Progressive deceleration in growth as an early sign of delayed puberty in boys

OBJECTIVE: To describe the prepubertal growth pattern in boys with delayed puberty. METHODS: Growth curves for height and height velocity covering the age range 4-14 years were constructed on the basis of retrospectively obtained data in 85 boys with delayed puberty, who attained a normal final height. RESULTS: Between the age of 4 and 14 years the height in this cohort progressively deviated from the normal reference. At the age of 4 years, the height SDS was already significantly lower (median -0.8; p < 0.001) and progressively diminished during childhood, resulting in a median height SDS of -1.1 at the age of 12 years (p < 0.001). The median final height of this cohort (-0.4) was not different from their target height (-0.2). The degree of deceleration in growth during childhood was not determined by birth weight or birth height and did not influence final height. The decline of the height velocity with age in this group of boys with delayed puberty was significantly smaller (p < 0.001) than predicted by the model of Rikken and Wit. CONCLUSION: Late-maturing boys often show a prepubertal deceleration in growth that starts at an early age but that does not affect final height.     

Testicular binding of 125I-HCG in developing estrogenized and androgenized rats.

The present work describes changes seen in the binding of 125I-HCG by testis homogenates of rats injected at the age of three days with 400 microgram estradiol-17beta-dipropionate, or 250 microgram testosterone propionate. Estrogenized and androgenized male rats showed a marked decrease of gonadotropin binding in testis at the 30th, 45th and 60th postnatal day. These results show that delayed sexual maturation of male rats treated with estrogen and androgen in the neonatal period is also related to pubertal decrease of testicular gonadotropin receptors.     

Puberty and recrudescence in cultured male yellowtail flounder: plasma androgens and spermatogenesis

Two year classes of cultured male yellowtail flounder Limanda ferruginea were followed in order to examine puberty and recrudescence at the gonadal level, and to assess the impacts of culture conditions on male reproduction. Cultured males demonstrated a propensity for maturation as 1 year‐old fish. Pubertal activation of testicular steroid production was associated with the appearance of primary spermatocytes, but a single case of a premeiotic endocrine activation was detected. The onset of puberty occurred during September and October, when adults were post‐spawned or in early recrudescence. Once initiated, pubertal development proceeded in an uninterrupted progression to full maturity by June at 22 months of age. Spermatogenetic activity during the autumn led to a peak in the gonado‐somatic index and total testicular mass by December. Milt could be first expressed from some pubertal males at this time, well in advance of the May to August spawning period in captivity. Meiotic activity could be absent from the testes by the spring, but residual areas of meiotic activity were found in pubertal males of one year class which may indicate a slower spermatogenetic rate. Androgen levels peaked during prespawning and early spawning; 11‐ketotestosterone (11‐KT) was the dominant androgen throughout spermatogenesis. Recrudescing 2 year‐old males showed greater testicular development and androgen production. Spermatogenetic patterns were similar to those seen in pubertal males, with the distinction that recrudescing males had a more discernable mitotic phase prior to meiotic activity; mitotic and meiotic activity overlapped considerably during early puberty. Testicular development well in advance of spawning may confer an evolutionary advantage to males of this cold‐water marine flatfish.     

Total pubertal growth and markers of puberty onset in adolescents with GHD: comparison between mathematical growth analysis and pubertal staging methods

Two methods of determining puberty onset (Preece- Baines model 1 (PB1) and Tanner staging) were used to calculate total pubertal growth (TPG) in adolescents with growth hormone deficiency (GHD). PATIENTS AND METHODS: 34 patients (11 girls) met the following inclusion criteria: isolated GHD, >2 years growth hormone therapy prior to puberty onset, regular weight-adjusted GH dosage, known final height (age >21 years or height velocity <0.5 cm/year), no induction of puberty. PB1 was used to define age and height at onset of the pubertal growth spurt ("take-off"). RESULTS: The results (mean +/- SD) were as follows: in girls, mean age at take-off was 9.8 years; 2.0 +/- 1.1 years before breast stage B2. In boys, mean age at take-off was 11.3 years; 1.4 +/- 0.8 years before testes volume >3 ml. Height at take-off was lower than at Tanner stage 2 by 12.4 +/- 7.6 cm in girls and 7.7 +/- 5.3 cm in boys. TPG was thus markedly greater (p < 0.001) using the PB1 method, as compared with Tanner stage2. Peak height velocity was normal. Final height was -0.5 +/- 0.7 SDS in females and -0.4 +/- 0.9 SDS in males. CONCLUSIONS: The method of measuring TPG from take-off is more objective, and has potentially greater implications for GH therapeutics than the Tanner stage method. In our study, 40% of TPG occurred before "breast stage B2" was attained in GHD girls; whereas 23% of TPG occurred before "testes >3 ml" in GHD boys.     

