Oxandrolone therapy in constitutionally delayed growth and puberty
Darrell M. Wilson
ABBREVIATIONS. IGF-I, insulin-like growth factor-I; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, [gamma]-glutamyltranspeptidase; LDL, low-density lipoprotein; HDL, high-density lipoprotein.
The age of puberty varies greatly among healthy adolescents, with 95% of boys entering puberty between 9.2 and 13.8 years of age.[1] Although some boys who are short and who have late onset of puberty have significant organic diseases, most have benign growth patterns referred to as constitutional, or pubertal, delay.[2] Before the onset of puberty, these boys have delayed bone ages and low serum gonadotropin and testosterone concentrations. Such boys are often short when compared with age-matched controls. Often these boys continue to grow and develop sexually after their peers have stopped and frequently reach final adult heights well within their expected genetic range.
Despite the normal ultimate adult height achieved by most of these adolescents, some have significant psychosocial difficulties relating to their sexual immaturity and short stature.[3] In some cases, these patients have been treated with exogenous androgens,[4-7] in an attempt to alleviate some of these psychosocial problems. One popular androgen is oxandrolone (Oxandrin; Bio-Technology General Corp). This synthetic anabolic steroid is a 17 [alpha]-alkylated derivative of testosterone, permitting adequate absorption when given orally. Oxandrolone acts directly as an androgen because it cannot be aromatized to estrogen.[8]
Although many potential uses of oxandrolone have been explored, current clinical use is generally limited to growth acceleration and the advancement of puberty. Few randomized, controlled trials have been performed (Table 1). Most other studies of the effect of oxandrolone on the growth of boys with delayed puberty have significant methodologic shortcomings. Many of these studies have no concurrent control groups and compare growth rates on oxandrolone with pretreatment growth rates. These comparisons can be confounded by the normal increase in growth velocity associated with puberty. Some studies with concurrent control groups do not randomly assign boys to treatment or observation, thus disallowing direct comparison of the groups. Given these limitations, most studies have concluded that 6 to 12 months of oxandrolone treatment can increase growth velocity in boys with normal variant constitutional delay significantly.
[TABULAR DATA 1 OMITTED]Acceleration in the rate of pubertal development is another goal of therapy with androgens in healthy boys with delayed puberty. Although some[9] advocate the use of short courses of injectable testosterone to achieve rapid acceleration of pubertal progression, this treatment is usually reserved for boys 14 years of age or older. Others recommend the use of oral oxandrolone in young boys (ie, 11 to 14 years of age) in whom increased growth velocity may be more important than accelerated pubertal development. Oxandrolone therapy in doses as great as 0.2 mg/kg daily for 6 to 12 months, however, does not seem to advance or interfere with the physical signs of pubertal progress significantly.[5] Accordingly, oxandrolone is regarded as a weak androgen.[8]
The purpose of the current study was to test the hypothesis that 1 year of oxandrolone therapy would increase growth velocity and thereby improve psychosocial functioning in boys with constitutional delay of growth and pubertal development.
METHODS
Boys
Forty-four boys from 14 medical centers (see footnote for a list of investigators) were invited to participate in this study if they met the following criteria: (1) age between 11 and 14 years; (2) height more than 2 SD below the mean height for age; (3) a bone age greater than or equal to 9 years; (4) a bone age delay of more than 1 year; 5) pubertal stage development of Tanner 2 or less; (6) normal intellectual skills; and (7) normal thyroid function. Boys were excluded if they had growth hormone deficiency, prior therapy with either growth hormone or androgens, or serious medical conditions. One older boy, 14.7 years of age, was inadvertently entered into the study.
The boys were randomized using a block design stratified for age to receive either oxandrolone (0.1 mg/kg daily; n = 23) or an identical-appearing placebo tablet (n = 21). The boys, the laboratories, and the on-site investigators were masked to the group assignment throughout the study. Two boys in the oxandrolone group (one lost to follow-up and one by patient request) and two in the placebo group (one noncompliant and one with stomach pain) left the study before its completion. Baseline characteristics of the study groups are shown in Table 2.
[TABULAR DATA 2 OMITTED]All studies were approved by the committee for the protection of human subjects in research at each center, and informed consent was obtained from each boy’s parents.
Assessments
An interval history and a physical examination were preformed at baseline and at 3, 6, 9, and 12 months.
