Sue Ellyn Sauder

62 FAMILIAL PARTIAL PERIPHERAL AND PITUITARY RESISTANCE TO THYROID HORMONE - A FREQUENTLY MISSED DIAGNOSIS?

Two boys, 7 and 9 yrs, and a girl, 11 yrs, presented with goiters and hyperthyroxinemia. The boys were treated with PTU/thyroidectomy or I131 for suspected thyrotoxicosis, but had poorly suppressible serum TSH post Rx. The girl had increasing goiter size on PTU 100 mg q 8 h x 1 mo. These findings led to re-evaluation of thyroid hormone dynamics in these patients and their families. The diagnosis of partial peripheral and pituitary resistance to thyroid hormone was made in the 3 index cases and 12 additional family members, ages 3-38 yrs, compatible with an autosomal dominant inheritance. All had elevated serum T4 RIA (13.9-25.8μg/dl), T3 RIA (205-396 ng/dl), and non-suppressed serum TSH (1.5-158 μU/ml). T3 resin uptakes were N→sl↑. Reverse T3, free T4 and 24h I131 uptakes were ↑ in 6/6. Goiters were present in 10/11 (4 were post thyroid ablation). TRH (200 μg iv) given to 5 pts (from 3 families) showed exaggerated TSH responses (Δ μU/ml = 26, 31, 32, 34, 268). After incremental doses of L-thyroxine up to 0.3 mg/d, goiter size decreased, and TSH response to TRH was now normal (Δ 13,19 μU/ml) in 2 pts with intact thyroids and still exaggerated (Δ 96 μU/ml) in the pt with I131 Rx. Misdiagnosis in 6/15 members of 3 families has led to significant morbidity (hypothyroidism, delayed growth, Rx risk). Appropriate management for this condition should include L-thyroxine in order to decrease goiter size and normalize TSH responses to TRH. A non-suppressed TSH in a patient with suspected thyrotoxicosis should lead to suspicion of this disorder.

30 ACUTE AND CHRONIC EFFECTS OF CLONIDINE ON GROWTH HORMONE AND GONADOTROPIN SECRETION IN ADOLESCENT BOYS

Clonidine, a presumed α2 agonist, is a potent stimulus for GH in man and gonadotropins in rodents. To assess the acute and chronic effects of this drug on GH and gonadotropins in adolescents, we studied 4 boys in early to mid-puberty, sampling blood every 15-20 min for LH and FSH (x ± SE mIU/ml) and hourly for GH, before and after one or two oral 0.15mg/m2 doses of clonidine. (*=p < .05 vs control):Clonidine had no effect on LH pulse frequency or the circadian pattern of LH, FSH or GH secretion. It was consistently followed within 2h by a GH peak comparable to the spontaneous pulses. This effect on GH was maintained in pt. #4 after chronic therapy. We conclude: 1) clonidine has a modest effect, if any, on gonadotropins at this stage of human puberty; 2) growth should be followed closely in adolescents on clonidine therapy.

171 VARIABLE EXPRESSION OF OVARIAN FAILURE IN GALACTOSEMIA

The pathogenesis of ovarian failure in females with classical galactosemia is incompletely understood, but is likely due to prenatal toxic effects of galactose or its metabolites on the immature ovary. We studied two sisters on dietary galactose restriction since birth who had hypergonadotropic hypogonadism. Serum prolactin and T4 were normal and karyotypes were 46xx. AB, 17 yrs, had adrenarche at 12 yrs, thelarche at 13 yrs and menarche at 14 yrs, followed by irregular periods q 3-6 wks. BB, 16 yrs, had adrenarche at 13 yrs, but no thelarche or menarche. Bone age was 11 yrs. Pelvic U/S showed no ovarian tissue. Both girls had blood withdrawn every 10 min over 12 h (0900-2100) for pulsatile secretion of LH/FSH. BB was studied during two separate cycles: 5 and 22 days after the onset of menstrual flow. In spite of a mean intermenstrual length of 28.5 d (R 18-42 d), studies during a 6 month period in BB (pulsatile LH/FSH, weekly progesterone (P) levels, and basal body temperatures) showed no evidence of ovulation.These studies show that ovarian failure may be variable in similarly treated siblings. Incomplete follicular maturation most likely explains the serial observations in the least affected sibling.

445 RENIN-ALDOSTERONE (R-A) RESPONSES IN A BOY WITH DEFECTIVE RENAL K+ EXCRETION

Hyperkalemia and acidosis were found in an asymptomatic 1310/12 year old boy during evaluation of short stature and delayed adolescence (HA&BA=10 yrs). Renin activity was not evaluated in two similar reported cases. We studied the R-A system during changes in posture and diet to evaluate the effects of primary hyperkalemia. Hyperkalemic hyperchloremic metabolic acidosis was documented (Na 139,K 7.1,C1 116,CO2 19 mEq/1). Cortisol, thyroxine, GH and FSH/LH secretion were normal as well as inulin and PAH clearance. Urinary K+ excretion was low when compared to the elevated serum K+, both before and after Na2SO4 infusion. Plasma renin activity (PRA) was low(Na+120 mEq/day-supine(S) 0, upright(U) .06 ng/ml/hr). Although appropriate for normokalemic subjects, serum aldosterone was low for the degree of hyperkalemia(Na+120 mEq/day-S 18, U 39 ng/dl). During Na+ restriction PRA remained low, serum K+ rose to 8 mEq/1, and the patient became tachycardic and hypotensive. After chlorothiazide treatment, electrolyte abnormalities corrected and PRA increased(S 3.2, U 7.8 ng/ml/hr). Our studies support the hypothesis that renal K+ excretion is defective. These alterations in R-A responses may be attributed to the effects of hyperkalemia. Although it suppresses PRA, hyperkalemia directly increases aldo and thus partially compensates for decreased renin-angiotensin stimulation. We speculate that low PRA and resultant low angiotensin II caused decreased vascular tone, decreased Na+ retention and the patients symptoms during Na+ restriction. CRC grant 5MO1RR42