This two-year study consisted of a comparison of oxandrolone and growth hormone for the treatment of five children with documented growth hormone deficiency. Previously, androgens have been reported to be relatively ineffective in accelerating linear growth In growth hormone deficient children. Oxandrolone was administered for one year. Growth hormone was added in the second six months and then was given as a single agent in the third six months. Growth accelerated markedly in all patients. Only one child showed more rapid growth with the addition of growth hormone while two children actually grew more rapidly under the Influence of oxandrolone alone. Growth was poor and diminished when growth hormone was given as a single agent in the third six-month period for three children but improved when oxandrolone was re-instituted in a fourth six-month treatment period. These results suggest that oxandrolone may prove to be an effective and safe substitute for growth hormone in the management of selected cases of hypopituitarism

Mellinger, Raymond C.

Morrow, Lewis B.

Saeed-uz Zafar, M.

Wolf, Charles B.

English

Henry Ford Health System Scholarly Commons

Henry Ford Hospital Medical JournalVolume 21 | Number 4 Article 212-1973The Effectiveness of Oxandrolone in PromotingLinear Growth in Growth Hormone DeficientChildrenCharles B. WolfRaymond C. MellingerLewis B. MorrowM. Saeed-uz ZafarFollow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournalPart of the Life Sciences Commons, Medical Specialties Commons, and the Public HealthCommonsThis Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in HenryFord Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons.Recommended CitationWolf, Charles B.; Mellinger, Raymond C.; Morrow, Lewis B.; and Saeed-uz Zafar, M. (1973) "The Effectiveness of Oxandrolone inPromoting Linear Growth in Growth Hormone Deficient Children," Henry Ford Hospital Medical Journal : Vol. 21 : No. 4 , 163-167.Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol21/iss4/2Henry Ford Hosp. Med . Journal Vol . 21 , No. 4, 1973 The Effectiveness of Oxandrolone in Promoting Linear Growth in Growth Hormone Deficient Children Charles B. Wol f , M D , * Raymond C. Mel l inger, M D , * * Lewis B. Mor row, MD,* and M. Saeed-uz Zafar, M D * * * * This two-year study consisted of a compari-son of oxandrolone and growth hormone for the treatment of five children with doc-umented growth hormone deficiency. Previ-ously, androgens have been reported to be relatively ineffective in accelerating linear growth In growth hormone deficient children. Oxandrolone was administered for one year. Growth hormone was added in the second six months and then was given as a single agent in the third six months. Growth accelerated markedly in all patients. Only one child showed more rapid growth with the addition of growth hormone while two children actually grew more rapidly under the Influence of ox-androlone alone. Growth was poor and di-minished when growth hormone was given as a single agent in the third six-month period for three children but improved when oxan-drolone was re-instituted in a fourth six-month treatment period. These results suggest that oxandrolone may prove to be an effective and safe substitute for growth hormone in the management of selected cases of hypopituitarism. •Department of Pediatrics, Henry Ford Hospi-tal. **Chief, Division of Endocrinology, Henry Ford Hospital, and Clinical Associate Profes-sor, University of Michigan College of Medicine, Ann Arbor, Michigan. ***Director, Endocrinology Unit, Highland Hospital of Rochester, and Assistant Professor of Medicine, University of Rochester College of Medicine, Rochester, New York. ****Division of Endocrinology, Henry Ford Hospital. O X A N D R O L O N E has been