Auxologic Measurements
Standing height was measured in triplicate to the nearest millimeter using direct-reading stadiometers at each visit. The median of these three determinations was used in the data analysis. To remove the confounding effects of differing ages, height SD scores (z score) were calculated[10,11] (Statistical Analysis System for the PC; SAS Institute, Cary, NC) using the normative data of Tanner and Davies.[1] Weight was determined to the nearest 0.1 kg. Pubertal stage was evaluated using the standards of Marshall and Tanner,[12] and testicular volume was determined by direct palpation using a Prader orchidometer.
Bone ages were determined from left hand and wrist radiographs obtained at the baseline, 6-, and 12-month visits. All radiographs were interpreted at the Fels Institute (Yellow Springs, OH). Bone age SD scores (z scores) were calculated using the normative data of Greulich and Pyle.[13] Predicted adult heights were calculated using the method of Bayley and Pinneau.
Laboratory Studies
Blood for laboratory studies was obtained from fasting boys at the baseline, 6-, and 12-month visits. All studies were performed at a central laboratory (SciCor, Indianapolis, IN). Insulin-like growth factor I (IGF-I) concentrations were measured using the INCSTAR (Stillwater, MN) radioimmunoassay after a solid-phase octadecasilyl-silica extraction step to remove binding protein.
Psychosocial Studies
Self-image was measured using the Piers-harris Self Concept Scale.[16] Scoring gives an overall self-concept score and subscale scores for six factors: behavior, intellectual and school status, physical appearance, anxiety, popularity, and happiness and satisfaction. Higher scores reflect higher self-esteem. The mean overall score from a normative sample of eighth graders was 52 with an SD of 13.5. The normal range for overall self-concept falls between 39 and 53, with scores of 29 or less rated “below average.” Social competence was measured using the Child Behavior Profile,[17-19] The social competency scales were used as outcome measures, whereas the behavior scales were used to screen for preexisting behavioral problems. Higher scores reflect higher social competence. For the overall social competency scale, the mean T score from a normative sample of boys 12 to 18 years of age was 50.3 with an SD of 9.7. Total social competence T scores greater than 35 are in the normal range; scores of 35 to 30 are in the borderline abnormal range; and scores less than 30 are in the abnormal range. These assessments were obtained at baseline and at the 6- and 12-month visits.
Analysis
The data were analyzed using Statistical Analysis System for the PC. The two-tailed Wilcoxon rank sum test was used to compare groups on continuous variables, because many were not normally distributed. The Spearman rank correlation method was used as a measure of association between variables. A z score (SD score) was calculated for some variables (see text) to reduce the confounding effects of chronologic age. P < .05 (two-tailed) was considered significant. Data are presented as mean [+ or -] SD.
RESULTS
Baseline characteristics of the boys in each group were similar (Table 2).
Growth
Boys in the oxandrolone group had rapid and sustained increases in growth velocity (Fig 1 and Table 3). Those boys in the oxandrolone group grew on average 2.6 cm more than those in the placebo group (P = .0007, Wilcoxon) during the year of study. The percentage of boys in each treatment group who achieved a given growth velocity during the 12-month study period is shown in Fig 2. Although all boys in both groups had growth velocities greater than 3.6 cm/y, substantially more boys treated with oxandrolone achieved growth velocities between 5 and 11 cm/y. Likewise, the mean height SD score increased 0.41 in the oxandrolone group, whereas it decreased 0.03 in the control group (P = .0007, Wilcoxon). Growth velocity during the year of the study was not associated with age (Fig 3), pubertal status at baseline (testicular volume), or rapidity of pubertal progress (change in testicular volume) in either group analyzed separately or in the group as a whole (P > .1, Spearman). Those in the oxandrolone group gained 2.4 kg more than those in the placebo group (P = .0006, Wilcoxon).
[TABULAR DATA 3 OMITTED]Although the boys receiving oxandrolone grew faster, their bone ages advanced more rapidly. Mean bone age advancement during the year of the study was 0.6 years greater in the oxandrolone group (P = .02, Wilcoxon). As a result, mean predicted adult heights (Table 3) did not change in either group (P > .5, Wilcoxon).
Pubertal Changes
The mean rates of pubertal progression, as measured by either Tanner stages or testicular volumes (Table 3), were equivalent in both groups. The mean change in the testosterone concentration (available in 12 boys in the oxandrolone group and 14 boys in the placebo group) tended to be greater in the placebo group (38 vs 188 ng/mL; P = .07, Wilcoxon).
