J Clin Endocrinol Metab 41: 788, 1975 A NOTE ON THE BONE AGE AT WHICH PATIENTS WITH TRUE ISOLATED GROWTH HORMONE DEFICIENCY ENTER PUBERTY J. M. Tanner and R. H. Whitehouse, Department of Growth and Development, Institute of Child Health, University of London. ABSTRACT. Nineteen boys with true isclated growth hormone deficiency developed the first stage of puberty at an average bone age of 12.0"years"(Tanner Whitehouse Method 2, RUS score). The average chronological age was 15.0
years. Seven similar girls entered puberty at 10.9"years" in bone age and 13.7 years in chronological age. The means and ranges of bone age at beginning of puberty of these patients are very close to those of normal children.
Prepubertal children with growth hormone deficiency not associated with demonstrable gross central nervous system lesions frequently appear to lack only growth hormone; their TSH, ACTH and posterior pituitary mechanisms function normally. Some of these children reveal a latent gonadotrophin deficiency when the time for puberty approaches, but in our series of cases the great majority enter a normal puberty spontaneously, hence receiving the diagnostic label true isolated GH deficiency. However, GH deficiency slows up maturation, so these children enter puberty at a late chronological age. The practical problem therefore arises of how long to wait before giving up hope of a spontaneous puberty and treating with LHRH, hCG or sex steroids. One answer to this may be provided by systematic application to these patients of LHRH tests, now being carried out by ourselves and many others. Another and more direct answer may be given by the simple observations of development and bone age reported here.
Group C: Five girls who had growth hormone deficiency combined with deficiency of other pituitary hormones. One had had a craniopharyngioma removed, but was on no replacement therapy except hGH, and the other four lacked posterior pituitary hormone as well as growth hormone, for reasons that were unclear in three cases and because of an old meningitis in the fourth case.
SUBJECTS AND METHODS There were three groups of subjects. Group A: Nineteen boys with true isolated growth hormone deficiency, who entered puberty spontaneously either before (two cases) or while on (17 cases) hGH treatment. Group B: Seven girls with true isolated growth hormone deficiency, who entered puberty spontaneously while on treatment. Submitted 8th August 1975
All patients were studied in the Growth Disorder Clinic of the Hospital for Sick Children, London, and were subjects in the Medical Research Council Clinical Trial of Human Growth Hormone. The methods and organization of the Trial and the auxological and biochemical criteria for diagnosis have been fully described elsewhere (1, 2 ) . All patients had a flat growth hormone but normal cortisol response to insulin hypoglycaemia. LHRH tests were not done before puberty in the patients under discussion. The patients were measured and X-rayed for bone age every three months in their first year of treatment and after that every six months until signs of puberty developed when some were again seen every three months. All patients except two of Group A had been continuously treated with two injections of 10 IU hGH each week for between one year and nine years when secondary sex characters appeared. Bone age was determined by the method of Tanner and Whitehouse 2 (3) using the radius, ulna and short bones (metacarpals and phalanges) only (i.e. method TW2, RUS bone age). 788
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RAPID COMMUNICATIONS Ratings of secondary sex characters were made according to the criteria formalized by Tanner (4) and the Zachmann-Prader orchidometer scale was used for testis size (5). Puberty was taken as beginning in boys when either the rating 4/4 for testis or 2 for pubic hair was first recorded; in girls when either 2 for breasts or 2 for pubic hair was recorded. Because we only saw most of the patients every six months the age at which these events begun will be some three months earlier on average than recorded. The same applies to the bone age. However, we have not interpolated backwards in either instance. RESULTS Group A: The range of bone age over which the boys with isolated GH deficiency entered puberty was quite restricted and quite normal. Of the 19, seven were between 11.0 and 11.9 "years", nine between 12.0 and 12.9, two between 13.0 and 13.2; one was an outlier at 14.2 "years". The mean was 12.0 "years" (or 11.8 if the outlier is excluded). The mean chronological age was 15.0 