Androgen therapy in constitutional delay of growth.

BACKGROUND/AIMS: Two modalities of androgen therapy prevail in the treatment of constitutional delay of growth (CDG): monthly injections of testosterone or daily tablets of the non-aromatizable oxandrolone. The present study was undertaken to prospectively compare both compounds and dose. METHODS: Thirty patients with CDG were the subjects of this study. The protocol required that they all be at age 12-14 years with a bone age delay of more than 2 'years', height less than -2 SDS and growth velocity less than -0.5 SDS. The subjects were at a Tanner stage 1 or 2 and testicular volume were no larger than 4 ml. They were randomly assigned into 3 treatment groups: group 1 patients received monthly injections of 25 mg testosterone propionate-enanthate; group 2 patients received monthly injections of 50 mg testosterone propionate-enanthate; group 3 patients received oral oxandrolone at a weekly dose of 0.7 mg/kg. Treatment was given for a period of 6 months and follow-up commenced 6 months later and yearly thereafter for 2 years. RESULTS: Height velocity and height increased significantly only in groups 2 and 3. Bone age advanced most in group 2. Puberty progressed faster in that group as compared with group 3. The predicted adult height before and 2 years after completion of treatment remained unchanged in the two testosterone groups. It increased significantly in the oxandrolone group from a mean 169.8 cm before therapy to a mean 177.5 cm 2 years after completion of therapy. Peak GH levels were significantly higher on both testosterone 50 mg and oxandrolone, as compared to pretreatment levels. The increment was significantly greater in group 2 as was the increment in serum IGF-1 and IGFBP3. CONCLUSIONS: These results imply that 6 months of testosterone injections at a dose of 50 mg, but not 25 mg, is an effective and safe treatment for patients with CDG, with no considerable impact on final height prediction. On the other hand, daily oxandrolone treatment, starting at age 12-14 years, may increase the predicted final adult height.

Prevention of growth deceleration after withdrawal of growth hormone therapy in idiopathic short stature.

The treatment of children with idiopathic short stature by daily injections of human GH (hGH) is followed after its withdrawal by a growth deceleration with normal serum GH and IGF-I levels. The present study was designed to understand and prevent growth deceleration. We hypothesized that this phenomenon is due to tolerance at the target organ level, that tolerance develops in response to the unphysiological pharmacokinetics of daily-injected hGH, and that alternate day hGH therapy will prevent it. Thirty-eight prepubertal children with idiopathic short stature, aged 3.3-9.0 yr, were studied. Their heights were less than -2 SD score, growth rate was above the 10th percentile for age, bone age was less than 75% of chronological age, and the stimulated serum GH concentration was greater than 10 microg/liter. The children were matched for sex, height, and growth velocity SD score to receive daily or alternate day hGH at the same weekly dose of 6 mg/m(2) for a period of 2 yr. The 1st and 2nd year mean growth velocities were 3.4 and 2.3 SD score for the daily therapy group and 3.0 and 2.0 SD score for the alternate day group, respectively (P = NS). Over the initial 6 months after withdrawal of therapy, and growth velocity decelerated to a nadir of -3.9 SD score in the daily therapy group, whereas it decelerated in the alternate day group to only -0.2 SD score (P < 0.01). Over the entire 2 yr off therapy the latter group maintained mean growth rates of -0.2 to -1.2 SD score, similar to their pretreatment velocities. The daily group recovered slowly to resume their mean pretreatment rate only on the fourth semiannual evaluation off therapy. The cumulative 4-yr growth velocity (2 yr on and 2 yr off therapy) of the alternate day group was greater than that of the daily therapy group (mean, 0.9 vs. 0.3 SD score; P < 0.002). At the end of the 4-yr therapy period, the adult height prediction of the alternate day group was greater than that of the daily group by a mean 6.5 cm (P = 0.06). It is concluded that growth deceleration after withdrawal of hGH therapy in idiopathic short stature is due to tolerance to GH and IGF-I in response to the unphysiological pharmacokinetics of daily-injected hGH and that alternate day therapy allows for an alternate day physiological GH profile, thus preventing tolerance during therapy and growth deceleration thereafter.

Estrogen mini-dose replacement during GnRH agonist therapy in central precocious puberty: a pilot study.

During GnRH agonist therapy of patients with central precocious puberty (CPP), growth is sometimes suppressed to subnormal velocity. The working hypotheses were that estrogen levels are suppressed by GnRH agonist therapy below normal prepubertal levels, that such suppression is responsible for the slow growth of girls with CPP during GnRH agonist therapy, and that a mini-dose of estrogen replacement will normalize growth. The present pilot study examined growth and bone maturation over 2 yr in 13 patients with CPP and compared therapy with a combination of GnRH agonist and 8 microg conjugated equine estrogen (group 1) to therapy with GnRH agonist alone (group 2). Both groups had adequate suppression of gonadotropins, and E2 levels were below detection levels of our assay throughout the study period. Group 2 patients decreased their growth velocity from 2.0 +/- 1.4 to -1.6 +/- 1.2 SD score compared with group 1, who maintained their growth velocity of 1.3 +/- 1.5 SD score and their height SD score for 2 yr (P < 0.01). In group 1 patients the ratio of the change in bone age/change in chronological age decreased from 1.2 +/- 0.7 to 0.75 +/- 0.3, and in group 2 patients it decreased to 0.6 +/- 0.3 and 0.4 +/- 0.2 (P < 0.05) during the first and second years of therapy, respectively. It is concluded on a pilot basis that estrogen suppression is responsible for the slow growth of girls with CPP during GnRH agonist therapy and that a mini-dose of estrogen replacement is safe and effective for at least 24 months in maintaining normal prepubertal growth without acceleration of bone maturation or pubertal development. The current pilot results do not suggest an indication or provide a justification for such therapy.