Psychosocial Changes
Self-image, as measured by Piers-Harris Self Concept Scale,[16] was normal at baseline in both groups. Although both groups exhibited modest improvement, neither the total score nor any of the subscale scores changed significantly during the course of the study (Table 3). Likewise, social competence, as measured using the Child Behavior Profile,[17,18] was normal at baseline in both groups and did not change significantly in either group. There was no association between changes measured using either of these instruments and growth velocity in the entire group (ie, placebo and oxandrolone groups combined). Additionally, no associations were seen when each of the groups were analyzed separately (Fig 4).
Laboratory Data
The potential effects of oxandrolone on the liver were monitored using serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and [gamma]-glutamyltranspeptidase (GGT) (Table 4). GGT rose slightly more in the placebo group than the oxandrolone group (P = .04, Wilcoxon). The changes in both the AST and ALT were equivalent in both groups (P > .18, Wilcoxon). Likewise, the changes in serum alkaline phosphatase concentrations were similar in both groups during the course of the study. Fasting glucose concentrations were similar in both groups.
[TABULAR DATA 4 OMITTED]Total and low-density lipoprotein (LDL) cholesterol did not change significantly in either group. The mean change in high-density lipoprotein (HDL) cholesterol was 5 mg/dL in the placebo group, significantly different (P = .0001, Wilcoxon) than the mean change of -9 mg/dL in the oxandrolone group (Table 4).
Mean IGF-I concentrations rose an equivalent amount in each group.
Complications
No complications of oxandrolone therapy were detected during this study.
DISCUSSION
Growth
In the current study, we found that those in the oxandrolone group grew, on average, 2.6 cm/y faster than those in the placebo group during the year of the study. Two smaller randomized,[20,21] controlled studies of the effect of oxandrolone (Table 1) in boys with pubertal delay also show similar acute increases in growth velocity.
As expected, based on earlier reports of the effect of androgens on skeletal maturation, oxandrolone also modestly increased the velocity of bone age advancement compared with that in control boys. Thus, despite the increase in growth rate, the predicted adult height did not change during the course of the study. Although there are no randomized, controlled studies of the effect of oxandrolone on final adult height, a number of investigators[6,22,23] have addressed this issue. These investigators found no increase in final adult height among the treated boys. Therefore, although high doses of androgens can decrease final adult height, the data from the current study and those past demonstrate that low-dose androgen therapy does not alter final adult stature significantly.
Pubertal Changes
On physical examination, we found that the two groups had equivalent rates of pubertal progression. Changes in testosterone concentrations during the first year were available in 63% of our boys. Increases in serum testosterone tended to be greater in the placebo group. This difference suggests that oxandrolone may have delayed pubertal progression transiently in those receiving oxandrolone. Malhotra et al[8] reported that 3 months of oxandrolone suppressed both luteinizing hormone and testosterone concentrations in boys with delayed puberty. Hopwood et al[5] similarly found that treatment with either oxandrolone or fluoxymesterone suppressed both gonadotropins and serum testosterone in boys with delayed puberty.
Psychosocial Function
Short stature[24-26] and delayed pubertal development has been associated with decreased social and academic functioning in boys. The boys enrolled in the current trial, however, had normal self-images (as measured using the Piers-Harris Self Concept Scale)[16] and normal social competence (as measured using the Child Behavior Profile).[17,18] Many investigators have suggested that increasing growth velocity and the rate of pubertal progression results in improved psychosocial functioning. There have been, however, few well-controlled studies that directly address the question, “Does normalization of either stature or the stage of pubertal development result in improved psychosocial functioning.” In analyzing data from the National Health Examination Survey, Wilson et al[24] demonstrated that spontaneous increases in height among 2117 children evaluated twice at 2- to 5-year intervals were not associated with any improvement in achievement test results. Conversely, Rosenfeld et al[3] demonstrated in a randomized study that a short course of high dose testosterone enanthate therapy improved the self-image and level of social activity in a group of 16 boys with delayed puberty.
In the current trial, we did not detect any significant improvement in self-image or social competence among the boys receiving oxandrolone. There are a number of possible reasons for this. Many clinicians suggest that only a minority of boys have adverse psychosocial impacts as a result of a delayed progression through puberty. The boys in this study were recruited from the practices of pediatric endocrinologists. This implies that they or their parents were not satisfied with their stature and/or their pattern of pubertal progression. Entry into this trial, however, did not require that the boys have demonstrable psychosocial problems. Thus, it is possible that any potential psychosocial benefit of oxandrolone therapy is restricted to those boys with significant preexisting behavioral dysfunction.