Serum osteocalcin and insulin-like growth factor I levels in children with congenital adrenal hyperplasia

Patients with the virilizing forms of congenital adrenal hyperplasia (CAH) need a life-long glucocorticoid replacement therapy and also an additional mineralocorticoid replacement in cases with the salt-wasting form of the disease. Glucocorticoids are reported to decrease the serum osteocalcin levels and to inhibit the effects of insulin-like growth factor I (IGF-I). To collect data on the age related patterns of osteocalcin and IGF-I production in patients with CAH, measurements of these compounds have been carried out in a considerably large sample of treated CAH patients and control subjects in childhood and adolescence. Data of 62 patients between 0. 3-19 years of age were compared to the data of 188 control children. Osteocalcin and IGF-I were determined by radioimmunoassay. A lower than normal level of serum osteocalcin was found in both male and female patients at chronological ages above 11.6 and 9.6 years, respectively. Furthermore, no pubertal osteocalcin peak could be seen when data were evaluated according to the bone age. Serum IGF-I levels were higher in male CAH patients at the chronological age of 0.3-15.5 years and in female patients at the chronological age of 4. 6-9.5 years. In pubertal years serum IGF-I concentrations were lower in CAH patients when data were evaluated according to the bone age. We conclude that serum osteocalcin is decreased during and after puberty in CAH patients on replacement doses of glucocorticoids. Normal to elevated serum levels of IGF-I in treated CAH cases suggest that the shorter final height of these patients may not be due to the decreased activity in the growth hormoneIGF-I axis, but rather to the advanced bone maturation and the premature epiphyseal fusion.     

Long-term follow-up of spontaneous development in a boy with familial male precocious puberty

BACKGROUND/AIMS: Limited data are available about spontaneous growth, pubertal growth spurt and the long-term outcome of patients suffering from familial male precocious puberty (FMPP). We report on a boy with FMPP whose growth pattern and pubertal development was studied longitudinally without treatment. METHODS: Long-term prospective follow-up without treatment of a 6.2-year-old boy with FMPP having inherited a mutation of the LH receptor gene (A568V) from his father. RESULTS: The pubertal growth spurt was of unusual maximal amplitude (growth rate 12.4 cm/year at the age of 5-6 years) and of extraordinary duration lasting for 5.2 years from age 3.8 to 9.0 years. No deterioration of height potential was observed. Height (174 cm) was within target height range (171.5-188.5 cm) at age 13 years. No central precocious puberty occurred. CONCLUSION: FMPP is an experiment of nature demonstrating that the amplitude and duration of the pubertal growth spurt are much more variable than previously described. Furthermore, this case emphasizes that the indication for treatment is highly dependent on intrafamilial and individual factors.     

No difference in pubertal growth and final height between treated hypogonadal and non-hypogonadal thalassemic patients

BACKGROUND: Many factors can negatively affect growth in thalassemic patients, and hypogonadism has been considered as the main factor responsible for their pubertal growth failure. OBJECTIVE: To evaluate the influence of hypogonadism and its treatment on pubertal growth and final height in thalassemic patients. METHODS: We compared the growth of 28 hypogonadal thalassemic patients in whom puberty was induced to that of 25 patients in whom puberty occurred spontaneously. RESULTS: In both groups of patients we observed reduced peak height velocity (induced puberty: females 4.9 +/- 2.1, males 6.0 +/- 1.8 cm/year; spontaneous puberty: females 6.1 +/- 1.5, males 7.3 +/- 2.1 cm/year) and pubertal height gain (induced puberty: females 11.3 +/- 4.0, males 18.0 +/- 4.5 cm/year; spontaneous puberty: females 15.8 +/- 2.7, males 18.1 +/- 5.3 cm/year) and a short final height (induced puberty: females -1.8 +/- 0.7, males -2.1 +/- 1.0 SDS; spontaneous puberty: females -2.3 +/- 1.0, males -1.9 +/- 1.0 SDS). CONCLUSIONS: Poor pubertal growth is present in thalassemic patients regardless of hypogonadism. Other factors are responsible for the reduced growth spurt and the final short stature observed in these patients.     

