Oxandrolone Therapy in Constitutionally Delayed Growth and Puberty

(1)

Oxandrolone

Therapy

in Constitutionally

Delayed

Growth

and

Puberty

PEDIATRICS Vol. 96 No. 6 December 1995 1095

Darrell M. Wilson, MD*; Elizabeth McCauley, PhD; David R. Brown, MD; Robert Dudley, PhDII; and

the Bio-Technology General Corporation Cooperative Study GroupI

ABSTRACT. Background. Male adolescents with

con-stitutional delay of growth and puberty may have

signif-icant psychosocial difficulties related to their sexual

im-maturity and short stature. The purpose of this 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

de-lay of growth and pubertal development.

Methods. Forty boys (ages 11 to 14.7 years) with

de-layed pubertal development and short stature were

re-cruited from the pediatric endocrine clinics of 14 medical

centers. The boys were randomized using a block design

stratified for age to receive either oxandrolone (0.1 mg/kg

daily for 1 year) or an identical-appearing placebo tablet, using a double-masked design.

Results. Growth velocity in the oxandrolone-treated boys was significantly greater than in the control boys (9.5 vs 6.8 cm/y). Likewise, the mean height SD score

increased 0.41 in the oxandrolone group, whereas it

de-creased 0.03 in the control group. Those in the

oxan-drolone group gained 2.4 kg more than those in the

placebo group. Mean predicted adult heights did not

change in either group. The mean rates of pubertal

pro-gression were equivalent in both groups. Self-image

(Piers-Harris Self Concept Scale) and social competence

(child Behavior Profile) were normal at baseline in both

groups and did not change significantly over the course

of the study in either group. No complications of

oxan-drolone therapy were identified.

Conclusions. This randomized, placebo-controlled trial

demonstrates that low-dose oxandrolone can increase

both height and weight velocity in boys with delayed

puberty safely. Under the conditions of this study,

how-ever, the increased growth velocity in the oxandrolone-treated boys was not associated with a greater

improve-ment in psychosocial status compared with the control boys. Pediatrics 199596:1095-1100; oxandrolone, growth, puberty, androgen, adolescents, randomized trial.

From the *pflent of Pediatrics, Stanford University, Stanford, Califor-iiia; Department of Psychiatry and Behavioral Sciences, Children’s Hospi-tal and Medical Center, Seattle, Washington; §Pediatric Endocrinology and

Metabolism, Minneapolis Children’s Medical Center; and IIBio-Technology General Corporation, Iselin, New Jersey.

#{182}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, MD; Jose

Gonzalez, MD; Inger L Hansen, MD; Campbell P. Howard, MD; Louie G.

Linareffi, 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, 5.302 Medical

Center, Stanford, CA 94305-5119.

PEDIATRK3 (ISSN 0031 4008). Copyright C 1995 by the American

Acad-emy of Pediatrics.

ABBREVIATIONS. IGF-I, insulin-like growth factor-I; AST,

aspar-tate aminotransferase; ALT, alanine aminotransferase; GGT,

‘y-glutamyltranspeptidase; LDL, low-density lipoprotein; HDL,

high-density lipoprotein.

The age of puberty varies greatly among healthy adolescents, with 95% of boys entering puberty

be-tween 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 pu-bertal, delay.2 Before the onset of puberty, these boys

have delayed bone ages and low serum

gonado-tropin and testosterone concentrations. Such boys are often short when compared with age-matched controls. Often these boys continue to grow and

de-velop 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

im-maturity and short stature.3 In some cases, these patients have been treated with exogenous andro-gens,47 in an attempt to alleviate some of these psy-chosocial problems. One popular androgen is oxan-drolone (Oxandrin; Bio-Technology General Corp).

This synthetic anabolic steroid is a 17a-alkylated

de-rivative of testosterone, permitting adequate absorp-lion 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

concur-rent control groups and compare growth rates on

oxandrolone with pretreatment growth rates. These

comparisons can be confounded by the normal

in-crease 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 conduded

that 6 to 12 months of oxandrolone treatment can

increase growth velocity in boys with normal variant

constitutional delay significantly.

