Salvatore Raiti

A COMPARISON OF THE EFFECTS OF INSULIN HYPOGLYCÆMIA AND ARGININE INFUSION ON RELEASE OF HUMAN GROWTH HORMONE

Abstract 31 pairs of insulin-tolerance (I.T.T.) and arginine-tolerance tests were performed in twenty-six patients (nineteen males and seven females) who responded with significant H.G.H. levels to one or both stimuli. In twenty-two cases there was a normal H.G.H. response to both stimuli. There was no response to the I.T.T. in four cases and to the A.T.T. in five separate cases. A diagnosis of growth-hormone deficiency cannot be made if there is failure to respond to one test, unless the other test has also been applied.

Degenerative neurologic disease in patients formerly treated with human growth hormone

One or more lots of pituitary GH supplied by the NHPP may have been contaminated with CJD pathogen. If so, it is probable that the contaminated hormone was dispensed before 1978, and there is reason to believe that it was dispensed in the late 1960s. The contamination may have been limited to one lot of GH, but this is not known with certainty. Purification methods used by the NHPP since 1978 probably exclude the CJD pathogen, but this is not yet certain. The risk to patients treated since 1978, therefore, probably is low. There is no evidence to date that GH from either of the pharmaceutical suppliers has been or is contaminated. Purification procedures used by these sources also should exclude the pathogen. To exclude the possibility that they are contaminated with the CJD pathogen, 1 1/2 to 3 years will be required to test batches of the pituitary GH used previously. The experiment needed to show that the purification method used by NHPP excludes the scrapie agent will take up to 1 year. Planning for epidemiologic studies in patients treated with pituitary GH is under way. Biosynthetic GH prepared by recombinant DNA techniques has been in clinical trial in the United States for 3 1/2 years. It has been shown to be as effective as pituitary GH in promoting growth. However, it produces a higher incidence of GH antibodies than pituitary GH preparations do. Pediatric endocrinologists support the FDA in its effort to gather the information needed to approve biosynthetic GH for treatment of GH deficiency at an early date.

22 GROWTH IMPAIRMENT ASSOCIATED WITH HYPERCORTISOLISM: RESPONSE TO GROWTH HORMONE THERAPY

Hypercortisolism decreases responsiveness to GH, leading to impairment of growth. The 24-h integrated concentration of cortisol (IC-F) proved to be an accurate diagnostic procedure for hypercortisolism. In children aged 7-18 yr (n=26) of normal stature, the IC-F, mean ±1SD, was 5.9±1.6 μg/dl. In Cushings disease, the IC-F was 20.2±4.7 μg/dl (n=13)(JCEM 54:1072, 1982).We have identified 5 children (ages 10-14 yr) who presented with short stature (less than 5% for age), slow growth (less than 4.5 cm/yr) and bone age delay (greater than 2 SD for age). All were euthyroid and their stimulated GH and 24-h IC-GH were normal. None of the patients were obese, had striae, or other classical physical findings of Cushings syndrome. However, their IC-F ranged from 13.2-17.2 μg/dl, clearly in the range of patients with Cushings syndrome. Two of the children were treated for 8 months with GH (0.2 U/kg three times per week) and had increased growth rate of 10.6 and 8 cm/yr respectively. A third child who was treated with less GH (0.1 U/kg three times per week) increased her growth rate from 4.5 to 5.7 cm/yr.Conclusion: 1/Poor growth associated with hypercortisolism may occur in children who do not look Cushingoid. 2/Such children are responsive to GH therapy.