years, with a range of 13.8 to 16.9 years. Group B: The bone age range for the seven girls with true isolated GH deficiency was 10.2 to 11.4 "years" with a mean of 10.9 "years". The corresponding mean chronological age was 13.7 years with a range of 11.3 to 16.2. Group C: The bone age on reaching puberty for the five girls with GH deficiency combined with vasopressin deficiency or with craniopharyngioma averaged 12.3 "years" with a range from 11.0 to 13.3 "years". The corresponding mean chronological age was 17.0 years, with a range from 13.8 to 21.0 years. DISCUSSION The bone age at which boys and girls with true isolated GH deficiency begin puberty is normal, both as regards its mean (12.0 "years" in boys and 10.9 "years" in girls) and its range. Marshall's (6) corresponding
789
values for normal children are 11.7 "years" for boys and 11.1 "years" for girls, both with standard deviations of about one year. All these patients are passing or have passed through puberty entirely normally. However, the chronological age at which the patients enter puberty is delayed, on average by three years in both sexes. All except two of these children had been treated with hGH for one to nine years, but the bone age at which puberty occurred was unrelated to length of treatment (and in the two untreated boys was 12.2 and 12.6 "years"). This result should not be taken to mean that bone age causes puberty to start; or that a critical bone age exists which in some way affects the hypothalamus, any more than a critical weight or body fat percentage does so. In growth hormone deficiency the whole process of physical maturing is slowed up and bone age is the best guide we have as to how far this process has gone. Bone age is a symptom of an underlying state, not a cause. From the practical point of view two conclusions may be drawn. 1. Bone age is a useful guide to the progress towards maturity of GH deficient children (though only if estimated strictly according to set criteria by persons who are properly trained and continuously practising), 2. That at present sex steroids should not be given to children with growth hormone deficiency until the bone age (TW2, RUS) has reached a level of at least 13.0 "years" and ceased to advance over a period of a year, except with the explicit explanation of what administration may do to future gonadotrophic function. This situation will obtain until a fully validated method for predicting whether spontaneous puberty will take place becomes available. In our clinic these children with true isolated growth hormone deficiency constitute the great majority of patients without gross central nervous system lesions. In the same period of
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790
RAPID COMMUNICATIONS
time in which we saw 19 boys and seven girls with true isolated GH deficiency entering puberty we had only four boys and one girl who failed to enter puberty at the appropriate bone age and height velocity. Two of the boys had classical panhypopituitarism without demonstrable CNS lesions and the other two boys and the girl had GH deficiency and gonadotrophin deficiency only. These remained for over a year at fixed bone ages of 13.3, 13.3 and 13.0 respectively, grew less than 3 cm during this year despite hGH treatment and showed no signs of puberty. ACKNOWLEDGEMENTS We are grateful to Miss Janet Baines for the organization of the Growth Disorder Clinic, to Dr. Michael Preece for discussion of the manuscript and to the Medical Research Council for the supply of Growth Hormone.
REFERENCES 1. Tanner, J. M., R. H. Whitehouse, P. C. R. Hughes and F. P. Vince. The
JCE & M . 1975 V o U l . No 4
effect of human growth hormone treatment for 1 to 7 years on growth of 100 children, with growth hormone deficiency, low birthweight, inherited smallness, Turner's syndrome and other complaints. Arch Dis Childh 46:745, 1971. 2. Preece, M. A. and J.. M. Tanner. Treatment of growth hormone deficiency. Proc Int Cong Paed Endocr, Bologna, 1975 (in press). 3. Tanner, J. M., R. H. Whitehouse, W. A. Marshall, M. J. R. Healy and H. Goldstein. Assessment of Skeletal Maturity and Prediction of Adult Height, Academic Press, London, 1975. 4. Tanner, J. M. In Forfar, J. 0. and G. C. Arneil, Textbook of Paediatrics, Churchill Livingstone, Edinburgh and London, 1973, p.224. 5. Zachmann, M., A. Prader, H. P. Kind, H. Haflinger and H. Budliger. Testicular volume during adolescence. Helv Paed Acta 29:61, 1974. 6. Marshall, W. A. Interrelationships of skeletal maturation, sexual development and somatic growth in man. Ann Hum Biol, 1:29, 1974.
