugs, (11 girls had galactorrhoea at the end of therapy; no pituitary prolactionoma was observed) or events happening by chance.

ABSTRACT

Lipoatrophic diabetes has been produced in rabbits by injection of a fraction prepared from the urine from patients with congenital generalized lipodystrophy. Both these conditions are considered to be hypothalamic syndromes. The animals, and a patient with congenital generalized lipodystrophy and latent diabetes were treated with the dopamine receptor blocker, pimozide, for 4 and 17 months, respectively. The results were discouraging even though the patient got a daily dose of 16 mg pimozide. Fenfluramine has a lowering effect on brain serotonin, and peripheral effects on glucose and triglyceride metabolism. This drug improved the general condition of the rabbits with lipoatrophic diabetes, as well as that of the patient with congenital generalized lipodystrophy. The rabbits became normoglycaemic and insulin sensitive. In the patient a normalization of the urinary excretion of the serotonin metabolite 5-OH-indole acetic acid was observed.

His voracious hunger and profuse perspiration were reduced, the hyperkeratotic layer of the skin peeled off, and the pigmentations of the skin decreased. There was observed an improvement of ALAT and ASAT, normalization of the fasting blood glucose, and increased sensitivity to exogenous insulin. After 11 months of 200 mg fenfluramine daily addtitional administration of 2 g clofibrate per day produced normalization of the serum triglyceride concentration and a marked reduction of the resistance to insulin. Three more patients with congenital generalized lipodystrophy, two of whom have manifest diabetes, have now started treatment with fenfluramine and are improving. The rabbits got relapse of their lipoatrophic diabetes when the fenfluramine treatment was stopped. It is suggested that a disturbance in the serotonin metabolism of the central nervous system may be of pathogenetic importance in congenital generalized lipodystrophy.

ABSTRACT

Urine from 5 patients with congenital generalized lipodystrophy has been fractionated by protein precipitation and Sephadex gel filtration. A fraction with a molecular weight in the range of 1000 was observed to be metabolically active in mice, rats, and rabbits. Hypophysectomized rats got hypoglycaemia following an injection, and the lipolytic-hyperglycaemic effect of ACTH was reduced after injection into intact mice. This effect was probably due to insulin release, because no insulin-like activity was observed on isolated fat cells in vitro. Persistant changes were observed in the animals after 3 weeks of daily injections of the urinary fraction. Adult mice and rabbits developed lipoatrophy with decrease of body weight in spite of a doubling of the food consumption. The metabolic rate and the body temperature were raised. Infantile animals developed a lipodystrophic state with increased growth velocity, and 50 per cent increase of the body weight, although no fat depots were observed. The treated animals got hyperglycaemia, hypertriglyceridaemia, hyperinsulinaemia, and insulin resistance. The rabbits developed manifest diabetes. The corresponding fraction prepared from the urine from the lipoatrophic rabbits produced lipoatrophy after injection into the mice. It is suggested that the lipodystrophic urinary fraction is of hypothalamic origin, and that it acts through the pituitary gland. The fraction is still heterogenous, and was observed to contain thyrotrophin releasing activity.

ABSTRACT

A lipid mobilizing factor (LMF) with an adipotrophic effect in man and animal adipose tissue has been prepared from human pituitary glands. In vitro studies have demonstrated that the lipolytic effect was dependent on the albumin used in the incubation medium. Two of the six albumins studied depressed the release of non-esterified fatty acids from human fat pads. Polyacrylamide gel disc-electrophoresis demonstrated the presence of contaminations in purchased serum albumins. They were eliminated by DEAE-cellulose chromatography, which gave one fraction that inhibited the adipokinetic effect of LMF, and a more homogeneous albumin fraction. In vitro lipolysis in rabbit as well as in human fat pads occurred more readily in the media containing purified serum albumin than in media with purchased serum albumin. It was concluded that in vitro lipolysis gives comparable results when studied in media containing the same batch of serum albumin only. Furthermore an agent should not be claimed to be non-lipolytic until it has been assayed in several, preferably homogeneous serum albumin media.

ABSTRACT

A lipid-mobilizing factor (LMF) with an adipotrophic effect in human and animal fat tissue has been prepared from human pituitary glands. The addition of normal human serum to LMF reduced its lipolytic effect, and it was completely abolished by serum from a group of obese patients, whereas the lipolysis was not influenced by serum from patients with generalized lipodystrophy.

By DEAE-cellulose chromatography of human serum the inhibitory effect on LMF was found to be present in a protein fraction less acidic than the main serum albumin fraction. The inhibitory fraction was deprived of some contaminants by Sephadex gel filtration. Disc electrophoresis demonstrated the presence of three components in the inhibitory protein (IP), and they were identified as albumin, transferin, and haemopexin by immuno-electrophoresis. Precipitation of these proteins by their rabbit antisera demonstrated that the inhibitory effect was present in the albumin fraction. Insulin like activity was not observed in IP. A protein binding of LMF by IP could not be demonstrated. Incubation at 37^°C for one hour of a mixture of LMF and IP eliminated the electrophoretic picture of LMF. It is concluded that the inhibitory effect of human serum may be due to proteolysis of LMF.