Excessive Follicle-stimulating Hormone Excretion and Production in Males with Untreated Congenital Adrenal Hyperplasia

Summary: The 24-hr urinary excretions of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured in seven males with untreated congenital adrenal hyperplasia. The patients aged 1–10 years had urinary FSH concentrations of 4.1–6.7 IU/day (normal = less than 2.5 IU/day). Elevated levels of 13.6 IU/day were found in the 81-year-old patient. During suppressive steroid therapy, the FSH excretion fell to the normal range in the one so studied; therapy was reduced in two patients and their FSH excretion rose by 20–30% in a 4-month period. The FSH production rate was 41.5 and 40.2 IU/day in the 1-and 6-year-old patients before therapy (these levels being at the upper limit of the normal range for adults). After 2.5 years of the FSH production rate in one of them fell to 10.3 IU/day.The excretion of LH was elevated for age and was 5.9 and 11.8 IU/day in the 1− and 6-year-old untreated patients (normal therapy, range = less than 3 IU/day). After suppressive therapy for 2.5 years, the LH excretion in the 1-year old fell only to 4.7 IU/day. In two patients, therapy was reduced for 4 months and the LH excretion actually fell from 5.1 to 2.9 and 10.0 to 7.4 IU/day. Similarly, the 81-year-old untreated adult male showed an LH excretion of 16.4 IU/day, which is lower than the normal adult range of 22.3–45.1 IU/day. The LH production rates in the 1− and 6-year-old patients before therapy were 166 and 141 IU/day, respectively both being lower than the range of 247.7–464.5 IU/day found in normal adult males.Speculation: The increased FSH production and excretion could be due to hypothalamic-pituitary stimulation by increased production of androgens or their precursors or from increased estrogens from the adrenal glands, or even to abnormal metabolites such as 17-hydroxyprogesterone.

RESPONSE TO THERAPY IN CHILDREN WITH LOW INTEGRATED CONCENTRATION OF GROWTH HORMONE

We have previously demonstrated that the response of GH to pharmacologic stimulation does not always correspond to the actual integrated concentration of GH (ICGH)(JCEM 48:811, 1979). Spiliotis et al have reported that 3 of 7 children who had a normal response to GH provocative tests but a reduced amplitude or frequency of GH pulses, responded to GH therapy (Abstract 528 Endocr. Soc. 1983).We measured ICGH in 15 growth hormone deficient (GHD) children and in 94 children with growth impairment who exhibited a normal response to GH provocative tests (GHNR). The ICGH of the 15 GHD children ranged from 0.2 to 2.6 ng/ml. In 75 of the 94 GHNR children, the ICGH was above 2.6 ng/ml.The ICGH of the 19 remaining GHNR children was below 2.6 ng/ml. To date, 6 of these 19 children have been treated with GH for more than 5 months. All 6 responded to GH therapy (2 more than doubled their growth rate, the remaining 4 increased their growth rate by more than 2 cm/yr).Conclusion: growth impaired patients with low ICGH should be treated with GH even if they exhibit a normal response to provocative tests.

THE RATIO OF GROWTH HORMONE (GH) BY TANDEM MONOCLONAL ASSAY/POLYCLONAL RIA DOES NOT PREDICT RESPONSE TO GH THERAPY

Blethen and Chaslow (JCEM 57:1031, 1983), recently reported that the ratio of GH by Tandem Hybritech monoclonal immunoradiometric assay (Tandem) to standard polyclonal radioimmunoassay (RIA), might predict the outcome of GH therapeutic trials.We studied the effect of GH therapy on 16 patients whose height was <3rd percentile and bone age delayed ≥2 SD. Each patient had a normal GH response (≥10 ng/ml) to insulin arginine stimulation (assayed by RIA). GH was also assayed by Tandem. Seven patients increased their pretreatment growth rate by >2 cm/yr (R). Nine patients did not respond to GH (NR).There was no significant difference between the Tandem/RIA ratio of R and NR patients. The ratio did not predict the response to GH therapy.

PRODUCTION, METABOLISM OF FSH AND LH IN PUBERTY DISORDERS

The production rates (PR) (IU/24 hours), metabolic clearance (MCR) (mls/min.) disappearance (T 1/2) (hours) and excretion rates (% excretion) and Plasma testosterone (T) and Δ4 androstenedione concentrations (ng/100 ml) were measured in males with Precocious Puberty (PP), Delayed Puberty (DP), Hypopituitarism (HP), and Congenital Adrenal Hyperplasia (CAH).We suggest that (1) in initiating puberty the LH PR rise precedes the plasma T rise and (2) precocious puberty might be a disorder of LH production.