Forty years trends in timing of pubertal growth spurt in 157,000 Danish school children

Background

Entering puberty is an important milestone in reproductive life and secular changes in the timing of puberty may be an important indicator of the general reproductive health in a population. Too early puberty is associated with several psychosocial and health problems. The aim of our study was to determine if the age at onset of pubertal growth spurt (OGS) and at peak height velocity (PHV) during puberty show secular trends during four decades in a large cohort of school children.

Methods and Findings

Annual measurements of height were available in all children born from 1930 to 1969 who attended primary school in the Copenhagen Municipality. 135,223 girls and 21,612 boys fulfilled the criteria for determining age at OGS and age at PHV. These physiological events were used as markers of pubertal development in our computerized method in order to evaluate any secular trends in pubertal maturation during the study period (year of birth 1930 to 1969). In this period, age at OGS declined statistically significantly by 0.2 and 0.4 years in girls and boys, respectively, whereas age at PHV declined statistically significantly by 0.5 and 0.3 years in girls and boys, respectively. The decline was non-linear with a levelling off in the children born between 1940 and 1955. The duration of puberty, as defined by the difference between age at OGS and age at PHV, increased slightly in boys, whereas it decreased in girls.

Conclusion

Our finding of declining age at OGS and at PHV indicates a secular trend towards earlier sexual maturation of Danish children born between 1930 and 1969. Only minor changes were observed in duration of puberty assessed by the difference in ages at OGS and PHV.     

Growth analysis in patients with 21-hydroxylase deficiency influence of glucocorticoid dosage,age at diagnosis,phenotype and genotype on growth and height outcome

OBJECTIVE: To evaluate the impact of hydrocortisone dosage, age at diagnosis, compliance, genotype and phenotype on growth and height outcome in 21-hydroxylase-deficient patients. METHODS: We analyzed 37 patients with 21-hydroxylase deficiency (17 had completed growth, 20 still growing). Final (FH)/predicted final height (pFH) and loss of height potential related to target height (TH) were calculated and the impact of 4 hydrocortisone (HC) dosage regimens on height outcome and growth velocities was evaluated. Mean FH SDS and pFH SDS were analyzed in accordance to age at diagnosis, compliance, genotype and phenotype. RESULTS: Mean (FH SDS, pFH SDS) was -1.8+/-1.06 SD, with 35.1% of all 37 patients exhibiting short stature. Doses >20 mg/m2/day during the first year and >15 mg/m2/day during age 1-5 and at puberty resulted in significantly lower FH SDS, pFH SDS and greater height losses. Age at diagnosis, compliance, genotype and phenotype played only a minor role in growth development. CONCLUSIONS: Hydrocortisone substitution in 21-hydroxylase-deficient patients should be kept at the lowest efficient level, if possible <20 during the first year and <15 mg/m2/day until age 5 and during puberty. Normal growth and not complete androgen suppression should be aimed for.     

Diagnosis of late puberty

Late puberty is defined as the lack of pubertal development at two standard deviations above the mean age for the general population of the geographical area. In practical terms, this is a chronological age of 14 years for males (testicular volume <4 ml) and 13 years for girls (lack of thelarche). The goal of the assessment is to determine whether the delay or lack of development is due to a lag in normal pubertal maturation or represents an abnormality that must be investigated. Etiologies of pubertal delay and pubertal failure include: a) Constitutional delay of puberty (healthy patients with a clinical history of delayed growth and development; b) Hypogonadotropic states (congenital abnormalities, tumours, endocrinopathies); c) Hypergonadotropic states (chromosomal alterations, syndromes, genetic disorders, radiotherapy/chemotherapy); d) Secondary to chronic illness (organic abnormalities, oncological diseases, malnutrition, eating disorders and endocrinopathies). Diagnostic evaluation must include: a detailed physical examination, including auxological parameters (height and bone maturation), personal and familial antecedents, measurements of general hematological and biochemical parameters, gonadotropins, prolactin, thyroid hormones, sex steroids, growth hormone and growth factors. When necessary, an MRI must be performed. A karyotype is indicated in girls with delayed puberty and short stature and in boys who have small testes and hypergonadotropism.     