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years. Seven similar girls entered puberty at 10.9"years" in bone age and 13.7 years in chronological age. The means and ranges of bone age at beginning of puberty of these patients are very close to those of normal children.
Prepubertal children with growth hormone deficiency not associated with demonstrable gross central nervous system lesions frequently appear to lack only growth hormone; their TSH, ACTH and posterior pituitary mechanisms function normally. Some of these children reveal a latent gonadotrophin deficiency when the time for puberty approaches, but in our series of cases the great majority enter a normal puberty spontaneously, hence receiving the diagnostic label true isolated GH deficiency. However, GH deficiency slows up maturation, so these children enter puberty at a late chronological age. The practical problem therefore arises of how long to wait before giving up hope of a spontaneous puberty and treating with LHRH, hCG or sex steroids. One answer to this may be provided by systematic application to these patients of LHRH tests, now being carried out by ourselves and many others. Another and more direct answer may be given by the simple observations of development and bone age reported here.
Group C: Five girls who had growth hormone deficiency combined with deficiency of other pituitary hormones. One had had a craniopharyngioma removed, but was on no replacement therapy except hGH, and the other four lacked posterior pituitary hormone as well as growth hormone, for reasons that were unclear in three cases and because of an old meningitis in the fourth case.
SUBJECTS AND METHODS There were three groups of subjects. Group A: Nineteen boys with true isolated growth hormone deficiency, who entered puberty spontaneously either before (two cases) or while on (17 cases) hGH treatment. Group B: Seven girls with true isolated growth hormone deficiency, who entered puberty spontaneously while on treatment. Submitted 8th August 1975
All patients were studied in the Growth Disorder Clinic of the Hospital for Sick Children, London, and were subjects in the Medical Research Council Clinical Trial of Human Growth Hormone. The methods and organization of the Trial and the auxological and biochemical criteria for diagnosis have been fully described elsewhere (1, 2 ) . All patients had a flat growth hormone but normal cortisol response to insulin hypoglycaemia. LHRH tests were not done before puberty in the patients under discussion. The patients were measured and X-rayed for bone age every three months in their first year of treatment and after that every six months until signs of puberty developed when some were again seen every three months. All patients except two of Group A had been continuously treated with two injections of 10 IU hGH each week for between one year and nine years when secondary sex characters appeared. Bone age was determined by the method of Tanner and Whitehouse 2 (3) using the radius, ulna and short bones (metacarpals and phalanges) only (i.e. method TW2, RUS bone age). 788
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RAPID COMMUNICATIONS Ratings of secondary sex characters were made according to the criteria formalized by Tanner (4) and the Zachmann-Prader orchidometer scale was used for testis size (5). Puberty was taken as beginning in boys when either the rating 4/4 for testis or 2 for pubic hair was first recorded; in girls when either 2 for breasts or 2 for pubic hair was recorded. Because we only saw most of the patients every six months the age at which these events begun will be some three months earlier on average than recorded. The same applies to the bone age. However, we have not interpolated backwards in either instance. RESULTS Group A: The range of bone age over which the boys with isolated GH deficiency entered puberty was quite restricted and quite normal. Of the 19, seven were between 11.0 and 11.9 "years", nine between 12.0 and 12.9, two between 13.0 and 13.2; one was an outlier at 14.2 "years". The mean was 12.0 "years" (or 11.8 if the outlier is excluded). The mean chronological age was 15.0 years, with a range of 13.8 to 16.9 years. Group B: The bone age range for the seven girls with true isolated GH deficiency was 10.2 to 11.4 "years" with a mean of 10.9 "years". The corresponding mean chronological age was 13.7 years with a range of 11.3 to 16.2. Group C: The bone age on reaching puberty for the five girls with GH deficiency combined with vasopressin deficiency or with craniopharyngioma averaged 12.3 "years" with a range from 11.0 to 13.3 "years". The corresponding mean chronological age was 17.0 years, with a range from 13.8 to 21.0 years. DISCUSSION The bone age at which boys and girls with true isolated GH deficiency begin puberty is normal, both as regards its mean (12.0 "years" in boys and 10.9 "years" in girls) and its range. Marshall's (6) corresponding
