Therapy in short children with subnormal integrated concentrations of growth hormone.

We evaluated the effect of growth hormone (GH) therapy on the posttreatment growth of 11 poorly growing children who had normal GH response to provocative stimuli but subnormal integrated concentrations of GH. Patients received 0.1 U/kg of GH three times per week. Their mean (+/- SD) growth rate increased from 3.3 +/- 1.0 cm/y before treatment to 6.5 +/- 1.4 cm/y after eight months of treatment. The growth rates of five patients declined to below 4.5 cm/y four months after treatment. Three of these patients resumed GH therapy and again responded with increased growth velocity (8.0 +/- 1.2 cm/y). After therapy, the growth rate of five remaining patients continued to be greater than 4.5 cm/y (6.8 +/- 1.4 cm/y). Two of these patients had entered puberty and their posttreatment growth rate might have been due to a pubertal growth spurt. The three prepubertal patients in this group had a gradual decline in growth velocity to 3.8 +/- 1.0 cm/y by the end of 12 posttreatment months. We conclude that maintenance of normal growth in patients with this pattern of GH deficiency is dependent on GH replacement therapy.

Pharmacokinetic studies of highly purified human prolactin in normal human subjects.

Previous estimates of PRL pharmacokinetics have been made using radioiodinated human PRL (hPRL) infusions or by measuring serum PRL disappearance following prolactinoma resection. The recent purification of hPRL in significant quantities made it possible to measure the clearance and volume of distribution directly. Studies were also carried out to determine absorption and clearance after im injection. In five normal men whose endogenous PRL secretion was suppressed by dopamine, a loading dose of hPRL (70-90 micrograms) followed by a constant infusion (1.39-2.9 ng/min) produced steady state serum PRL levels of 15.2-25.4 ng/mL by 30-60 min. The calculated mean volume of distribution was 7.3 +/- 2.9 (+/- SD) L. The calculated MCR was 71 +/- 19 mL/min X m2, and the calculated production rate was 802 +/- 377 micrograms/24 h X m2. The plasma disappearance half-life following discontinuation of the infusion was 37 +/- 10 min. The PRL infusate consisted primarily (75.6%) of a 22.5 K dalton species, probably PRL monomer, a component eluting at 45K daltons (16.1% of the total radioimmunoreactivity), probably dimer, and a small amount of a larger mol wt species. Serum obtained during dopamine infusion but before hPRL infusion contained 68.1% of the 22.5K, 7.2% of the 45K, and 24.7% of the larger mol wt moieties. During hPRL infusion in two men there was a relative decrease in the proportion of PRL monomer to 55% and 69% and a relative increase in the PRL dimer to 33% and 18%, respectively. hPRL was injected im in doses of 1, 2, 4, and 8 micrograms/kg without prior dopamine infusion. No significant changes in serum PRL levels occurred after the 1 and 2 micrograms/kg doses (n = 5). After the 4 micrograms/kg dose (n = 8), mean serum PRL levels rose from 10.0 +/- 1.8 (+/- SEM) ng/mL to peak levels of 13.1 +/- 1.8 ng/mL (P less than 0.01). After the 8 micrograms/kg dose (n = 7), PRL levels rose from 9.3 +/- 1.6 to 16.5 +/- 1.8 ng/mL (P less than 0.01). The PRL rise began between 60 and 80 min after injection; peak levels occurred at 160-180 min. In two men given 8 micrograms/kg who were sampled for an additional 3 h, PRL levels peaked at 200-220 min and began to fall by 220-240 min, but had not returned to baseline by 6 h. There were no side-effects of PRL administration, although the 8 micrograms/kg dose caused transient local discomfort.(ABSTRACT TRUNCATED AT 400 WORDS)

Short-term treatment of short stature and subnormal growth rate with human growth hormone.