Acceleration in the rate of pubertal development is

at Viet Nam:AAP Sponsored on September 1, 2020 www.aappublications.org/news

(2)

TABLE 1. Randomized, Controlled Studies of Oxandrolone in Boys With Delayed Puberty

Investigators Year n Dose Duration

(mo)

Growth Rate (cm/y)

Increase in Predicted Adult Height

Psychosocial

Clayton et al2#{176}

Stanhope et al2’

Current study 1988 1988 1993 7 9 10 9 22 20

2.5 mg daily (0.072 mg/kg)

No drug 2.5 mg daily

(0.072 mg/kg) Placebo 0.1 mg/kg Placebo

3 mo on

then 3 mo off 6 3 3 12 12 6.2 3.8 9.6 5.2 9.5 6.7 Not done Not done Not done Not done No change No change Not done Not done Not done Not done No change No change

another goal of therapy with androgens in healthy

boys with delayed puberty. Although some9

advo-cate 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

ox-androlone in young boys (ie, 11 to 14 years of age) in

whom increased growth velocity may be more

im-portant than accelerated pubertal development.

Ox-androlone 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

pu-bertal progress significantly.5 Accordingly,

oxan-drolone is regarded as a weak androgen.8

The purpose of the current study was to test the

hypothesis that I year of oxandrolone therapy would

increase growth velocity and thereby improve

psy-chosocial functioning in boys with constitutional

de-lay of growth and pubertal development.

Boys

METHODS

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

ther-apy 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

labora-tories, 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.

All studies were approved by the committee for the protection

of human subjects in research at each center, and informed

con-sent 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

mu-limeter using direct-reading stadiometers at each visit. The

me-dian 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’#{176}” (Statistical Analysis System for

TABLE 2. Characteristics o f the Study Popula tion at Baseline*

Oxandrolone Placebo

Group Group

No.ofboys 21 19

Age (y) 12.4 ± 0.9 12.4 ± 0.9

Height (cm) 135.4 ± 6.0 134.4 ± 5.1

Height z score (SD) -2.7 ± 0.6 -2.8 ± 0.6

Weight (kg) 29.8 ± 3.8 30.2 ± 4.5

Percent with pubic hair 87% 90%

stage I (%)t

Percent with genital 87% 90%

stage 1 (%) t

Testicular volume (cm3) 3.4 ± 1.8 2.8 ± 2.1

Testosterone (ng/dL) 85 ± 122 79 ± 103

Bone age (y) 10.4 ± 1.6 10.7 ± 1.3

Bone age z score (SD) -2.7 ± 1.3 -2.2 ± 1.0

Predicted adult height (cm) 166.5 ± 6.6 163.9 ± 5.5

Piers-Harris Total Self 61 ± 15 60 ± 13

Concept Scal&6

Total Child Behavior 53 ± 10 54 ± 12

Profile17”8

*Values are mean ± SD. None of these variables were significantly different (P > .1, Wilcoxon rank sum test).

t Tanner stage.

the PC; SAS Institute, Cary, NC) using the normative data of

Tanner and Davies.’ Weight was determined to the nearest 0.1 kg.

Pubertal stage was evaluated using the standards of Marshall and

Tanner,’2 and testicular volume was determined by direct

palpa-tion using a Prader orchidometer.

Bone ages were determined from left hand and wrist

radio-graphs obtained at the baseline, 6-, and 12-month visits. All

radio-graphs 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.’3 Predicted adult heights were

calcu-lated using the method of Bayley and Pinneau.’4’5

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.’6 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

sat-isfaction. Higher scores reflect higher self-esteem. The mean

over-all score from a normative sample of eighth graders was 52 with

an SD of 13.5. The normal range for overall sell-concept falls

between 39 and 53, with scores of 29 or less rated “below average.”

Social competence was measured using the Child Behavior

Pro-file,’7’9 The social competency scales were used as outcome

mea-sures, whereas the behavior scales were used to screen for

preex-isting behavioral problems. Higher scores reflect higher social

(3)

cm/yr

Months

ARTICLES 1097

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 ± 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 I 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.

Al-though 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), puber-tal 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

15

E 10

0

Fig 1. Growth during the course of the study. This graph shows

the mean increase (±SD) in height at each visit compared with the

baseline height.

