Aromatase Inhibitors in Pubertal Boys: Clinical Implications

Vincenzo Rochira

Department of Internal Medicine University of Modena and Reggio Emilia 41100 Modena, Italy

To the editor:

I enjoyed the manuscript by Mauras et al. (1) because it opens interesting perspectives in the possible clinical use of aromatase inhibitors (AIs) in the treatment of growth disorders, as previously suggested by Grumbach and Auchus (2). AI constitutes a selective tool useful to obtain a delay in epiphyseal closure during skeletal development. The advantage of using AIs consists in a selective block of estrogen action without affecting biological effects due to androgens per se (1). Thus, a pharmacological "decoupling" of androgen action from that of its estrogen metabolite is reached. In this view, AIs permit to extend longer the time of growth in boys with growth disorders (e.g. GH deficiency, idiopathic short stature), thus leading to an increased powerful of GH therapy and to a better final height. Presently, skeletal maturation could be restrained only by using GnRH analogs. AIs, however, do not affect the progression of pubertal development because a block of estrogen action could occur together with a normal advancement of virilization. Thus, AIs could prevent the psychological problems related to delayed puberty that often occur when GnRH analogs are used.

The authors state that AIs are safe in young adolescents (1), and this is the case if a short-term period of treatment is considered. By contrast, the issue becomes very complex if the treatment is carried out for long time, as it is necessary in the case of short stature, being a great prolongation of the period available for growth desirable to fill the gap of height. Several issues need to be clarified before AIs will be considered safe at puberty. Puberty, in fact, is the time for the children to mature sexual organs, to reach both adult proportions of the skeleton and a complete adult psychosexual behavior. If undesirable effects due to pharmacological treatments occurred in this fragile phase of development some physiological functions could be compromised forever.

Before analyzing the hypothetical disadvantages of AIs, estrogen actions at puberty in the male have to be underlined. First, estrogens act on bone tissue in men. Epiphyseal closure and skeletal maturation do not happen without estrogens (2, 3). The finding of eunuchoid proportions of the skeleton in estrogen-deficient men (2) suggests that estrogens are involved in the establishment of the proportions of the growing skeleton, leading to eunuchoid body habitus (3). It seems that growth spurt also is an estrogen-dependent process (2), although a conclusive consent on this issue has not been reached, because a detailed growth chart of estrogen-deficient men has never been provided (2, 3). Estrogens are needed to achieve the peak of bone mass (2, 3) during early to late adolescence.

Second, estrogens could modulate reproductive function in men. Aromatization of androgens is required for a normal male sexual behavior in mice, but much less is known about estrogens and human male sexuality (4). Estrogens are necessary for a normal fertility in male rodents. Presently, more research is required to prove whether the same mechanisms operate in the human testis, although recent findings (e.g. the presence of estrogen receptors and aromatase activity in the male reproductive system) strongly support an estrogen role on human spermatogenesis. In any case, estradiol is the major modulator of gonadotropin secretion in normal men, acting both at pituitary (1, 2, 3, 5) and hypothalamic levels (6), and estrogens are consequently involved in the control of testicular function.

Third, abnormalities of lipid and carbohydrate metabolism in men with congenital estrogen deficiency (2, 3) suggest that estrogens could modulate some metabolic pathways, having a protective role also on the male cardiovascular system (2).

Stated both well-documented and supposed effects of estrogens in men, it should be considered that AIs could interfere with each of these physiological processes at puberty (Table 1Go). A delay in skeletal maturation could induce a disproportional growth, accounting for final eunuchoid body proportions. A peak of bone mass lower than normal could result from AI administration, predisposing the occurrence of osteoporosis later during adulthood. Accordingly, spermatogenesis, the psychosexual behavior, the cardiovascular system, and some metabolic pathways also could be impaired with an increased risk for health during adulthood.


