Geoffrey P Redmond

Induction of liver acetaldehyde dehydrogenase, possible role in ethanol tolerance after exposure to barbiturates.

Mice were injected twice a day for 4 days with saline or phenobarbital or ethanol. Treatment with phenobarbital, but not ethanol, increased the amount of liver acetaldehyde dehydrogenase activity. More rapid removal of acetaldehyde, which is a toxic metabolic intermediate of ethanol, may contribute to the alcohol tolerance exhibited by persons who use barbiturates regularly.

Effect of human growth hormone on amobarbital metabolism in children

Drug metabolism changes during the course of growth and development. Hormones mediate somatic growth and may mediate other developmental changes. To determine the effect of human growth hormone (hGH) on human drug metabolism, 6 hGH‐deficient children were given single oral doses of amobarbital before and 6 wk after beginning hGH replacement therapy. Amobarbital was selected as a marker of hepatic microsomal oxidation. Half‐lives rose from 13.89 ± 2.78 hr to 22.75 ± 3.97 hr, volume of distribution was unchanged, and clearance fell from 62.2 ± 15.2 ml/kg/hr to 31.2 ± 11.4 ml/kg/hr. Results indicate that hGH slows the metabolism of amobarbital, probably through an effect on the hepatic microsomal drug‐oxidizing system.

1215 PROPRANOLOL INHIBITS BRAIN AND SOMATIC GROWTH IN THE RAT

Maternal use of the beta blocker propranolol (PRO) has been associated with intrauterine growth retardation (IUGR) in the offspring. Because mothers received the drug for hypertension or cardiac disease, it is uncertain whether the drug or the disease produced the IUGR. To determine whether PRO itself could inhibit growth, it was given to rats at various ages. Administration by gavage at a dose of 50 mg/kg to pregnant rats on days 17-21 resulted in significantly lower birth weight (5.76±0.28g vs. 6.41±0.63, p<0.05) even though mean litter size was also slightly reduced. In contrast, administration to pair-fed post-weanling rats had no effect on growth. Suckling rats given PRO 50 mg/kg by gavage starting on day 4 had a 22% deficit in body weight (p<0.01) and a 10% deficit in brain weight (p<0.01),in comparison to controls by day 16. A dose of 25 mg/kg did not affect growth while 75 mg/kg produced a 33% weight deficit on day 16.Conclusion: PRO produces a dose-dependent impairment of somatic and brain growth in the absence of maternal disease. Administration after the completion of the phase of rapid brain growth had no effect.

363 ALTERED BEHAVIOURAL DEVELOPMENT AFTER EARLY PROPRANOLOL EXPOSURE

Studies on the rat indicate that, as suggested by human case reports, early propranolol exposure results in a growth deficit. Brain weight was significantly smaller in suckling rats given daily propranolol 50 mg/kg by gavage starting on day 4. Mean brain weight was 1.36±0.02g vs 1.45±0.01g in vehicle treated controls (p<0.01). To determine whether there was a functional deficit accompanying the anatomical one, behavioural studies were carried out when the rats were 50-60 days of age. Propranolol exposed animals required significantly more trials to reach criterion on a passive avoidance task. There was a trend toward decreased head dip response. Rats given propranolol 50 mg/kg but supplemented with triiodothyronine (T3) in a dose of 700 ng/kg performed normally on passive avoidance and were intermediate in head dip between PRO treated rats and vehicle controls.Conclusion: Early propranolol exposure produces an alteration in behavioural development. T3 supplementation protects against this effect of propranolol.

GROWTH PATERNS AND ENDOCRINE STATUS IN CHILDREN WITH OPTIC NERVE HYPOPLASIA

Optic nerve hypoplasia (ONH) is known to be associated with hypothalamic-pituitary dysfunction including growth hormone deficiency (hGH-D), panhypopituitarism and diabetes insipidus (DI). Previous series have focused on specific subgroups and probably did not include the full range of patients with ONH.We have examined growth and endocrine data on 66 subjects (38M, 23F) with ONH aged 1 to 33 yrs (mean 9.5 ± 7.3 yrs). Several distinct patterns of growth and erdocrine faction were found: 1) Normal height arbitrarily defined as rank ≥ 5% ile was present in 68%. All 7 adults were in this group demonstrating that at least some with ONH achieve normal adult height. 2) Growth failure occurred in 21 subjects (32%). Its onset was 2 years in 10/21, between 2 and 3 years in 4/21, and unknown in 7/21. This age of onset is younger than reported by G. Costin, et al. Growth hormone therapy was able to normalize the growth in 2 subjects. Among this subgroup 6/21 were hypothyroid, 8/21 had definite cortisol deficiency and 3/21 had spontaneous hypoglyoemia. hGH-D was documented in 21% of all ONH subjects, significant DI was present in 11% of subjects. Two additional abnormal growth patterns ware noted. 3) Early or precocious puberty occured in 4/21 growth deficient children, Directing the observation of C.A. Huseman, et al. 4) Progressive obesity and normal growth with hGH-D similar to craniopharyngioma occurred in 2 subjects.Conclusions: 1) Children with ONH should be followed carefully for emergence of growth and endocrine abnormalities from infancy. 2) A brief period of normal growth associated with puberty or obesity should not mislead the pysician into assuming later growth will be normal.