TABLE 3. Changes Dorm g 12 Months of Treatment*

Oxandrolone Group

Placebo Group

Nuxnberofboys Change in height

(cm/y)t

Change in height z

score (SD/y)t

Change in weightt

(kg/y)t

Change in pubic hair

stage (stage/y)

Change in genital stage

(stage/y) Change in testicular

volume (cm3/y)

Change in testosterone (ng/mL)

Change in bone age (y4

Change in bone age z

score (5D4 Change in predicted

adult height (cm) Change Piers-Harris Self

Concept Scal&6

Change Child

Behavior Profile’7”8

21 9.5 ± 1.7

0.41 ± 0.29

6.6 ± 1.6

0.9 ± 0.6

1.2 ± 0.7

2.6 ± 2.9

38 ± 149

2.2 ± 0.9 1.6 ± 1.1j

-0.2 ± 5.4

4.7 ± 10.0

-2.5 ± 7.2

19 6.8 ± 2.8

-0.03 ± 0.43

4.2 ± 2.6

0.9 ± 0.9

0.9 ± 0.7

2.3 ± 2.0

188 ± 193

1.6 ± 0.9 0.8 ± 1.0

0.5 ± 3.8

5.2 ± 6.6

-2.8 ± 7.2

* Values are mean ± SD, oxandrolone versus placebo (Wilcoxon

rank sum test). tP < .001. j: P < .05.

8

a’

>

.c

0

C,

03 C 0

a’

0 x w C a’ e a’

0.

Fig 2. Growth velocity. Each bar shows the percentage of boys

who exceed a given growth velocity (x axis). Solid bars denote the

oxandrolone group; open bars denote the placebo group.

group gained 2.4 kg more than those in the placebo

group (P = .0006, Wilcoxon).

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

mea-sured 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).

(4)

A

13

12

11

10

9

8

7 6 5

4 3 I

5

0

.5

11.5 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5

a’ 10

1 g

I-C

-15

0

-20

11.5 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5

Age (yr)

Fig 3. Growth velocity versus age. Triangles denote those boys in

the oxandrolone group; cirdes denote those in the placebo group.

Boys who remained prepubertal (testicular volume mL) through

the study year are shown by the solid symbols; those who entered

puberty are shown by the open symbols.

Psychosocial Changes

Self-image, as measured by Piers-Harris Self

Con-cept Scale,16 was normal at baseline in both groups.

Although both groups exhibited modest

improve-ment, neither the total score nor any of the subscale

scores changed significantly during the course of the

study (Table 3). Likewise, social competence, as mea-sured using the Child Behavior Proffle,’7”8 was nor-mal at baseline in both groups and did not change significantly in either group. There was no

associa-lion between changes measured using either of these

instruments and growth velocity in the entire group

(ie, placebo and oxandrolone groups combined).

Ad-ditionally, 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

as-partate aminotransferase (AST), alanine

aminotrans-ferase (ALT), and ‘y-glutamyltranspeptidase (GGT) (Table 4). GGT rose slightly more in the placebo

group than the oxandrolone group (P = .04,

Wil-coxon). The changes in both the AST and ALT were

equivalent in both groups (P > .18, Wilcoxon).

Like-wise, the changes in serum alkaline phosphatase

con-centrations were similar in both groups during the

course of the study. Fasting glucose concentrations

were similar in both groups.

Total and low-density lipoprotein (LDL)

choles-terol did not change significantly in either group. The mean change in high-density lipoprotein (HDL)

cholesterol was 5 mg/dL in the placebo group,

sig-nificantly 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.

25

20

I

15

E 10

a’

a.

C

.10

.15

-20

- A

0 Oxandrokne

. A Pubertal

A A ANOI

. A A A Placebo

S. . 0. PubertalNot

A A AO _OA

-0A #{176}A AA

I I I I

11.5 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5

B

Age (yr)

0

A

0

A

0 A AAo

A A

A

. #{149}

SA 0 A

Obo

004’ A Aputerta

A

. . A Placebo

. 0 OPubertal

. Not

I I I I A

Age (yr)

Fig 4. Psychosodal changes versus age. A, changes in the

Piers-Harris Seff Concept Scale.’6 B, changes in the Child Behavior

Proffle.’7’8 Triangles denote those boys in the oxandrolone group;

cirdes denote those in the placebo group. Boys who remained

prepubertal (testicular volume 4 mL) through the study year are

shown by the solid symbols; those who entered puberty are

shown by the open symbols.

Complications

No complications of oxandrolone therapy were

detected during this study.

