ex_banana-eater
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Introduction
Therapy was started at a BA of 14 yr or older, adult final height significantly exceeded height prognosis at the time of start of treatment. This suggests that treatment had resulted in induction rather than reduction of growth -- this was treatment of constitutionally tall stature (CTS) children with androgen therapy (Testosterone Enanthate at 500mg/wk).
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High doses of T induce suppression of the hypothalamo-pituitary-gonadal axis (113, 136). Contraceptive studies in adult men have shown that androgen-induced suppression of gonadotropins and of spermatogenesis is reversible (137, 138). However, extrapolation of these data to the management of tall stature in pubertal boys must be viewed with caution since factors that regulate spermatogenesis in normally functioning adult testes may not be the same as during puberty (139). Androgen therapy in tall boys is usually initiated at the first signs of puberty, and it is in this peripubertal period that important maturational changes take place in the testis (139, 140, 141, 142, 143, 144). Influenced by complex hormonal actions, these maturational processes eventually lead to initiation of spermatogenesis. Onset of spermatogenesis (spermarche) as detected by urine analysis (spermuria) appears to be an early pubertal event: the median age of spermarche has been estimated to be 13–14 yr (145, 146, 147, 148). In addition, it is noteworthy that administration of T esters at high doses may cause morphological and cytological changes, as shown in rat and human adult testes (149, 150, 151).
1. Plasma hormone levels: High T levels are obtained during treatment with supraphysiological doses of androgens suppressing the hypothalamo-pituitary-gonadal axis (152).
Zachmann, Prader, and co-workers (98, 113) reported a slow recovery of pituitary gonadotropins during LHRH-stimulation tests after discontinuation of T therapy. Brämswig et al. (136) demonstrated normalization of gonadotropin levels in 100 tall boys after discontinuation of treatment with follow-up periods up to 48 months, although transient hypergonadotropic LH- and FSH- secretory patterns were observed. In a recently published study by the same group (153), hormonal levels and testicular function were evaluated after a follow-up period of approximately 10 yr and compared with normal volunteers. Mean values of LH, FSH, PRL, T, estradiol, and sex hormone-binding globulin were in the normal range in both groups. T was lower and FSH was higher in treated tall men compared with volunteers, but the only statistically significant difference was for T. We observed different levels of gonadotropins in previously treated tall men compared with controls (tall and ‘normal’ men) (154). Androgen-treated tall men had significantly higher FSH levels compared with controls. Levels of plasma hormones were not significantly correlated with parameters of sperm quality; however, we observed significant negative correlations between plasma FSH levels and sperm concentration as well as the age at start of therapy in the androgen-treated men. We speculate that the higher levels of FSH may reflect intratesticular changes due to androgen treatment received during a period of testicular maturation especially during the earlier pubertal stages (155). These increased FSH levels may compensate for partially disturbed germinal function to maintain normal sperm quality (156). In a subgroup of previously treated and untreated men, we also measured inhibin B, which probably is a more direct marker of spermatogenesis than FSH (157). We found similar levels, well within the normal range (F. H. De Jong and W. J. De Waal, unpublished results). On the other hand, the difference in gonadotropin levels may also reflect a change in responsiveness at the hypothalamo-pituitary level (136).
2. Testicular volume: Treatment with high doses of androgens induces reduction in testicular volume in adult men (158) as well as in tall adolescent boys (98, 99, 113). This implies major intratesticular changes during therapy such as a decrease in seminiferous tubule size (149, 150). These processes are likely to be reversible since testicular volume normalizes after discontinuation of therapy as shown in several studies (98, 99, 113, 158). This is in contrast to the observations of Willig et al. (159, 160), who reported significantly smaller testicular sizes in previously treated men. In contrast, in our studies at a mean follow-up period of 8 yr after cessation of treatment, there was no difference in mean testicular volume between treated and untreated tall men (154).