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Table 1. Role of estrogen at puberty in the male and possible advantages and disadvantages of using AIs in young adolescent males

 
AIs directly decrease serum estradiol with an increase of the testosterone to estradiol ratio (1). The imbalance between circulating sex steroids is more severe if we consider also the effects of AIs on gonadotropin feedback (6): higher LH levels cause a testosterone overproduction without a concomitant increase of estradiol (1), a hormonal pattern accounting for macro-orchidism in congenital estrogen-deficient men. What are the consequences due to such a severe imbalance in circulating sex steroids during an important phase of development, which is puberty? Awaiting an answer to this question from future studies, some ethical perspectives should be considered. The aim of this letter is to consider clinical implications related to the pioneering use of these drugs in boys to promote a successful debate among researchers on the possible inherent risks and benefits. The real impact of AIs on several physiological processes, which take place at puberty, remains to be well established because a well-conducted, controlled clinical trial has never been performed. Presently, although the unique work performed by Mauras et al. (1) opens this novel form of therapy to study, it also leaves several questions unanswered. In that short-term treatment, the effects of AIs on skeletal maturation, fertility, and sexual behavior were not studied in detail (1). Besides, caution is needed when data are extrapolated from a short-term treatment because a drug affecting physiological processes related to the developing body reveals its potential negative effects when a long-term treatment is performed. What’s more, the issue is complicated by the fact that some adverse events could be detectable only later during adult life (e.g. infertility).

Again, what is the impact of AIs on local estrogen production? A block of estrogenic functions involves both autocrine and paracrine mechanisms in each tissue in which aromatase is expressed. One of the tissue-specific implications related to the iatrogenic "decoupling" of androgen from estrogen action in adolescent boys is represented by environmental changes in the testis (testosterone is higher with estradiol lower than normal). Are the consequences on spermatogenesis occurring later during adulthood predictable? The answer to this latter question is not so easy. Presently, in fact, we still do not know in detail the effects on male fertility of the treatment with GnRH analogs during adolescence (7).

To establish both the true rates of possible adverse events and the efficacy of AIs in male growth disorders, results from a long-term treatment are anxiously awaited. Obviously, the following parameters should be carefully monitored: sperm count, testicular size and morphology, height velocity, anthropometric measurements of several skeletal districts, bone mineral density, and psychosexual behavior. Changes in these parameters during long-term treatment of adolescent boys will permit to establish in detail the side effects of these drugs. Presently, it is only possible to speculate on some adverse events only by starting from our knowledge on the physiological estrogen role in males. Thus, also progress in the field of estrogen physiology will probably permit us to forecast side effects due to the experimental use of AIs in boys.

In conclusion, AI has to be regarded as an experimental regimen at puberty, being a therapeutic approach not miming physiological pubertal changes of sex steroids. To transfer the use of AIs in pubertal boys into clinical practice, results from clinical trials on long-term treatment need to be available and researchers need to clarify all of the androgen actions that are really to be ascribed to estrogen. Accordingly, until much larger studies on these two issues have been done, physicians should continue to exercise caution with regard to the potential for adverse effects of AI administration to male adolescents.

References

  1. Mauras N, O’Brien KO, Klein KO, Hayes V. 2000 Estrogen suppression in males: metabolic effects. J Clin Endocrinol Metab. 85:2370–2377.[Abstract/Free Full Text]
  2. Grumbach MM, Auchus RJ. 1999 Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab. 84:4677–4694.[Abstract/Free Full Text]
  3. Faustini-Fustini M, Rochira V, Carani C. 1999 Oestrogen deficiency in men: where are we today? Eur J Endocrinol. 140:111–129.[Medline]
  4. Carani C, Rochira V, Faustini-Fustini M, Balestrieri A, Granata A. R.M., 1999 Role of estrogen in male sexual behaviour: insights from the natural model of aromatase deficiency. Clin Endocrinol (Oxf). 51:517–525.[CrossRef][Medline]
  5. Rochira V, Faustini-Fustini M, Balestrieri A, Carani C. 2000 Estrogen replacement therapy in a man with congenital aromatase deficiency: effects of different doses of transdermal estradiol on bone mineral density and hormonal parameters. J Clin Endocrinol Metab. 85:1841–1845.[Abstract/Free Full Text]
  6. Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley Jr WF. 2000 Aromatase inhibition in the human male reveals a hypothalamic sit of estrogen feedback. J Clin Endocrinol Metab. 85:3027–3035.[Abstract/Free Full Text]
  7. Lee PA. 1999 Central precocious puberty. An overview of diagnosis, treatment, and outcome. Endocrinol Metab Clin North Am. 28:901–918.[Medline]