Serum lipids, body mass index and waist circumference during pubertal development in Spanish adolescents: the AVENA Study.

AIM: To describe the effects of chronological age and biological age (pubertal development) on serum lipid and lipoprotein levels, body mass index (BMI) and waist circumference in Spanish adolescents. METHODS: A representative Spanish sample of 526 adolescents (254 males and 272 females), were studied. Total cholesterol (TC), high density lipoprotein cholesterol (HDLc), triglycerides, apolipoprotein A1 and B, and lipoprotein(a) were measured, and low density lipoprotein cholesterol (LDLc) was calculated. Additional measurements included BMI and waist circumference. Adolescents were classified according to chronological age, and pubertal development (also age of menarche in females). RESULTS: In males, serum TC levels were lower at late puberty in comparison with early puberty, and serum LDLc levels were lower at late puberty in comparison with mid and early puberty. Serum HDLc levels were lower at mid puberty in comparison with early and late puberty. Serum TC and LDLc levels were not different when analyzed according to chronological age. In females, HDLc levels were lower at late puberty in comparison with early and mid puberty, but no differences were found when HDLc and the other studied lipid and lipoprotein variables were analyzed according to chronological age, or age of menarche. All the observed differences persisted after adjusting for BMI and waist circumference. In female adolescents, both BMI and waist circumference were higher at late puberty in comparison with early and mid puberty, while in males, BMI and waist circumference were different when analyzed according to chronological age. CONCLUSION: The results suggest that the assessment of pubertal development may provide additional valuable information when interpreting lipid profile and body fat in adolescents.     

Hormone responses to clomiphene citrate in young chimpanzees

The responses of gonadotropin and gonadal steroids to the administration of clomiphene citrate were studied in male and female chimpanzees, aged 3.6 to 9.9 years. Follicle-stimulating hormone (FSH) was significantly reduced after treatment in the prepubertal females (n = 4) and in early pubertal males (n = 2) but not in prepubertal males (n = 5). FSH was unchanged or increased in early pubertal females (n = 2) and late pubertal males (n = 2). There was no consistent response to treatment with clomiphene citrate by luteinizing hormone (LH) in either males or females, nor by 17 beta-estradiol in the females. Testosterone levels were reduced in the early pubertal males only. These results support the hypothesis that negative feedback by gonadal steroids is operative in prepubertal chimpanzees and that puberty is accompanied by a reduction in the sensitivity to such feedback.     

Factors affecting onset of puberty

In humans, foetal and early postnatal growth failure may have persistent consequences for growth and pubertal development in later life. During this period, the developing organs are still plastic to change their function, which may have long-lasting effects. At the time of onset of puberty, acute factors may also interfere with pubertal development. Malnutrition, as seen in anorexic patients, and chronic diseases with malabsorption or diseases with systemic effects result in a delayed onset of puberty. We have observed an earlier onset of puberty in girls with low birth weight; menarcheal age also tended to be earlier. In boys, a low birth weight tended to be associated with a later development. Two rat models with growth failure based on perinatal malnutrition have been examined, one with intrauterine growth retardation (IUGR) by ligation of the uterine arteries and one with postnatal food restriction (FR) by increasing the litter size postnatally. In both models, the rats had a persistent postnatal growth failure. The onset of puberty in female rats, defined by vaginal opening, was delayed only in the IUGR group. Despite a significantly lower weight, there was no difference in the timing of puberty onset in the FR group. In IUGR rats, the ovaries had fewer follicles, while FR rats had a normal number of follicles but an abnormal maturation pattern. In male rats, both models showed a delayed onset of puberty, defined by the balano-preputial separation, as well as impaired testicular function, shown by decreased testosterone levels. These data indicate that early malnutrition during a critical developmental time window may have long-lasting effects on pubertal development, including gonadal maturation in both humans and rats.     