3. Sperm quality: When sperm quality is evaluated, one must be aware of the normal distribution in the population as well as of confounding factors interfering with parameters of sperm quality. It is well established that varicocele (161, 162, 163, 164), smoking (165), sexually transmitted disease (166), and cryptorchidism (167) are likely to affect sperm quality and/or plasma hormone levels. Semen analysis in our study of previously androgen-treated men showed that sperm quality was comparable with a control group of untreated tall men, even after correction for the above mentioned possible interfering conditions, after a mean follow-up period of 8 yr. These findings are in agreement with the experiences reported by Zachmann and Prader and co-workers (98, 113). In contrast, Willig and co-workers (159, 160) found significantly reduced sperm concentrations in previously treated tall men compared with controls. Their control group, however, showed a relative high mean value of sperm concentration of 120.2 x 10'6/ml, almost twice as high as values found in the normal population at present (168, 169). Their treated group showed a mean sperm concentration of 63.4 x 10'6/ml, which is comparable with values found in our study (154). It is possible that differences in patient selection, semen analysis methodology, and treatment regimens may account for the observed differences. In addition, the extent to which interfering conditions are present may cause important bias as well. In a recent report Lemcke and co-workers (153) showed that 10 yr after T treatment, none of the tall men had azoospermia, and the mean ejaculate parameters were in the normal range or only slightly subnormal. Overall, seminal parameters of T-treated tall men were slightly, but not significantly, lower compared with normal statured volunteers. Interestingly, they found a significantly higher prevalence of varicocele and maldescended testes in the tall men compared with their control group of normal volunteers (153). They surmised that varicocele and maldescended testes, rather than T treatment, caused the somewhat lower semen quality in the tall men. In our studies in treated and untreated tall men, we observed an overall prevalence of varicocele of 42% (12% subclinical and 30% clinical) (154). This would suggest that varicocele occurs more often than reported in the normal population (12.4–25.8%) (170, 171, 172). A relationship to androgen treatment is unlikely since no difference in the prevalence of varicocele was observed between androgen-treated men and controls. One could speculate on the impact of stature on the pathogenesis of varicocele (153, 154).
4. Pregnancy/paternity: Thus far, only casuistic and exclusive female data have been available on successful pregnancies after height-reductive therapy. At the time of our follow-up studies five of the 43 androgen-treated men and six of the 30 untreated tall men had fathered one or more children (154). All 11 men reported that pregnancy had occurred in their partners after less than 1 yr of unprotected coitus. Two other pregnancies, fathered by a previously treated man and a control, respectively, ended in spontaneous abortion. These very limited numbers do not allow any further conclusions.
Other clinical effects
Many patients experience side effects during therapy (98, 99, 113, 132, 173, 174). Most of these, however, are mild and transient (see Table 7). In some patients, slight to moderate edema, notably in the pretibial or malleolar area, was associated with marked weight gain during the first 6 months of treatment. This indicates that the early gain in weight is not only due to protein anabolism but also to water retention (98). Acne was by far the most reported side effect (98, 99, 175). Occasionally acne fulminans has been reported and necessitated discontinuation of therapy (173, 176). A causal relationship with androgen therapy is likely as shown by Fyrand et al. (177). Hinkel et al. (178) investigated the effects of high doses of androgens on lipoproteins during and after the cessation of therapy. Although during treatment a significant fall of triglycerides and HDL was observed, all values normalized after the end of treatment (178). In our studies, gynecomastia occurred in 13% of the cases. Since gynecomastia is rather prevalent in population studies in pubertal boys (179), it is difficult to say whether the condition had increased. One would expect that treatment would have effects on sexuality (sex interest, masturbation). Although in one study a marked increase of sexuality in younger, but not in older patients, was noted, it never exceeded the normal range seen in adolescence (98). Treatment with supraphysiological doses of T were not shown to provoke aggressive behavior in adolescents or young adults (180, 181).