Although oxandrolone clearly caused significant increases in both height and weight velocity, these changes may be too small for the individual boy or parent to notice over the short term. The boy’s perception of physical change may be important to achieving a measurable benefit. Moreover, oxandrolone therapy did not induce detectable changes in the boys’ genitalia. This is in contrast to the dramatic changes in genitalia seen after short-term therapy with testosterone as described by Rosenfeld et al[3] and Wilson et al.[9] It is not difficult to hypothesize that noticeable changes in external genitalia are important for psychosocial benefit, particularly for older boys (ie, older than 14 years of age).
Finally, outside of clinical trials, physicians and nurses often accentuate the positive aspects of even small changes in stature or pubertal development. As a consequence, it is possible that this placebo effect results in much of the improvement claimed for oxandrolone therapy in previous uncontrolled trials. To our knowledge, no other randomized, placebo-controlled trial has examined the effect of oxandrolone on psychosocial status or achievement.
Laboratory Results
Oxandrolone therapy did not result in any clinically significant changes in laboratory results. This is particularly true for liver function tests, because androgenic anabolic steroids as a therapeutic class have been associated with hepatotoxicity. A trend toward higher alkaline phosphatase concentrations was observed in the oxandrolone group. The magnitude of the change from baseline for individual boys did not exceed 1.5 times the upper range of normal, and increases were seen in both the oxandrolone-treated (n = 7) and placebo-treated (n = 3) boys. Alkaline phosphatase activity increases during skeletal bone growth, and because oxandrolone stimulates growth and increased bone maturation, the changes in alkaline phosphatase activity were not considered clinically important.
There was a significant fall in mean HDL cholesterol concentrations among those in the oxandrolone group. Oral androgenic anabolic steroids are known to cause a decrease in HDL cholesterol. However, levels after 12 months of oxandrolone therapy were near the lower limit for normal, and LDL cholesterol levels did not rise. The suppression of HDL cholesterol levels by drugs such as oxandrolone is transient, with levels returning to normal after cessation of therapy, and, thus, the lower HDL cholesterol levels were not considered clinically significant.
One reason for the use of growth-promoting agents in boys with constitutional delay of growth and puberty is to foster a linear growth pattern that is more consistent with their peers. The results from the current randomized, placebo-controlled clinical trial indicate that low-dose oxandrolone can be used safely to increase growth velocity and weight gain in boys with constitutional delay of growth and puberty. Compared with other available treatment modalities (eg, testosterone enanthate and growth hormone), oxandrolone has the advantage of being an oral medication, which may appeal to both physicians and their patients.
ACKNOWLEDGMENT
Supported by Bio-Technology General Corporation (formerly Gynex Pharmaceuticals, Inc).
REFERENCES
[1.] Tanner JM, Davies PSW. Clinical longitudinal standards for height and height velocity of North American children. J Pediatr. 1985;107:317-3292 [2.] Rosenfeld RG. Evaluation of growth and maturation in adolescence. Pediatr Rev. 1982;4:175-183 [3.] Rosenfeld RG, Northcraft GB, Hintz RL. A prospective, randomized study of testosterone treatment of constitutional delay of growth and development in male adolescents. Pediatrics. 1982;69:681-687 [4.] Kaplan JG, Moshang T Jr, Bernstien R, Parks JS, Bongiovanni AM. Constitutional delay of growth and development: effects of treatment with androgens. J Pediatr. 1973;82:38-44 [5.] Hopwood NJ, Kelch RP, Zipf WB, Hernandez RJ. The effect of synthetic androgens on the hypothalamic-pituitary-gonadal axis in boys with constitutionally delayed growth. J Pediatr. 1979;94:657-662 [6.] Blethen SL, Gaines S, Weldon V. Comparison of predicted and adult heights in short boys: effect of androgen therapy. Pediatr Res. 1984;18: 467-469 [7.] Martin MM, Martin ALA, Mossman KL. Testosterone treatment of constitutional delay in growth and development: effect of dose on predicted versus definitive height. Acta Endocrinol (Copenh). 