Division of Endocrinology and Metabolism, Department of Medicine and the Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA
EFFECT OF ANDROGEN ON GROWTH HORMONE SECRETION AND GROWTH IN BOYS WITH SHORT STATURE
By Luis G. Martin, Milton S. Grossman, Thomas B. Connor, L. Levitsky, John W. Clark and Francine D. Camitta
Lynn
ABSTRACT
plasma growth hormone (GH) to insulin-induced hypoglycaemia (IIH) and arginine infusion (AI) was studied in 22 young males (ages 8 to 17 years) with short stature and absent or delayed sexual maturation, before and after androgen administration. During initial evaluation, 5 patients had blunted GH response to IIH, 12 responded subnormally to AI and 4 failed to respond normally to either stimulus. These same studies were repeated in each patient following androgen administration. The source of androgen was as follows: a) 5 days of testosterone propionate (25 mg intramuscularly daily) in 20 patients. b) Methyltestosterone, 10 mg t. i. d. orally for four days in the other 2 subjects. In almost every case, androgen administration resulted in raising the levels of fasting GH and The response of
enhancement of the GH responses to IIH and AI was observed. Patients manifesting subnormal GH responses to these stimuli before androgen consistently demonstrated a normal response when challenged with identical stimuli during androgen administration. Growth velocities during the year following these studies were significantly increased in most instances and the growth spurts correlated well with the progression of sexual maturation. Sustained improvement in the GH responses to IIH and AI were This work supported in part by USPHS training grant TIAM 5058 and USPHS Clinical Research Center grant 5 MOI FR 33.
·) Present address: Mt. Sinai Hospital of Greater Miami, 4300 Alton Road, Miami, Florida 33140. -) Present address:
University
of Illinois, Abraham Lincoln School of Medicine,
Chicago,
Illinois.
uniformly observed in 3 patients when repetitive studies were performed 8 to 12 months later during spontaneous advancing sexual development. The results indicate that brief androgen administration can be helpful in delineating the cause of growth retardation in boys with short stature and delayed sexual maturation, particularly when the diagnosis of isolated growth hormone deficiency is suspected. They also offer prognostic value in determining growth potential in this same group of young males.
Growth retardation in association with delayed sexual maturation is a common clinical problem among boys at puberty. Recent studies have clearly demon¬ strated that in some males with delayed sexual development and short stature, the plasma growth hormone (GH) response to standard stimuli may be markedly impaired. Androgen administration or spontaneous puberty has been shown to enhance the plasma growth hormone response to these stimuli (Deller et al. 1966; Martin et al. 1968; Illig 8c Pruder 1970). These observations have suggested that androgens may play a role in the control of growth hormone secretion at
puberty. The present investigation was designed to further study the role of androgens as mediators of the growth hormone response in a larger group of young boys with short stature and absent or delayed sexual maturation. In many patients, the plasma growth hormone response to standard stimuli was impaired and these were significantly improved following brief androgen administration. Long-term observation of these patients indicated that progression of sexual maturation was associated with sustained improvement in the plasma GH responses to these stimuli and impressive increase in linear growth occurred.
MATERIALS AND METHODS
Clinical data
Twenty-two non-obese male patients ranging in age from 8 to 17 years (Table 1) were studied in the Clinical Research Center at the University of Maryland Hospital. All subjects were in good health, though sexually immature and all had short stature, with a mean delay in height age of 4 years; bone age was delayed by a mean of 3 years. During the year prior to the studies, the patients had grown between 1.3 and 5.4 cm per year. None had received medications known to affect growth or plasma GH levels. Written informed consent to perform these studies was obtained from the parents or legal guardian of each subject. Each subject had a complete evaluation for all possible etiologic factors known to produce lack of sexual maturation or stunted growth. Chronic occult illness was ex¬ cluded by the history, physical examination and appropriate laboratory and radiographic studies. Additional examinations included radiographs of the sella turcica. visual fields, renal concentrating ability, serum thyroxine, radioactive iodine uptake, and urinary 17-hydroxycorticosteroid response to metyrapone. In these studies, normal results were found in each subject. Urinary gonadotrophins, measured by a modification
of the method of Klinefelter et al. (1943), were undetectable except in cases 8, 11 and 20 in whom normal levels were observed. Bone ages were determined using the male stan¬ dards of Greulich &· Pyle (1959). Height standard deviation scores (SDS) were derived from the method of Churchill (1966) using as normal mean heights and standard devia¬ tions those published by Tanner et al. (1965). On the basis of family history as well as clinical and biochemical findings, the pa¬ tients were classified into groups as follows (Table 1):
I.
