PRIMARY HYPOTHYROIDISM OF CHILDHOOD: EVALUATION OF THE HYPOTHALAMIC‐PITUITARY GONADAL AXIS BEFORE AND DURING L‐THYROXINE REPLACEMENT

SUMMARY Hypothyroidism is frequently associated with abnormal sexual development. To determine the longitudinal influence of thyroxine replacement on the hypothalamic pituitary gonadal axis, we studied five prepubertal hypothyroid girls and two boys before, and all the girls six weeks and one year after, thyroxine replacement. All girls showed significantly elevated basal gonadotrophin concentrations before treatment. Following one year of therapy, despite all girls having begun puberty, basal gonadotrophin concentrations were significantly decreased in the four euthyroid girls as compared with our normal pubertal girls. The fifth girl studied at one year was hypothyroid at the time of testing and her gonadotrophin values were increased even above previous basal values. Pretreatment serum TSH values inversely correlated with maximum pretreatment incremental LH (r= ‐0.54) and FSH (r= ‐0.52) responses to LHRH. Serum TSH values directly correlated with PRL concentrations (r =+0.82). Of the two hypothyroid boys evaluated, Patient 1 was mildly hypothyroid and showed normal prepubertal basal LH, FSH, testosterone and low normal LHRH responsiveness. Patient 2, who was more severely hypothyroid, had elevated basal gonadotrophin secretion and responsiveness to LHRH but prepubertal testosterone concentrations. These data indirectly show that thyroxine may increase the biological/ immunological potency of gonadotrophins. The elevated gonadotrophin values in the hypothyroid state suggest that the metabolic clearance rate of gonadotrophins is prolonged. The more severe the elevation in TSH secretion, the more marked was the alteration in the hypothalamic pituitary axis in respect to PRL secretion and Δ max LH and FSH response to LHRH. Replacement with thyroxine was followed by normal pubertal development, and normal pubertal explanation for delayed peak LH responses to LHRH in the hypothyroid state is not known but could relate to a decreased readily releasable LH pool. Pre‐treatment serum TSH values inversely correlated with the Δ max LH and FSH responses to LHRH and directly correlated with prolactin concentrations. From this we infer that the more severely hypothyroid the patient is, the greater is the derangement in the hypothalamic pituitary axis. Pituitary responsiveness to synthetic LHRH is known to be affected by at least two factors 1) previous exposure to LHRH and 2) sex steroids (Roth et al. , 1972). Reduced responsiveness is seen in the prepubertal child in the presence of low concentrations of gonadal steroids. One of the earliest changes in puberty is the increased LH responsiveness to synthetic LHRH which probably reflects the self‐priming effect of the increased pulsatile LHRH secretion. Serum FSH responsiveness to synthetic LHRH has been noted to be less in females after the onset of puberty (Roth et al. , 1972). In our euthyroid pubertal girls studied at one year, the expected increase in basal LH secretion and responsiveness to LHRH at puberty did not occur. The expected decrease in pubertal FSH responsiveness to LHRH did occur, and indeed no response to FSH was seen in the four euthyroid girls. Patient 5 had discontinued thyroxine medication for two weeks before LHRH testing. Her pubertal gonadotrophin responses to LHRH may be explained by a brief period of hypothyroidism having occurred prior to the testing. The underlying pathophysiology of the decreased immunoreactive basal LH and FSH secretion in the euthyroid pubertal girls after one year of treatment remains unclear. Beitins and Bode (1980) reported increased serum LH and alpha subunit secretion in children with hypothyroidism when compared with normal controls. Following treatment with thyroxine, LH and alpha subunit decreased, whereas in vitro biological activity of LH increased in basal and stimulated samples. Since our patients did show early pubertal oestradiol secretion and pubertal changes on physical examination, but subnormal immunoreactive gonadotrophins, this suggests that thyroxine may increase the biological/immunological ratio of gonadotrophins. Lucky et al. have demonstrated that LH bioactivity increases more than immunoreactivity during normal puberty. In girls, a 23.1 fold increase of biological LH activity occurred but only a 4.9 fold increase in immunological activity (Lucky et al. , 1980). Thyroxine may alter this qualitative change in gonadotrophin secretion during puberty. The exaggerated gonadotrophin responses of the prepubertal male, Patient 2, may also reflect increased alpha subunit of LH in basal and stimulated samples since testosterone values and physical examination were prepubertal. From our study we can conclude that the more severe the TSH elevation the more marked is the alteration in the hypothalamic pituitary axis in regard to LH, FSH, and PRL secretion. Replacement with thyroxine for one year permitted normal progression of puberty as evidenced by normal oestradiol concentrations and pubertal development despite low immunoreactive gonadotrophin concentrations.