employed increasingly in thet reatment of shortness of stature of d i f fer ing etiology because of its high anabolic potency and low viri l iz-ing p r o p e r t i e s . S t r u c t u r a l l y the an-drogen is 17 alpha-methyl-2-oxa-5 alpha androstan-17 beta-ol-3-one. It has been suggested that androgens enhance the secretion of growth hormone and that this may be responsible for the pubertal growth s p u r t . A l s o , there is evidence that an androgen is inef fect ive as an anabolic agent in hypophysectomized animals. ' " Androgens previously have been found to be less anabolic in growth hormone deficient chi ldren than in chil-dren w i th shortness of stature due to other causes . " " " The nitrogen storing ef-fect of androgen is not dependent upon growth hormone, however, and does not involve exclusively the same metabolic mechanism inasmuch as the two hor-mones have been shown to manifest separate protein anabolic effects and to These data were presented in part at the XIII International Congress of Pediatrics, Vienna, 1971. Address reprint requests to Dr. Wolf at Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Ml 48202 163 Wolf, Mellinger, Morrow and Zafar synergize when given to rats.'" Further-more , testosterone is capable of aug-menting nitrogen storage in acromegalic subjects w h o are presumably already max ima l l y s t i m u l a t e d by g r o w t h h o r m o n e . A study was therefore de-signed in wh ich oxandro lone was ad-m i n i s t e r e d to f ive c h i l d r e n w i t h d o c u m e n t e d g r o w t h h o r m o n e d e f i -ciency, and compared to growth hor-mone as an agent for induc ing linear growth in the same chi ldren. Materials and Methods Subjects: f o r study five chi ldren were chosen ranging in age f rom 10 and ''/12 years to 12 and */i2 years. All were dwarfed and had physical characteristics compatible wi th hypop i tu i ta r i sm. All had g rowth hor-mone def ic iency p roved by rad io im-munoassay after arginine and insulin in-f us i on . They had no o ther d isorders which might cause shortness of stature. All had retardation of osseous maturation (delayed bone age). None had clinical h y p o g l y c e m i a . O n e pa t i en t had a craniopharyngioma (postoperative) wi th residual diabetes insipidus and had not manifested a "ca tch-up" spurt of growth fo l lowing surgery. 5fud/es; Growth hormone deficiency was reaf-f i rmed after arginine and insulin stimula-t ion immedia te ly p r io r to t rea tment . Growth hormone release was then reas-sessed after nine days of oxandrolone treatment and after six months of oxan-d ro lone t rea tment . Oxandro lone was given (.1 mg per ki logram body weight per day) for six months and then growth hormone was added to the regimen for six mon ths ( two uni ts th ree t imes a week) . The th i rd six-month treatment in-terval consisted of human growth hor-mone wi thout concomitant oxandrolone and the four th treatment period of six months consisted of the administration of oxandrolone alone. The total durat ion of treatment was two years. SGOT, PBI, CBC and growth hormone antibody were determined every two months and bone age was assessed every six months. Results Growth accelerated markedly in all cases ranging f r om 3% inches to bVi inches wi th one year and 6Vs inches to 9^* inches wi th two years of treatment (Table 1). The addit ion of HGH after six months of oxandrolone led to more rapid growth in only one ch i ld . Two chi ldren actually grew more rapidly under the inf luence of oxandrolone alone. In two , growth was equal dur ing both six-month treatment per iods. Reassessment of growth hor-mone responsiveness after oxandrolone admin is t ra t ion showed no signif icant augmen ta t i on or increase in g r o w t h Figure 1 Graph showing growth