Therapy was started at a BA of 14 yr or older, adult final height significantly exceeded height prognosis at the time of start of treatment. This suggests that treatment had resulted in induction rather than reduction of growth -- this was treatment of constitutionally tall stature (CTS) children with androgen therapy (Testosterone Enanthate at 500mg/wk).
__________________________________________________ _________________
High doses of T induce suppression of the hypothalamo-pituitary-gonadal axis (113, 136). Contraceptive studies in adult men have shown that androgen-induced suppression of gonadotropins and of spermatogenesis is reversible (137, 138). However, extrapolation of these data to the management of tall stature in pubertal boys must be viewed with caution since factors that regulate spermatogenesis in normally functioning adult testes may not be the same as during puberty (139). Androgen therapy in tall boys is usually initiated at the first signs of puberty, and it is in this peripubertal period that important maturational changes take place in the testis (139, 140, 141, 142, 143, 144). Influenced by complex hormonal actions, these maturational processes eventually lead to initiation of spermatogenesis. Onset of spermatogenesis (spermarche) as detected by urine analysis (spermuria) appears to be an early pubertal event: the median age of spermarche has been estimated to be 13–14 yr (145, 146, 147, 148). In addition, it is noteworthy that administration of T esters at high doses may cause morphological and cytological changes, as shown in rat and human adult testes (149, 150, 151).
1. Plasma hormone levels: High T levels are obtained during treatment with supraphysiological doses of androgens suppressing the hypothalamo-pituitary-gonadal axis (152).
Zachmann, Prader, and co-workers (98, 113) reported a slow recovery of pituitary gonadotropins during LHRH-stimulation tests after discontinuation of T therapy. Brämswig et al. (136) demonstrated normalization of gonadotropin levels in 100 tall boys after discontinuation of treatment with follow-up periods up to 48 months, although transient hypergonadotropic LH- and FSH- secretory patterns were observed. In a recently published study by the same group (153), hormonal levels and testicular function were evaluated after a follow-up period of approximately 10 yr and compared with normal volunteers. Mean values of LH, FSH, PRL, T, estradiol, and sex hormone-binding globulin were in the normal range in both groups. T was lower and FSH was higher in treated tall men compared with volunteers, but the only statistically significant difference was for T. We observed different levels of gonadotropins in previously treated tall men compared with controls (tall and ‘normal’ men) (154). Androgen-treated tall men had significantly higher FSH levels compared with controls. Levels of plasma hormones were not significantly correlated with parameters of sperm quality; however, we observed significant negative correlations between plasma FSH levels and sperm concentration as well as the age at start of therapy in the androgen-treated men. We speculate that the higher levels of FSH may reflect intratesticular changes due to androgen treatment received during a period of testicular maturation especially during the earlier pubertal stages (155). These increased FSH levels may compensate for partially disturbed germinal function to maintain normal sperm quality (156). In a subgroup of previously treated and untreated men, we also measured inhibin B, which probably is a more direct marker of spermatogenesis than FSH (157). We found similar levels, well within the normal range (F. H. De Jong and W. J. De Waal, unpublished results). On the other hand, the difference in gonadotropin levels may also reflect a change in responsiveness at the hypothalamo-pituitary level (136).
2. Testicular volume: Treatment with high doses of androgens induces reduction in testicular volume in adult men (158) as well as in tall adolescent boys (98, 99, 113). This implies major intratesticular changes during therapy such as a decrease in seminiferous tubule size (149, 150). These processes are likely to be reversible since testicular volume normalizes after discontinuation of therapy as shown in several studies (98, 99, 113, 158). This is in contrast to the observations of Willig et al. (159, 160), who reported significantly smaller testicular sizes in previously treated men. In contrast, in our studies at a mean follow-up period of 8 yr after cessation of treatment, there was no difference in mean testicular volume between treated and untreated tall men (154).