Forty-eight children with short stature, growth rate less than 4 cm/yr, and normal growth hormone response to secretagogues were given exogenous human growth hormone (hGH) for 6 months to determine its effect on the short-term growth rate in these children. All except three had an increase in growth rate with hGH therapy. The mean +/- SD pretreatment growth rate (3.4 +/- 0.8 cm/yr) was significantly less than either the growth rate during 6 months of hGH therapy (6.9 +/- 2.6 cm/yr) or after therapy (4.1 +/- 1.8 cm/yr). Several patterns of response were observed after treatment was stopped: the mean growth rate in 22 children decreased after treatment but remained above basal rates, the mean growth rate in seven children was similar to the rates during treatment, and the mean growth rate in 16 children was less than basal rates. Twenty children received therapy for an additional 6 months and had a mean increase in growth rate from 3.6 +/- 1.3 to 6.7 +/- 2.4 cm/yr. The decreased growth rate after discontinuation of treatment and increased rate with resumption of therapy indicates that maintenance of the increased growth rate might be dependent on continuation of hGH therapy.

Comparison of dose frequency of human growth hormone in treatment of organic and idiopathic hypopituitarism.

Two weekly (biw) injections of pituitary human growth hormone (hGH) were compared with three weekly (tiw) injections of hGH (0.24 IU hGH/kg body weight/wk for both groups) for effect on growth rate in children with idiopathic and organic hypopituitarism. Both dosage schedules resulted in increased growth rate during the first 12 months of therapy; the tiw dosage was more effective in the first 6 months in patients with organic hypopituitarism, and in the second 6 months in patients with idiopathic hypopituitarism. There was no advantage to tiw therapy during the second year of therapy in either group. The additional increment in height after 1 year of therapy using tiw compared with biw therapy was 2 cm and 1 cm for the patients with organic and idiopathic hypopituitarism, respectively. This increment should be weighed against the cost, pain, and inconvenience of tiw versus biw doses of hGH in the treatment of hGH deficiency. With the dosages used in this study, tiw therapy was more effective during the first year, when patients are more responsive, and should be recommended. Twice weekly therapy could be considered for the second and possibly subsequent years of therapy. Other schedules of treatment may be more effective than either of these schedules.

Growth-stimulating effects of human growth hormone therapy in patients with Turner syndrome.

We determined the effect of pituitary human growth hormone treatment on the growth rate of 52 children with Turner syndrome. The pretreatment growth rate was 3.2 +/- 0.8 cm/yr. Growth hormone treatment (0.2 IU/kg three times per week) resulted in enhancement of the growth rate to 5.9 +/- 1.4 cm/yr for the first year of therapy. The bone age advanced approximately 1 year during the year of therapy. The growth hormone therapy was discontinued at 12 months, and the mean growth rate decreased to pretreatment levels, 3.1 +/- 1.9 cm/yr; 26 of 41 patients actually had post-treatment growth rates that were less than the pretreatment rate. Glucose tolerance tests at 6-month intervals did not indicate an effect of hGH treatment on glucose intolerance. Several patients had glucose intolerance that preceded hGH treatment, but this remained stable during treatment; glucose intolerance likely was related to obesity in this group of patients. Basal and hGH-stimulated somatomedin C levels (32 patients) correlated with age of the patient but not with growth rate during therapy. We conclude that hGH therapy can accelerate the growth rate of patients with Turner syndrome. The growth rate increased to "normal" levels and was dependent on continued treatment with hGH. If the response continues, long-term treatment of Turner syndrome may result in increased adult height.

Do short children secrete insufficient growth hormone?

The 24-hour integrated concentration of growth hormone from 46 children of normal stature was compared with that of 90 short children. Nineteen of the short children had classic growth hormone deficiency by standard pharmacologic growth hormone stimulation tests. Seventy-one children had normal growth hormone responses to stimulation. The mean integrated concentration of growth hormone for children with normal stature (6.6 +/- 1.9 ng/mL) was greater than the mean value for those with normal stimulated growth hormone (3.8 +/- 2.3 ng/mL) and greater than the mean value for those with growth hormone deficiency (1.6 +/- 0.6 ng/mL); differences between groups were all statistically significant (P less than .0001). Forty-five percent of children with normal stimulated growth hormone responses had integrated concentration of growth hormone within the range of values for the group with growth hormone deficiency; this finding may provide the explanation for their poor growth. Thus, patients with normal growth hormone responses have a spectrum of spontaneous growth hormone secretion ranging from normal to impaired. Recent reports indicate that children with normal growth hormone responses who have very low integrated concentration of growth hormone may have the potential to improve their growth with growth hormone therapy. Therefore, use of the integrated concentration of growth hormone may be a more effective method than standard pharmacologic stimulation tests for determining which short children are potentially able to respond to growth hormone therapy.