increments for the five children for the two-year treatment period. The various treatment regimens are indicated. Each lasted six months. Fleight is in centime-ters. 164 Oxandrolone and Growth Hormone T A B L E I CL IN ICAL DETAILS AND GROWTH DATA FOR THE 5 CHILDREN FOR 2 Y E A R S 6 Months Before 6 Months Oxandrolone 6 Months 6 Months Patients Treatment Oxandrolone Growth Hormone Growth Hormone Oxandrolone RR (M) 10 4/12 yrs. N thyroid i ACTH SW (M) 11 8/12 yrs. Craniopharyngioma Diabetes insipidus i thyroid LK(F) 12 6/12 yrs. N thyroid N ACTH Familial CT (M) 12 6/12 yrs. N thyroid N ACTH ST (M) 11 3/12 yrs. N thyroid i ACTH HT HTt BA HT HTt BA HT HT-BA HT HT' BA HT HT-BA 45 4 46y4 7 44'/4 8 ' ! 51 5 4 7 U 4V2 48V2 2V4 7V2 3'... 10'/2 53'.-. 2'-4 8'; 49% 2Ve 6''2 491/2 21/4 41/2 501/2 2 8 31/4 1 1 ' r 543/4 11/2 9'-': 521/4 2% 7 501/8 5'7 51 1/2 10 531/4 2'/2 12 • 561/4 11/2 10 • 52 17/a 6 b2' 1'2 10'j 571/e 1 % 12 54 1 9 BA - bone age HT - height in inches HTt - height increment for 6 months •* - gonadotropins appeared T A B L E II P E A K R E S P O N S E S O F P L A S M A GROWTH HORMONE TO A R G I N I N E AND INSULIN STIMULATION* Before After 9 Days After 6 Months Patients Treatment Oxandrolone Oxandrolone R.R. A 3.3 A 2.3 1 5.6 1 1.7 S.W. A 1,3 A 1.3 A 1.3 1 1.6 1 1.7 1 1.0 L.K. A 1.2 A 1.0 1 1.1 1 1.0 C.T. A 4.1 A 5.3 A 4.0 1 2.6 1 2.9 1 1.7 S.T. A 6.3 A 6.7 A 9.0 1 4.3 1 2.9 1 27 A - Arginine I - Insulin Values expressed are for nanograms/l ml (normal> 10 ng/l ml) hormone levels as an explanation for the linear growth that occurred (Table 11). In the th i rd six-month treatment per iod growth hormone was given wi thout con-current oxandrolone. Growth , although better than before any treatment, was poor compared to the first two regimens — ranging f rom Vi to IV i inches. For the last six months of the two-year study, ox-androlone was again given alone wi thout concomitant HGH and growth ranged f rom % of an inch to 1 % inches. Three of t he pat ients again man i fes ted more growth than when receiving HGH alone and one grew equally as wel l (Figure 1). One patient (RR) developed transient m i ld l eukopen ia w h i c h p r o m p t l y re-sponded to withdrawal of oxandrolone for seven days. No nausea, pr iapism, hir-sutism, SGOT elevat ion, deepening of 165 Wolf, Mellinger, Morrow and Zafar voice or other side effects occurred due to oxandrolone. All the patients man-ifested increase in v igor, muscular i ty, weight and appetite. In none was there an unacceptable increase in osseous maturat ion. Bone age increased in al l , but remained signif icant ly be low chrono-logical age. None developed antibodies to human growth hormone. LK appar-ently responded best, growing bV2 inches in the first year and IV i inches in the th i rd t rea tment pe r i od under HGH a lone . Then she grew only % of an inch in the last pe r iod . She had begun excret ing gonadotropins and had breast develop-ment at that t ime. Discussion and Conclusion Published data indicate that androgens general ly are relat ively inef fec t ive in hypop i tu i ta r i sm. ' ' - " In this series oxan-drolone was not only effective, but it re-mained effective even after the chi ldren had been treated for one year wi th HGH. Growth occurred at a maximal rate in four chi ldren in the first six-month treatment per iod when oxandrolone was given as a single agent. It has been suggested that patients wi l l grow maximally (manifest "ca tch-up" growth) in response to the first agent administered. However, these patients in general responded better to oxandrolone than to growth hormone except for LK who may have exhibited "d imin ish ing returns" due to age (Table I). We have studied other GH deficient patients (unreported data) w h o , having grown wel l in response to growth