789
values for normal children are 11.7 "years" for boys and 11.1 "years" for girls, both with standard deviations of about one year. All these patients are passing or have passed through puberty entirely normally. However, the chronological age at which the patients enter puberty is delayed, on average by three years in both sexes. All except two of these children had been treated with hGH for one to nine years, but the bone age at which puberty occurred was unrelated to length of treatment (and in the two untreated boys was 12.2 and 12.6 "years"). This result should not be taken to mean that bone age causes puberty to start; or that a critical bone age exists which in some way affects the hypothalamus, any more than a critical weight or body fat percentage does so. In growth hormone deficiency the whole process of physical maturing is slowed up and bone age is the best guide we have as to how far this process has gone. Bone age is a symptom of an underlying state, not a cause. From the practical point of view two conclusions may be drawn. 1. Bone age is a useful guide to the progress towards maturity of GH deficient children (though only if estimated strictly according to set criteria by persons who are properly trained and continuously practising), 2. That at present sex steroids should not be given to children with growth hormone deficiency until the bone age (TW2, RUS) has reached a level of at least 13.0 "years" and ceased to advance over a period of a year, except with the explicit explanation of what administration may do to future gonadotrophic function. This situation will obtain until a fully validated method for predicting whether spontaneous puberty will take place becomes available. In our clinic these children with true isolated growth hormone deficiency constitute the great majority of patients without gross central nervous system lesions. In the same period of
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790
RAPID COMMUNICATIONS
time in which we saw 19 boys and seven girls with true isolated GH deficiency entering puberty we had only four boys and one girl who failed to enter puberty at the appropriate bone age and height velocity. Two of the boys had classical panhypopituitarism without demonstrable CNS lesions and the other two boys and the girl had GH deficiency and gonadotrophin deficiency only. These remained for over a year at fixed bone ages of 13.3, 13.3 and 13.0 respectively, grew less than 3 cm during this year despite hGH treatment and showed no signs of puberty. ACKNOWLEDGEMENTS We are grateful to Miss Janet Baines for the organization of the Growth Disorder Clinic, to Dr. Michael Preece for discussion of the manuscript and to the Medical Research Council for the supply of Growth Hormone.
REFERENCES 1. Tanner, J. M., R. H. Whitehouse, P. C. R. Hughes and F. P. Vince. The
JCE & M . 1975 V o U l . No 4
effect of human growth hormone treatment for 1 to 7 years on growth of 100 children, with growth hormone deficiency, low birthweight, inherited smallness, Turner's syndrome and other complaints. Arch Dis Childh 46:745, 1971. 2. Preece, M. A. and J.. M. Tanner. Treatment of growth hormone deficiency. Proc Int Cong Paed Endocr, Bologna, 1975 (in press). 3. Tanner, J. M., R. H. Whitehouse, W. A. Marshall, M. J. R. Healy and H. Goldstein. Assessment of Skeletal Maturity and Prediction of Adult Height, Academic Press, London, 1975. 4. Tanner, J. M. In Forfar, J. 0. and G. C. Arneil, Textbook of Paediatrics, Churchill Livingstone, Edinburgh and London, 1973, p.224. 5. Zachmann, M., A. Prader, H. P. Kind, H. Haflinger and H. Budliger. Testicular volume during adolescence. Helv Paed Acta 29:61, 1974. 6. Marshall, W. A. Interrelationships of skeletal maturation, sexual development and somatic growth in man. Ann Hum Biol, 1:29, 1974.
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