Disorders of puberty commonly accompany chronic renal failure and require age-appropriate medical management. Although centrally mediated precocious puberty, which is reversed by renal transplantation, has been reported (46), the most characteristic feature of chronic renal failure in boys is delayed puberty with retarded bone age (1). The delayed puberty usually progresses slowly to completion during dialysis, whereas transplantation accelerates maturation unless complicated by poor graft function and/or high-dose glucocorticoids (47). Because puberty involves the unleashing by the hypothalamus of pulsatile GnRH secretion that subsequently entrains pituitary gonadotropin secretion, the delayed puberty is further evidence of neuroendocrine dysfunction in uremia. This is consistent with experimental models of chronic renal failure, which show a predominant defect in the regulation of hypothalamic GnRH secretion (12). In concert, these findings raise the issue of gonadotropin or androgen treatment for delayed puberty in chronic renal failure.
Three available studies of androgen therapy for delayed puberty in adolescents with uremia are small and uncontrolled (48-50), so they provide little evidence of efficacy or safety. Oxandrolone (0.25 mg/kg per day for 2 mo, then alternate days) therapy for an average of more than 1 yr (48) in nine adolescent boys undergoing regular hemodialysis produced a modest increase in growth, which was slightly greater than the concomitant advance of skeletal maturation and improved appetite and vigor. However, one boy was dismissed from the study because of oxandrolone-induced hepatotoxicity, and the remainder developed fluid overload. In another study of four boys with uremia exhibiting severe growth and pubertal delay, injections of testosterone ester (50 mg escalating to 100 mg) each third week for 9-45 mo (49) accelerated growth and pubertal development, but skeletal maturation was preferentially enhanced and bony deformity developed. In 11 boys with normal renal function but pubertal delay associated with steroid treatment of nephrotic syndrome, oxandrolone (2.5 mg/d) therapy for 6 mo (50) did not increase growth more than untreated historical controls matched for age and pubertal status. Hence, the efficacy and safety of androgen therapy for uremic pubertal delay remains inadequately demonstrated. Whether androgen sensitivity is modified by chronic renal failure, for example, remains unclear. As in other clinical circumstances, improvement of underlying renal function (e.g., transplantation) is more likely to be effective than hormonal therapy in boys with chronic renal failure.
Pulsatile GnRH stimulation (~150 ng/kg subcutaneously every 120 min) administered for 7 d produced greater LH and testosterone responses in five boys with uremia than in six nonuremic controls with equivalent pubertal delay (51). This intriguing and important observation warrants further evaluation. If reproducible, this would provide further corroboration for a state of functional GnRH (and gonadotropin) deficiency in uremia and would encourage further studies of estrogen blockade or hCG treatment in adolescents with uremia with delayed puberty, none of which is yet reported.
Cystinosis is a rare autosomal recessive disease characterized by defective extrusion of cystine from lysosomes, causing lysosomal storage and crystal formation that can lead to early renal failure, with the need for dialysis and/or transplantation before puberty. Cross-sectional studies have shown marked delay in growth and pubertal development, which improves after transplantation (52) but that remains more severe than other patients matched for age, gender, puberty, and renal status (53). This suggests that toxic cystine accumulation in the testis can lead to hypergonadotrophic hypogonadism when life is prolonged by transplantation. If chelation therapy does not prevent progression to renal failure with attendant growth and pubertal delay, therapeutic trials of androgen therapy could be useful.
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