hor-mone, sustained their growth rate wi th oxandrolone therapy after GH supplies were exhausted. It therefore appears that the excellent growth seen in the first treatment period is not necessarily due to the fact that there had been no pr ior treatment. In view of the fact that hypopituitary patients in this small series grew wel l when oxandro lone was admin is te red alone, it appears to us that this anabolic steroid may be used as a safe substitute for growth hormone in the management of some cases of d w a r f i s m due to hypopitui tar ism. Acknowledgments The growth hormone for this study was f u r n i s h e d by the Na t i ona l P i tu i tary Agency. Doctors Eng-Chin Cheah and Hadi Sawaf assisted in the study and we are also indebted to the personnel o f t h e Endocrinology Laboratory of the Henry Ford Hospital. References 1. Danowski TS, Lee FA, Cohn RE, D'Ambrosia RD and Limaye NR: Oxan-drolone therapy of growth retardation. Amer J Dis Child 109:526, 1965 2. Danowski TS, Weir TF, Girdany B and Lee FA: Oxandrolone therapy in stunting and in ovarian dysgenesis. C//n Pharm and Therapeutics 8:54«, 1967 3. Geller J: Oxandrolone effect on growth and bone age in idiopathic growth failure. Acta fndocr 59:307, 1968 4. Ray CG, Kirschvink )F, Waxman SH and Kelley VC: Studies of anabolic steroids. AfT7er J Dis Child 110:618, 1965 5. Zangeneh F and Steiner M M : Oxan-drolone therapy in growth retardation of children. Amer J Dis Child 113:234, 1967 6. Royer R, Rappaport R, Elsair), Ciric S and Cachin O: Activities comparees de I'hormone de croissance humaine et des anabolisants de synthese sur la vitesse de croissance dans le nanisme hypethal-amo-hypophysaire. Ann d'endocrinol 31:121, 1970 7. Bettmann HK, Goldman HS, Abramowicz M and Sobel EH: Oxandrolone treatment of short stature: Effect on predicted ma-ture height. I Pediatr 79:1018, 1971 166 O x a n d r o l o n e a n d G r o w t h H o r m o n e Mart in LG, Clark JW and Commor TB: Growth ho rmone secretion enchanced by androgens. ) Clin Endocr 28:425, 1968 9. Reiss M , Hi l lman J, Pearse JJ, Reiss JM, Daley N and Suwalski R: Long term obser-vation o f t h e growth p romot ing action of human chor ionic gonadot rop in . Acta En-docr 49:349, 1965 10. Scow RO and Hagan SN: Effect of testos-terone propionate and growth hormone on growth and chemical composi t ion of muscle and other tissues in hypophysec-tomized male rats. Endocrinology 77:852, 1965 11. Wi lk ins L: Diagnosis and treatment o f en-d o c r i n e d i so rde rs in c h i l d h o o d a n d a d o l e s c e n c e , e d . 3, S p r i n g f i e l d , I I I . , Charles C. Thomas Publisher, 1965, p 178 12. Zachmann M and Prader A: Anabol ic and androgenic effect of testosterone in sexu-ally immature boys and its dependency on g row th h o r m o n e . ] Cl in Endocr 30:85, 1970 13. Prader A, l l l ig R, Szeky J and Wagner H: The effect of human growth hormone in hypopi tu i tary dwarf ism. Arch Dis Chl idh 39:535, 1964 14. Kochakian C D : Summat ion of p ro te in anabolic effects of testosterone p rop ion -ate and g rowth ho rmone . Proc Soc Exper Bio l and M e d 103:196, 1960 15. Kinsell LW, Michaels GD, Li CH and Larsen WE: Studies in g row th . I. Inter-relat ionship b e t w e e n p i t u i t a r y g r o w t h fac to r and g r o w t h - p r o m o t i n g a n d r o g e n s in ac-romegaly and gigant ism. I I . Quant i tat ive evaluation of bone and soft tissue g rowth in acromegaly and gigant ism. / C//n f n -docr 8:1013, 1948 167 

The Effectiveness of Oxandrolone in Promoting Linear Growth in Growth Hormone Deficient Children

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The Effectiveness of Oxandrolone in Promoting Linear Growth in Growth Hormone Deficient Children

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