3. Sperm quality: When sperm quality is evaluated, one must be aware of the normal distribution in the population as well as of confounding factors interfering with parameters of sperm quality. It is well established that varicocele (161, 162, 163, 164), smoking (165), sexually transmitted disease (166), and cryptorchidism (167) are likely to affect sperm quality and/or plasma hormone levels. Semen analysis in our study of previously androgen-treated men showed that sperm quality was comparable with a control group of untreated tall men, even after correction for the above mentioned possible interfering conditions, after a mean follow-up period of 8 yr. These findings are in agreement with the experiences reported by Zachmann and Prader and co-workers (98, 113). In contrast, Willig and co-workers (159, 160) found significantly reduced sperm concentrations in previously treated tall men compared with controls. Their control group, however, showed a relative high mean value of sperm concentration of 120.2 x 10'6/ml, almost twice as high as values found in the normal population at present (168, 169). Their treated group showed a mean sperm concentration of 63.4 x 10'6/ml, which is comparable with values found in our study (154). It is possible that differences in patient selection, semen analysis methodology, and treatment regimens may account for the observed differences. In addition, the extent to which interfering conditions are present may cause important bias as well. In a recent report Lemcke and co-workers (153) showed that 10 yr after T treatment, none of the tall men had azoospermia, and the mean ejaculate parameters were in the normal range or only slightly subnormal. Overall, seminal parameters of T-treated tall men were slightly, but not significantly, lower compared with normal statured volunteers. Interestingly, they found a significantly higher prevalence of varicocele and maldescended testes in the tall men compared with their control group of normal volunteers (153). They surmised that varicocele and maldescended testes, rather than T treatment, caused the somewhat lower semen quality in the tall men. In our studies in treated and untreated tall men, we observed an overall prevalence of varicocele of 42% (12% subclinical and 30% clinical) (154). This would suggest that varicocele occurs more often than reported in the normal population (12.4–25.8%) (170, 171, 172). A relationship to androgen treatment is unlikely since no difference in the prevalence of varicocele was observed between androgen-treated men and controls. One could speculate on the impact of stature on the pathogenesis of varicocele (153, 154).
4. Pregnancy/paternity: Thus far, only casuistic and exclusive female data have been available on successful pregnancies after height-reductive therapy. At the time of our follow-up studies five of the 43 androgen-treated men and six of the 30 untreated tall men had fathered one or more children (154). All 11 men reported that pregnancy had occurred in their partners after less than 1 yr of unprotected coitus. Two other pregnancies, fathered by a previously treated man and a control, respectively, ended in spontaneous abortion. These very limited numbers do not allow any further conclusions.
Other clinical effects
Many patients experience side effects during therapy (98, 99, 113, 132, 173, 174). Most of these, however, are mild and transient (see Table 7). In some patients, slight to moderate edema, notably in the pretibial or malleolar area, was associated with marked weight gain during the first 6 months of treatment. This indicates that the early gain in weight is not only due to protein anabolism but also to water retention (98). Acne was by far the most reported side effect (98, 99, 175). Occasionally acne fulminans has been reported and necessitated discontinuation of therapy (173, 176). A causal relationship with androgen therapy is likely as shown by Fyrand et al. (177). Hinkel et al. (178) investigated the effects of high doses of androgens on lipoproteins during and after the cessation of therapy. Although during treatment a significant fall of triglycerides and HDL was observed, all values normalized after the end of treatment (178). In our studies, gynecomastia occurred in 13% of the cases. Since gynecomastia is rather prevalent in population studies in pubertal boys (179), it is difficult to say whether the condition had increased. One would expect that treatment would have effects on sexuality (sex interest, masturbation). Although in one study a marked increase of sexuality in younger, but not in older patients, was noted, it never exceeded the normal range seen in adolescence (98). Treatment with supraphysiological doses of T were not shown to provoke aggressive behavior in adolescents or young adults (180, 181).