1986; 113(supp] 279):147-152 [8.] Malhotra A, Poon E, Tse WY, Pringle PJ, Hindmarsh PC, Brook CG. The effects of oxandrolone on the growth hormone and gonadal axes in boys with constitutional delay of growth and puberty. Clin Endocrinol (Oxf). 1993;38:393-398 [9.] Wilson DM, Kei J, Hintz RL, Rosenfeld RG. Effects of testosterone therapy for pubertal delay. Am J Dis Child. 1988;142:96-98 [10.] Wilson DM, Killen JD, Hammer LD, et al. Insulin-like growth factor-I as a reflection of body composition, nutrition, and puberty in sixth and seventh grade girls. J Clin Endocrinol Metab. 1991;73:907-912 [11.] Wilson DM, Lee PDK, Morris AH, et al. Growth hormone therapy in hypophosphatemic rickets. Am J Dis Child. 1991;145:1165-1170 [12.] Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 1970;45:13-23 [13.] Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist. 2nd ed. Stanford, CA: Stanford University Press; 1959 [14.] Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. J Pediatr. 1952;50:423-441 [15.] Post EM, Richman RA. A condensed table of predicting adult stature. J Pediatr. 1981;98:440-441 [16.] Piers EV. Revised Manual for Piers-Harris Children’s Self Concept Scale. Los Angeles: Western Psychological Services; 1984 [17.] Achenbach T. The Child Behavior Profile: I. Boys aged 6-11. J Consult Clin Psychol. 1978;43:478-488 [18.] Acbenbach T, Edelbrock C. The Child Behavior Profile. II. Boys aged 12-16 and girls aged 6-11 and 12-16. J Consult Clin Psychol. 1979;47: 223-233 [19.] Achenbach T, Edelbrock C. Behavioral problems and competencies reported by parents of normal and disturbed children age 4-16. Monogr Soc Res Child Dev. 1981;46:1-82 [20.] Clayton PE, Shalet SM, Price DA, Addison GM. Growth and growth hormone responses to oxandrolone in boys with constitutional delay of growth and puberty (CDGP). Clin Endocrinol (Oxf). 1988;29:123-130 [21.] Stanhope R, Buchanan CR, Fenn GC, Preece MA. Double blind placebo controlled trial of low dose oxandrolone in treatment of boys with constitutional delay of growth and puberty. Arch Dis Child. 1988;63: 501-505 [22.] Joss EE, Schmidt HA, Zuppinger KA. Oxandrolone in constitutionally delayed growth, a longitudinal study up to final height. J Clin Endocrinol Metab. 1989;69:1109-1115 [23.] Bassi F, Neri AS, Gheri RG, Cheli D, Serio M. Oxandrolone in constitutional delay of growth: analysis of the growth patterns up to final stature. J Endocrinol Invest. 1993;16:133-137 [24.] Wilson DM, Hammer LD, Duncan PM, et al. Height and intellectual development. Pediatrics. 1986;78:646-650 [25.] Gordon M, Crouthamel C, Post EM, Richman RA. Psychosocial aspects of constitutional short stature: social competence, behavior problems, self-esteem, and family functioning. J Pediatr. 1982;101:477-480 [26.] Stabler B, Underwood L, eds. Slow Grows the Child: Psychosocial Aspects of Growth Delay. Hillsdale, NJ: Lawrence Erlbaum Associates; 1986Darrel M. Wilson, MD(*); Elizabeth McCauley, PhD([double dagger]); David R. Brown, MD([sections]); Robert Dudley, PhD([parallel]); and the Bio-Technology General Corporative Study Group([paragraph])
From the (*)Department of Pediatrics, Stanford University, Stanford, California; ([double dagger])Department of Psychiatry and Behavioral Sciences, Children’s Hospital and Medical Center, Seattle, Washington; ([sections])Pediatric Endocrinology and Metabolism, Minneapolis Children’s Medical Center; and ([parallel])Bio-technology General Corporation, Iselin, New Jersey. ([paragraph])Members of the Bio-Technology General Corporation Cooperative Study Group: Michael Ainslie, MD; Dennis Carey, MD; Mark M. Danney, MD; Larry C. Deeb, MD; Michael A. Donlan, MD; Deborah V. Edidin, NW; Jose Gonzalez, MD; Inger L. Hansen, MD; Campbell P. Howard, MD; Louie G. Linarelli, MD; Karen Rubin, MD; Rogelio Ruvalcaba, MD; Desmond Schatz, MD; and Jeffery S. Shulz, MD. Received for publication Sep 9, 1994; accepted Dec 22, 1994. Reprint requests to (D.M.W.) Associate Professor, Pediatrics, S-302 Medical Center, Stanford, CA 94305-5119. PEDIATRICS (ISSN 0031 4005). Copyright [C] 1995 by the American Academy of Pediatrics.
COPYRIGHT 1995 American Academy of Pediatrics
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