Plasma androgens in children and adolescents. Part I: control subjects

In this cross-sectional study, plasma levels of dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), delta 4-androstenedione (delta 4) and testosterone (T) were measured by RIA in 232 normal subjects of both sexes, aged 2 weeks to 20 years. The results were analyzed in relation to chronological age, body surface and pubertal stage. High levels of plasma androgens were found in newborn infants of both sexes. After 3 months of age, androgen levels were uniformly low and rose with increasing chronological age and body surface. The first significant increase in mean androgen levels was found for DHEA-S. It occurred after 6 years of age in girls and after 8 years in boys. DHEA and T rose in both sexes after 8 years of age. delta 4 increased steadily with chronological age and body surface in both sexes. When androgen levels were related to body surface, a first significant increase was observed above 1.00 m2 for the four androgens, in both boys and girls. Above 1.20 m2 and 12 years of age, girls had higher mean levels of DHEA-S, DHEA and delta 4, but lower mean T levels than boys of the same body surface and chronological age. Before puberty, a positive correlation was found in both sexes between the plasma androgen levels on the one hand, and both chronological age and body surface on the other. Plasma androgen levels markedly increased at stage P2 in both sexes, and further increased with pubertal development. During puberty, girls had higher plasma delta 4, but lower plasma T levels than boys of the same pubertal stage. Plasma DHEA-S and DHEA levels were similar in both sexes. In contrast to the plasma androgens, plasma cortisol levels did not show any change in relation either to chronological age or to body surface or pubertal development. Body surface appears to be as good a discriminating factor as chronological age, at least in young children. It also appears from this study that DHEA-S is a good guide for the clinical evaluation of adrenal maturation and may be very useful in evaluating patients with growth or pubertal disturbances.     

Experience with growth hormone therapy in Turner syndrome in a single centre: low total height gain, no further gains after puberty onset and unchanged body proportions

The experience gained since 1987, through observation of 85 girls with Turner syndrome under growth hormone (GH) treatment, has enabled the analysis of one of the largest cohorts. Our results show that age, karyotype and height reflect the heterogeneity of the patients examined at our growth centre. In 47 girls, followed over 4 years on GH (median dose 0.72 IU/kg/week), the median age was 9.4 years and mean height SDS was -3.55 (Prader) and -0.14 (Turner-specific), while height and other anthropometrical parameters [weight, body mass index, sitting height (SH), leg length (LL) SH/LL, head circumference, arm span] were documented and compared to normative data as well as to Turner-specific references established on the basis of a larger (n = 165) untreated cohort from Tübingen. The latter data are also documented in this article. Although there was a trend towards normalization of these parameters during the observation period, no inherent alterations in the Turner-specific anthropometric pattern occurred. In 42 girls who started GH treatment at a median age of 11.8 years, final height (bone age >15 years) was achieved at 16.7 years. The overall gain in height SDS (Turner) from start to end of GH therapy was 0.7 (+/- 0.8) SD, but 0.9 (+/- 0.6) SD from GH start to onset of puberty (spontaneous 12.2 years, induced 13.9 years) and -0.2 (+/- 0.8) from onset of puberty to end of growth. Height gain did not occur in 12 patients (29%) and a gain of > 5 cm was only observed in 16 patients (38%). Height gain correlated positively with age at puberty onset, duration, and dose of GH, and negatively with height and bone age at the time GH treatment started. Final height correlated positively with height SDS at GH start and negatively with the ratio of SH/LL (SDS). We conclude that, in the future, GH should be given at higher doses, but oestrogen substitution should be done cautiously, owing to its potentially harmful effect on growth. LL appears to determine height variation in Turner syndrome and the potential to treat short stature successfully with GH.     

Early puberty: what is normal and when is treatment indicated?

Girls and boys who enter puberty before 8 and 9 years of age, respectively (corresponding to about -3 SDS), are arbitrarily considered to need referral for endocrine investigation. A recent report from the Lawson Wilkins Pediatric Endocrine Society suggested that the limit for investigation of girls and boys should be lowered to 7 and 8 years, respectively. For African-American girls, 6 years is the suggested age. This recommendation has been criticized. Although short stature is a common end result of precocious puberty, short- and long-term psychological symptoms may be more important, since several studies have indicated psychopathology in this patient group. Whether this can be prevented by gonadotropin releasing hormone agonist treatment remains to be shown. This review will highlight the psychological aspects of early puberty. In short, aspects other than height should also be evaluated when considering treatment of the early maturing child.     

Presentation of 493 Consecutive Girls with Idiopathic Central Precocious Puberty: A Single-Center Study

Background

Despite the number of reported data concerning idiopathic central precocious puberty (CPP) in girls, major questions remain including its diagnosis, factors, and indications of gonadotropin releasing hormone (GnRH) analog treatment.

Methods

A retrospective, single-center study was carried out on 493 girls with CPP.

