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Author’s Response: Aromatase Inhibitors in Pubertal Boys—Clinical Implications

Division of Endocrinology Nemours Children’s Clinic Jacksonville, Florida 32207

To the editor:

I appreciate the opportunity to reply to the letter of Dr. Rochira regarding the use of aromatase inhibitors in pubertal boys.

In our work published in JCEM this summer (1), we report our results on the investigation of the intermediate metabolism of substrates, bone calcium metabolism, body composition and strength in young males given an aromatase inhibitor (Anastrozole) for 10 weeks and compared the results with those of identical experiments in young men given a GnRH analog. In it, we clearly restrict our conclusions to the effects observed over 10 weeks and only speculate to the potential use of this compound in delaying epiphyseal fusion in short pubertal boys. I personally agree with the substance of the concerns expressed by Dr. Rochira, and I echo the warning that the use of this and other similar aromatase inhibitors cannot be advocated until careful, methodical studies, like the one reported, can be carried out in a large enough group of patients and the data analyzed. Much more work needs to be done, and such studies are presently underway.

That estrogen is important in bone health is not questioned here. Actually, we used the model of aromatase inhibition with concomitant GH treatment in pubertal boys, and preliminary results show no detrimental effects on bone mineralization after 1 yr of combined treatment (unpublished observations). More data are also needed on the issue of the impact of estrogen deficiency on sperm function and fertility. More is written about the negative effects of estrogen exposure to the testis than the effects of estrogen deficiency. Animal data clearly offer mixed results with both apparent disruption of spermatogenesis in mice lacking functional aromatase (2), and no difference in the number of Sertoli cells, germ cells, the volume of seminiferous epithelium, tubule lumens, and interstitium between controls, and Anastrozole-treated rats after 1 yr (3). Extrapolating the effect of complete, lifelong aromatase blockade on sperm function from the published report of the man with this aromatase deficiency (whose brother also had decreased sperm counts even though he had no aromatase gene mutation; Ref. 4), to the effects of timed pharmacological aromatase blockade may not be directly comparable. The latter achieves a 50% reduction in circulating estrogen concentrations and not a complete suppression. A critical question yet to be answered, however, is not only if this intervention, like treatment with a GnRH analog, affects sperm function, but more importantly, is it reversible after discontinuation of treatment. This family of compounds, and the new class of estrogen receptor blockers, will require thorough and analytical study in the years to come. Only when proven efficacious and safe in long-term studies, can their potential usefulness in the pharmacological arsenal available to the clinican be fully assessed.

References

1. Mauras N, O’Brian KO, Derter Klein K, Hayes V. 2000 Estrogen suppression in males: metabolic effects. J Clin Endocrinol Metab. 85:2370–2377.
2. Robertson KM, O’Donnell L, Jones MC, et al. 1999 Impairment of spermatogenesis in mice lacking a functional aromatase (Cyp19) gene. Proc Natl Acad Sci USA. 96:7986.[Abstract/Free Full Text]
3. Turner KJ, Morley M, Atanassaua N, et al. 2000 Effect of chronic administration of an aromatase inhibitor to adult male rats on pituitary and testicular function and fertility. J Endocrinol. 164:225.[Abstract]
4. Carani C, Qin K, Simoni M, et al. 1997 Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med. 337:95.

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