Growth

DISCUSSION

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,#{176}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 pre-dicted adult height did not change during the course

(5)

TABLE 4. Laboratory Data*

ARTICLES 1099

Oxandrol one Group Placebo Group

Baseline 12 mo Baseline 12 mo

GGT (U/L)t 13.8 ± 4.0 13.8 ± 3.0 11.9 ±4.3 13.2 ± 4.0

AST (U/L) 27.1 ± 4.4 25.8 ±4.0 24.7 ±4.5 26.1 ± 7.8

ALT (U/L) 14.7 ± 4.2 20.4 ± 10.3 16.6 ± 6.1 18.5 ± 13.4

Alkaline phosphatase (U/L) 245 ± 78 337 ± 105 218 ± 65 291 ± 108

Glucose (mg/dL) 87± 7 89 ± 6 88 ± 8 90±12

Cholesterol (mg/dL) 170 ± 22 156 ±25 169 ±42 166 ± 43

HDL(mg/dL4 43±9 36±13 44±9 49±9

LDL (mg/dL) 115 ±21 108 ±29 111 ±36 103 ± 35

IGF-I (nmol/L) 19.8 ± 7.1 27.9 ±9.2 20.0 ±6.2 29.0 ± 10.4

* Change in value (12-month minus baseline values), oxandrolone versus placebo (Wilcoxon rank sum

test). t P < .05.

:t:P < .0001.

of the study. Although there are no randomized, controlled studies of the effect of oxandrolone on

final adult height, a number of investigators6’

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

oxan-drolone may have delayed pubertal progression

transiently in those receiving oxandrolone. Mathotra

et al8 reported that 3 months of oxandrolone

sup-pressed both luteinizing hormone and testosterone

concentrations in boys with delayed puberty.

Hop-wood et al5 similarly found that treatment with ei-ther oxandrolone or fluoxymesterone suppressed both gonadotropins and serum testosterone in boys with delayed puberty.

Psychosocial Function

Short statur&426 and delayed pubertal

develop-ment 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)’6 and normal social competence (as measured

using the Child Behavior Profile).17’18 Many

investi-gators have suggested that increasing growth

veloc-ity and the rate of pubertal progression results in

improved psychosocial functioning. There have

been, however, few well-controlled studies that

di-rectly address the question, “Does normalization of

either stature or the stage of pubertal development

result in improved psychosocial functioning.” In

an-alyzing data from the National Health Examination

Survey, Wilson et al24 demonstrated that

spontane-ous increases in height among 2117 children evalu-ated twice at 2- to 5-year intervals were not

associ-ated with any improvement in achievement test

results. Conversely, Rosenfeld et al3 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

signifi-cant 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

pro-gression through puberty. The boys in this study

were recruited from the practices of pediatric endo-crinologists. 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

demon-strable psychosocial problems. Thus, it is possible

that any potential psychosocial benefit of oxan-drolone therapy is restricted to those boys with

sig-nificant 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

per-ception of physical change may be important to

achieving a measurable benefit. Moreover,

oxan-drolone 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 a13

and Wilson et al.9 It is not difficult to hypothesize

that noticeable changes in external genitalia are

im-portant 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

ox-androlone therapy in previous uncontrolled trials. To

our knowledge, no other randomized,

placebo-controlled trial has examined the effect of oxan-drolone on psychosocial status or achievement.

(6)

Laboratory Results

Oxandrolone therapy did not result in any

clini-cally significant changes in laboratory results. This is

particularly true for liver function tests, because

an-drogenic anabolic steroids as a therapeutic class have

been associated with hepatotoxicity. A trend toward

higher alkaline phosphatase concentrations was

ob-served 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

alka-line phosphatase activity were not considered

cmi-cally important.

There was a significant fall in mean HDL

choles-terol 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

choles-terol levels by drugs such as oxandrolone is

fran-sient, 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

pu-berty. Compared with other available treatment

mo-dalities (eg, testosterone enanthate and growth

hor-mone), oxandrolone has the advantage of being an

oral medication, which may appeal to both

physi-cians and their patients.

ACKNOWLEDGMENT

Supported by Bio-Technology General Corporation (formerly

Gynex Pharmaceuticals, Inc).

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4. Kaplan JG, Moshang T Jr. Bernstien R, Parks JS, Bongiovanni AM. Constitutional delay of growth and development: effects of treatment with androgens. I Pediatr. 197382:38-44

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Pediatrics

Bio-Technology General Corporation Cooperative Study Group

Darrell M. Wilson, Elizabeth McCauley, David R. Brown, Robert Dudley and