HORMONAL MECHANISMS OF GROWTH FAILURE IN MODERATE CHRONIC METABOLIC ACIDOSIS(CMA) WITH NORMAL FOOD INTAKE. 392

Hormonal changes in rats subjected to high doses of NH₄Cl are similar to those observed in non acidotic rats with similar degree of food deprivation. To assess the effect of CMA with normal food intake on the growth hormone (GH)-insulin-like growth factor (IGF) axis, we compared 3-6 month-old mice with congenital deficiency in carbonic anhydrase II (CAD) to B6AF1 controls (Con). Because of the differences in secretory pattern of GH in rats, genders were analyzed separately. We measured hourly serum GH concentrations(avg±sem) by ELISA using a species-specific antiserum (provided by Genentech), and assessed free serum levels of IGF-1 and IGF-2 by the ratio of the concentration of total IGF-1 or IGF-2 (measured by RIA) to that of high molecular weight IGF-binding protein (IGF-BP3, measured by densitometric analysis of western ligand blots). In male Con (n=6) the number of peak GH levels (defined as > 5 ng/ml) and the average daytime GH concentration were similar to nocturnal values. The average daytime GH concentration and the incidence of GH peaks (8%) in Con males were approximately twice as high as in the other groups. Table

Table 1

Female, but not male, CAD mice had higher serum levels of free IGFs than Con. Prolonged administration of recombinant GH (week 5 to week 12) did not raise serum free IGF levels compared to saline placebo in either gender, although it significantly improved linear growth and weight gain (Jandsizak, this SPR). We conclude that growth deficiency in male CAD mice may result in part from a decrease in pulsatile secretion of GH in male mice. The high serum levels of free IGFs in female CAD mice suggests that their growth failure may result from hormonal resistance. Funded by Genentech Foundation for Growth& Development and by Pharmacia & Upjohn, Inc.