170 MENSTRUAL DYSFUNCTION IN ADOLESCENTS WITH INCREASED JNTIMCRANLAL PRESSURE

The menstrual cycle is controlled by the central nervous system and alterations in its function may be a reflection of neurological disease. Although longstanding increased intracranial pressure (ICP) may produce subtle but important changes such as learning disabilities, there may be few clues to identify increased ICP as the cause. We have recently seen two patients with longstanding learning disabilities in whom amenorrhea provided the impetus for CT scanning. One patient presented at 20 years of age and had an initial prolactin of 42. She had a 3rd ventricle cyst causing obstructive hydrocephalus. The second patient presented at 17 years of age with amenorrhea and severe headaches. Prolactin was 29.5 ng/ml. Hydrocephalus due to a 4th ventricle ependymoma was found on CT. Spontaneous menses occurred in the second patient after placement of a shunt. Her prolactin level gradually fell to normal but menses resumed before the prolactin fall. The first patient initially required medroxyprogesterone acetate postoperatively but resumed spontaneous menses when she was placed on spironolactone for her hirsuitism.CONCLUSIONS: 1) Amenorrhea may be an important clue to the presence of increased intracranial pressure and intracranial neoplasia, 2) Hypo-thalamic compression rather than hyperprolactinemia appears to be the mechanism of amenorrhea in our cases.

140 SYNDROME OF ACANTHOSIS NIGRICANS, POLYCYSTIC OVARIES, AND INSULIN RESISTANCE: A COMMON ENDOCRINOPATHY IN ADOLESCENTS

Although the association of acanthosis nigricans (ACN), with abnormalities of carbohydrate metabolism and ovarian function has recently received attention in the medical literature, the impression remains that this is a rare condition. Over the last 2 years, we have seen 21 patients with this syndrome. 73% were younger than 20 years. Amenorrhea was the most common presenting complaint but others came because of hirsuitism, obesity, diabetes or the skin changes.Initial results on 10 patients indicate that 2 had 1° amenorrhea, 6 had 2° oligo-or amenorrhea, 2 continued to menstruate. 8 were caucasion and 2 were black. Age at diagnosis ranged from 14 and 3/12 to 20 years. ACN had been present between 2 months and 4½ years but many patients were unaware that they had the condition. 7 of the 10 patients had one or more elevated androgen levels (free or total testosterone, androstenedione or DHEA-S); 4 of 10 had abnormal glucose tolerance but 8 had elevated 1 hr insulin levels which ranged from 100 to 720 μU/ml. Treatment remains problematic but weight loss or glyburide improves glucose tolerance in some.CONCLUSIONS: 1) The syndrome of ACN-POO is common in adolescents, 2) Most patients with ACN have elevated androgens, and 3) Most have abnormal insulin action.

EFFECT OF HUMAN GROWTH HORMONE (hGH) ON ACETAMINOPHEN (APAP) ELIMINATION

Previous work has indicated that hGH has quantitatively significant effects on drug elimination in human children. For many substrates, such as amobarbital, which are metabolized by the hepatic MFO system, elimination is slowed (G.P. Redmond, et al. Clin Pharmacol Ther 24:213, 1978). We wished to determine whether hepatic conjugation reactions are also altered by hGH treatment. 5 children were given APAP orally in a dose of 10 to 15 mg/kg before and again 6 weeks after hGH replacement therapy. HGH was generously supplied by the National Hormone and Pituitary Program (NHPP); all children met NHPP criteria for hGH deficiency. Preliminary results on 3 children are as follows:These results indicate that elimination of APAP by hGH deficient children is similar to the 1.74 hr t½ observed in normal febrile children (J.T. Wilson, et al. Ther Drug Monitoring 4:147, 1982). HGH replacement did not affect t½, Td or Cl. Studies of urinary metabolites are in progress to determine whether the ratio of sulfate to glucuronide is altered.

HYPERPROLACTINEMIA IN ADOLESCENCE

Hyperprolactinemia is recognized commonly as a cause of menstrual dysfunction and hypogonadism in adults but is often assumed to be rare in adolescents. The clinical features of this in adolescence have not been well characterized. We have studied 20 patients with adolescent onset of hyperprolactinemia. Initial results on 16 (13 females and 3 males) are as follows: The cause of hyperprolactinemia was microadenoma in 6, macroadenoma in 7, pituitary cyst in 1 and tumor hydrocephalus in 2. Onset was between 9 and 19 years with a mean of 14.6 years but the diagnosis was delayed almost 5 years to a mean age of 19.3 years. Prolacting levels varied from 33 to 3450 ng/ml. Presenting complaints in females were: Amenorrhea in 64%, galactorrhea in 18%, cystic acne in 9%. Galactorrhea was present in 73% but only 1/3 of these were aware of it. Headaches were present in 82%. 6 of 8 patients had withdrawal bleeding after Provera.3 patterns of pubertal progression were seen: 1)primary amenorrhea 18%, 2)normal menarche with only a few periods 36%, 3) normal menarche, irregular menses for several years and amenorrhea in 46%. 4 of 5 patients with macroadenomas have had surgery, radiotherapy or both and 3 of these have residual hyperprolactinemia and other residua. Although hyperprolactinemia is a common cause of menstrual or pubertal disturbance in adolescence, diagnosis is usually delayed. Because outcome is often suboptimal, an effort toward timely diagnosis is indicated.

89 ROLE OF GROWTH HORMONE (GH) IN THE GROWTH RETARDATION PRODUCED BY PERPHENAZINE (PER)

Previous studies have demonstrated that the phenothiazine anti-psychotic drug PER blocks r (rat) GH secretion (Redmond, Neuroendocrinol 30:243, 1980) and retards growth (Redmond and Hirshman, Ped Pharmacol, in press). In order to determine whether the diminished rGH secretion was causally related to the growth retardation, an experiment was performed in which rGH replacement was given with PER. Raw results in male Sprague-Dawley rats were as follows:When data was transformed using covariate analysis to adjust for food intake, there was significant restoration by rGH of growth in both weight and length of PER treated rats.Conclusion: Inhibition of rGH secretion is at least one of the mechanisms by which PER impairs growth.