Pre-pubertal genetic short
stature
II. Patients with delayed puberty A) Genetic short stature. B) Idiopathic short stature.
(age 8
(age
> 13
to 13
years). years).
Patients were considered to have "genetic short stature" when they had a history of stunted growth among family members and no other etiology for the short stature was demonstrable. Puberty was defined as "delayed" in those patients presenting with in¬ fantile genitalia or minimal sexual development after age 13 years. Those subjects in whom no genetic or other identifiable cause for growth retardation could be found were classified as having idiopathic short stature. The method of Tanner (1962) was used to grade sexual maturation. In only 4 cases, (Subjects 11, 14, 16 and 19) were signs of early sexual development (Grade II—III) noted at the time of the initial studies.
Plasma
growth
hormone
(GH) studies
All blood studies were performed after an overnight fast with the patient recumbent. Hypoglycaemia was induced by iv administration of 0.1 unit of crystalline insulin per kg of body weight. A reduction in blood glucose of 50% or more from the fasting level was achieved in each patient. Arginine monohydrochloride3) (0.5 g/kg) was infused iv over 30 min. Serial plasma samples were obtained during 90 min following each stimu¬ lus. All samples were stored at -20°C until analyzed for growth hormone, using the radioimmunoassay method of Glick et al. (1963), as previously published from this labo¬ ratory (Martin et al. 1968). In our experience, plasma growth hormone values obtained at rest in the fasting state range from 0 to 3 ng/ml. Normal responders to hypogly¬ caemia and/or arginine stimuli achieve peak plasma growth hormone levels of 5 ng/ml or greater within 30 to 60 min. Those patients achieving peak GH levels less than 5 ng/ml to these stimuli were considered to have "blunted" or subnormal responses. In order to minimize any variations inherent in the method, all plasma samples from each patient, obtained both before and after androgenic influence, were always ana¬ lyzed in the same assay.
Androgen
administration
The type of androgenic influence under which the GH studies were performed in each patient is listed in Table 2. In all but 2 patients (Nos. 7 and 16) the GH response to both arginine infusion and insulin-induced hypoglycaemia were tested before and after 5 days of testosterone propionate (25 mg im daily). Subjects 7 and 16 were tested before and after 4 days of oral methyltestosterone administration. 3)
R-Gene, Cutter Laboratories, L. .. Calif.
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EFFECT OF ANDROGEN ON GROWTH HORMONE SECRETION AND GROWTH IN BOYS WITH SHORT STATURE
By Luis G. Martin, Milton S. Grossman, Thomas B. Connor, L. Levitsky, John W. Clark and Francine D. Camitta
Lynn
ABSTRACT
plasma growth hormone (GH) to insulin-induced hypoglycaemia (IIH) and arginine infusion (AI) was studied in 22 young males (ages 8 to 17 years) with short stature and absent or delayed sexual maturation, before and after androgen administration. During initial evaluation, 5 patients had blunted GH response to IIH, 12 responded subnormally to AI and 4 failed to respond normally to either stimulus. These same studies were repeated in each patient following androgen administration. The source of androgen was as follows: a) 5 days of testosterone propionate (25 mg intramuscularly daily) in 20 patients. b) Methyltestosterone, 10 mg t. i. d. orally for four days in the other 2 subjects. In almost every case, androgen administration resulted in raising the levels of fasting GH and The response of
enhancement of the GH responses to IIH and AI was observed. Patients manifesting subnormal GH responses to these stimuli before androgen consistently demonstrated a normal response when challenged with identical stimuli during androgen administration. Growth velocities during the year following these studies were significantly increased in most instances and the growth spurts correlated well with the progression of sexual maturation. Sustained improvement in the GH responses to IIH and AI were This work supported in part by USPHS training grant TIAM 5058 and USPHS Clinical Research Center grant 5 MOI FR 33.
·) Present address: Mt. Sinai Hospital of Greater Miami, 4300 Alton Road, Miami, Florida 33140. -) Present address:
University
of Illinois, Abraham Lincoln School of Medicine,
Chicago,
Illinois.
uniformly observed in 3 patients when repetitive studies were performed 8 to 12 months later during spontaneous advancing sexual development. The results indicate that brief androgen administration can be helpful in delineating the cause of growth retardation in boys with short stature and delayed sexual maturation, particularly when the diagnosis of isolated growth hormone deficiency is suspected. They also offer prognostic value in determining growth potential in this same group of young males.