Collecting pituitaries: why the program continues to need your help.

The human pituitary collection program provides hormone for thousands of hypopituitary dwarfs each year. Though the past two decades have been years of great progress, the need for your dedication and assistance in years to come is more acute than ever.

Convergence of two types of familial short stature in a pedigree.

This study reports an unusual family with coexistence of isolated growth hormone deficiency transmitted as an autosomal dominant trait (Rimoin Type II) and constitutional short stature.

Precocious and delayed puberty. Studies of FSH and LH production and metabolism.

We measured the production rates and metabolic clearance, disappearance and excretion rates of FSH and LH as well as plasma testosterone and delta 4-androstenedione in males with precocious and delayed puberty. In precocious puberty, we found modestly elevated FSH production early in puberty, reaching adult levels by midpuberty and remaining constant thereafter. LH production was low early in puberty, reached high levels at midpuberty and then fell. The plasma testosterone concentrations paralleled the changes in LH. This suggests that moderate FSH production is achieved by early puberty and adult levels are reached by midpuberty. On the other hand LH production is low early in puberty, reaches high levels by midpuberty and then falls again towards the end of puberty. Constitutional delay in sexual development probably consists of several syndromes due either to a delay in LH production or to FSH production or to both. One patient with hypogonadotrophic hypogonadism was also studied. He showed relatively normal LH production but very low FSH production.

Endocrine causes of short stature.

The primary clinical characteristic of shortness of stature due to endocrine deficiency is a slow rate of growth (less than 1.5 in., or 4 cm, each year). Dental and skeletal ages are delayed. Specific tests of thyroid and pituitary function must be done to document the deficiency. Replacement therapy with levothyroxine or human growth hormone, or both, should be given as indicated. Short children who do not have hormone deficiency grow about 1.5 in. (4 cm) each year but have normal skeletal and dental ages. Children with Turner syndrome, primordial or genetic short stature, or intrauterine growth retardation do not respond to levothyroxine or human growth hormone replacement therapy. Constitutional delay in sexual development is a common cause of short stature in adolescent males and must be differentiated from hypopituitarism.

Abnormalities in growth hormone and insulin release in short but otherwise normal patients. The arginine-insulin-glucose (AIGT) stimulation and suppression test.

Arginine-insulin stimulation and IV glucose suppression (AIGT) tests were used to evaluate release of insulin and growth hormone. Adult patients responded normally. Hypopituitary patients showed no hGH response. One third of short normal patients showed abnormal hGH responses to glucose suppression. Two thirds of the short normal patients showed poor insulin responses to either amino acid or glucose stimulation. Such patients might have abnormalities in release mechanisms for insulin and suppression mechanisms for hGH and this might contribute to their growth failure.

Empty sella syndrome secondary to intrasellar cyst in adolescence.

A 15-year-old boy had growth failure and failure of sexual development. The probable onset was at age 10. Endocrine studies showed hypopituitarism with deficiency of growth hormone and follicle-stimulating hormone, an abnormal response to metyrapone, and deficiency of thyroid function. Luteinizing hormone level was in the low-normal range. Posterior pituitary function was normal. Roentgenogram showed a large sella with some destruction of the posterior clinoids. Transsphenoidal exploration was carried out. The sella was empty except for a whitish membrane; no pituitary tissue was seen. The sella was packed with muscle. Recovery was uneventful, and the patient was given replacement therapy. On histologic examination,the cyst wall showed low pseudostratified cuboidal epithelium and occasional squamous metaplasia. Hemosiderin-filled phagocytes and acinar structures were also seen. The diagnosis was probable rupture of an intrasellar epithelial cyst, leading to empty sella syndrome.