Results

Eleven girls (2.2%) were aged less than 3 years. Breast development was either isolated (Group 0, n = 99), or associated with one sign, pubic hair development, growth rate greater than 2 standard deviation score (SDS) or bone age (BA) >2 years above chronological age, (Group 1, n = 187), two signs (Group 2, n = 142) or three signs (Group 3, n = 65). The interval between onset of puberty and evaluation, body mass index (BMI) SDS, plasma luteinising hormone (LH) concentrations (basal and peak) and LH/ follicle-stimulating hormone (FSH) peak ratio after GnRH test, plasma estradiol and uterus length were significantly greater in Groups 2 and 3 than in Groups 0 and 1 respectively. 211 (42.8%) patients were obese and/or had excessive weight gain during the year before puberty. Obese girls more often had BA advance of >2 years (p = 0.0004) and pubic hair development (p = 0.003) than the others. BMI did not correlate with LH or with LH/FSH peak ratio. Girls with familial history of early puberty (41.4%) had greater frequencies of pubertal LH/FSH peak ratios (p = 0.02) than the others. During the 31 years of the study, there was no increase in the frequency of CPP or variation in its characteristics.

Conclusion

Obesity is associated with a higher BA advance and higher frequency of pubic or axillary hair development but not with LH secretion, suggesting that obesity accelerates adrenarche but not the maturation of the hypothalamic-pituitary-ovarian axis. The LH/FSH peak ratio was more frequently pubertal in girls with a familial history of early puberty, suggesting that this maturation depends on genetic factors.     

Final height in children with medulloblastoma treated with growth hormone

BACKGROUND: Medulloblastoma is the most frequent primary solid central nervous system tumour in children. The 5-year survival rate is at present at about 60%. Height in general is severely compromised in survivors. The present study is an extension of the investigation by the author's group of the effect of exogenous growth hormone (GH) among medulloblastoma patients. METHODS: A total of 113 patients with medulloblastoma (out of 682 cases documented in KIGS, Pfizer International Growth Database) were treated with GH till final height was achieved. At the start of GH therapy (median dose 0.18 mg/kg/week), patients were 8.9 years old and had a median height SDS of -1.6. RESULTS: After 6.8 years of GH, final height SDS was -1.9, reflecting an overall loss in height of 0.3 SDS. This contrasted with an age-matched group of patients with idiopathic growth hormone deficiency (iGHD, n = 1,986), whose gain in height was 1.6 SDS on the same dose. The index of responsiveness averaged -0.9 during the first prepubertal year and -2.0 during total pubertal growth, thus indicating a major impairment in responsiveness to GH as compared to iGHD. Height at GH start, which correlated positively with the age at disease onset, was found to be the major determinant of final height. CONCLUSIONS: Our findings show that attempts to improve the height outcome in medulloblastoma must involve earlier recognition and treatment with higher-than-replacement doses of GH; additionally, modifications in cancer treatment programs need to be considered, such as lowering the dose of craniospinal irradiation or avoiding it as far as possible.     

Precocious or early puberty and growth failure in girls treated for acute lymphoblastic leukaemia

We have studied 41 children with early or precocious puberty who have been treated for acute lymphoblastic leukaemia with prophylactic cranial irradiation (1,800-2,400 cGy) accompanied by intrathecal methotrexate and systemic chemotherapy. Mean age at radiotherapy was 3.9 years (range 1.7-7.7) in the girls and 4.8 years (range 2.6-7.8) in the boys. Mean age at the onset of puberty was 8.6 years (range 6.7-9.7) in the girls and 9.3 years (range 7.8-10.3) in the boys. Of the 41 children with early puberty (greater than 1.4 SD from the mean) 36 were females and 5 were males. 21 of the 36 girls had an absent or inadequate growth acceleration of puberty. 7 of 12 girls who had a pharmacological test of growth hormone (GH) secretion had GH insufficiency (peak level less than 20 mU/l). Early or precocious puberty combined with GH insufficiency may produce severe growth failure and we have used a treatment regimen of a gonadotrophin-releasing hormone analogue, in order to reduce the rate of epiphyseal maturation, combined with biosynthetic GH to increase or sustain growth rate. We have treated 4 girls in this manner. During a mean treatment period of 0.86 years, height SDS for bone age rose from a mean of -1.06 to -0.59. Longer treatment periods will be required to assess the effect on final height.