Growth retardation in association with delayed sexual maturation is a common clinical problem among boys at puberty. Recent studies have clearly demon¬ strated that in some males with delayed sexual development and short stature, the plasma growth hormone (GH) response to standard stimuli may be markedly impaired. Androgen administration or spontaneous puberty has been shown to enhance the plasma growth hormone response to these stimuli (Deller et al. 1966; Martin et al. 1968; Illig 8c Pruder 1970). These observations have suggested that androgens may play a role in the control of growth hormone secretion at
puberty. The present investigation was designed to further study the role of androgens as mediators of the growth hormone response in a larger group of young boys with short stature and absent or delayed sexual maturation. In many patients, the plasma growth hormone response to standard stimuli was impaired and these were significantly improved following brief androgen administration. Long-term observation of these patients indicated that progression of sexual maturation was associated with sustained improvement in the plasma GH responses to these stimuli and impressive increase in linear growth occurred.
MATERIALS AND METHODS
Clinical data
Twenty-two non-obese male patients ranging in age from 8 to 17 years (Table 1) were studied in the Clinical Research Center at the University of Maryland Hospital. All subjects were in good health, though sexually immature and all had short stature, with a mean delay in height age of 4 years; bone age was delayed by a mean of 3 years. During the year prior to the studies, the patients had grown between 1.3 and 5.4 cm per year. None had received medications known to affect growth or plasma GH levels. Written informed consent to perform these studies was obtained from the parents or legal guardian of each subject. Each subject had a complete evaluation for all possible etiologic factors known to produce lack of sexual maturation or stunted growth. Chronic occult illness was ex¬ cluded by the history, physical examination and appropriate laboratory and radiographic studies. Additional examinations included radiographs of the sella turcica. visual fields, renal concentrating ability, serum thyroxine, radioactive iodine uptake, and urinary 17-hydroxycorticosteroid response to metyrapone. In these studies, normal results were found in each subject. Urinary gonadotrophins, measured by a modification
of the method of Klinefelter et al. (1943), were undetectable except in cases 8, 11 and 20 in whom normal levels were observed. Bone ages were determined using the male stan¬ dards of Greulich &· Pyle (1959). Height standard deviation scores (SDS) were derived from the method of Churchill (1966) using as normal mean heights and standard devia¬ tions those published by Tanner et al. (1965). On the basis of family history as well as clinical and biochemical findings, the pa¬ tients were classified into groups as follows (Table 1):
I.
Pre-pubertal genetic short
stature
II. Patients with delayed puberty A) Genetic short stature. B) Idiopathic short stature.
(age 8
(age
> 13
to 13
years). years).
Patients were considered to have "genetic short stature" when they had a history of stunted growth among family members and no other etiology for the short stature was demonstrable. Puberty was defined as "delayed" in those patients presenting with in¬ fantile genitalia or minimal sexual development after age 13 years. Those subjects in whom no genetic or other identifiable cause for growth retardation could be found were classified as having idiopathic short stature. The method of Tanner (1962) was used to grade sexual maturation. In only 4 cases, (Subjects 11, 14, 16 and 19) were signs of early sexual development (Grade II—III) noted at the time of the initial studies.
Plasma
growth
hormone
(GH) studies
All blood studies were performed after an overnight fast with the patient recumbent. Hypoglycaemia was induced by iv administration of 0.1 unit of crystalline insulin per kg of body weight. A reduction in blood glucose of 50% or more from the fasting level was achieved in each patient. Arginine monohydrochloride3) (0.5 g/kg) was infused iv over 30 min. Serial plasma samples were obtained during 90 min following each stimu¬ lus. All samples were stored at -20°C until analyzed for growth hormone, using the radioimmunoassay method of Glick et al. (1963), as previously published from this labo¬ ratory (Martin et al. 1968). In our experience, plasma growth hormone values obtained at rest in the fasting state range from 0 to 3 ng/ml. Normal responders to hypogly¬ caemia and/or arginine stimuli achieve peak plasma growth hormone levels of 5 ng/ml or greater within 30 to 60 min. Those patients achieving peak GH levels less than 5 ng/ml to these stimuli were considered to have "blunted" or subnormal responses. In order to minimize any variations inherent in the method, all plasma samples from each patient, obtained both before and after androgenic influence, were always ana¬ lyzed in the same assay.
Androgen
administration
The type of androgenic influence under which the GH studies were performed in each patient is listed in Table 2. In all but 2 patients (Nos. 7 and 16) the GH response to both arginine infusion and insulin-induced hypoglycaemia were tested before and after 5 days of testosterone propionate (25 mg im daily). Subjects 7 and 16 were tested before and after 4 days of oral methyltestosterone administration. 3)
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