Children with Attention Deficit Hyperactivity Disorder Are More Likely to Fail Growth Hormone Stimulation Testing than Children without Attention Deficit Hyperactivity Disorder: A Retrospective Chart Review.

INTRODUCTION: Children with ADHD often present to pediatric endocrinologists due to growth concerns. Growth hormone stimulation testing (GHST) may be utilized as part of the workup. We evaluate whether children with ADHD and short stature or growth failure are more likely to fail GHST compared to children without ADHD. METHODS: We retrospectively studied children who underwent GHST as part of evaluation for short stature and/or growth failure and had an intact pituitary over a 16-year period (2002-2018). We performed univariate and logistic regression analyses with stratification by age. RESULTS: We included 260 children; 78 children had ADHD and were older, mean age (±SD) 12.2 (±2.6) years versus children without ADHD, mean age (±SD) 10.4 (±3.8) years. The population was largely Caucasian, and boys outnumbered the girls. Of the children with ADHD, only 9 were not medically treated. There was no difference in z-scores for height, weight, and BMI, or mid-parental height between the two groups. We found that children with ADHD were more likely to fail GHST than children without ADHD across the peak GH cut-offs of 10, 7, and 5 ng/mL (p = 0.003, p = 0.023, and p = 0.046 accordingly). The same trend persisted after regression analysis with adjustment for sex and stratification by age, and effect was more robust in the older group. DISCUSSION: The result shows higher likelihood of lower GH peaks in response to GHST in children with ADHD and short stature or impaired linear growth. Future work should evaluate possible mechanistic explanation and the role of psycho-stimulant medications.

Growth and Growth Hormone through the Ages: Art and Science.

BACKGROUND: People have long been fascinated with the size and growth of living things, from the giants of classic mythology and art to the little people who also have appeared in classical art, as well as the courts of European monarchs, and were exploited in "shows." Serious medical evaluation began in the late 19th century with the description of acromegaly and its association with pituitary tumors. In the early 20th century, multiple investigators attempted to extract a growth-promoting factor from the anterior pituitary and then, over the decades, to purify it and distinguish it from other anterior pituitary hormones. With relatively pure growth hormone (GH), its biological activity in growth promotion and as a metabolic hormone were studied, and species specificity became apparent: primate GH was the only GH active in man. Human GH was prepared from cadaveric pituitaries and distributed by the NIH to treat children with GH deficiency, but there was never enough pituitary hGH for all of the children who required it. When Creutzfeldt-Jakob disease was found in some patients who received pituitary GH, the production and FDA approval of biosynthetic hGH dramatically accelerated. With a large supply, one could treat those who were GH deficient and test its efficacy in other causes of short stature; longer acting versions of hGH have now been developed, tested, and in a few instances received FDA approval. SUMMARY: It has been a long journey from the description of over- and underproduction of GH in animals to the production and clinical use of the biosynthetic hormones. KEY MESSAGES: The efforts of basic scientists led to the extraction and purification of GH. Clinical scientists have expanded the appropriate use of hGH for short children with conditions in addition to GH deficiency.

Human Growth and Growth Hormone: From Antiquity to the Recominant Age to the Future.

Since antiquity Man has been fascinated by the variations in human (and animal) growth. Stories and art abound about giants and little people. Modern genetics have solved some of etiologies at both extremes of growth. Serious study began with the pathophysiology of acromegaly followed by early attempts at treatment culminating in modern endoscopic surgery and multiple pharmacologic agents. Virtually at the same time experiments with the removal of the pituitary from laboratory animals noted the slowing or stopping of linear growth and then over a few decades the extraction and purification of a protein within the anterior pituitary that restored, partially or in full, the animal's growth. Human growth hormone was purified decades after those from large animals and it was noted that it was species specific, that is, only primate growth hormone was metabolically active in primates. That was quite unlike the beef and pork insulins which revolutionized the care of children with diabetes mellitus. A number of studies included mild enzymatic digestion of beef growth hormone to determine if those "cores" had biologic activity in primates and man. Tantalizing data showed minimal but variable metabolic efficacy leading to the "active core" hypothesis, for these smaller peptides would be amenable to peptide synthesis in the time before recombinant DNA. Recombinant DNA changed the landscape remarkably promising nearly unlimited quantities of metabolically active hormone. Eight indications for therapeutic use have been approved by the Food and Drug Administration and a large number of clinical trials have been undertaken in multiple other conditions for which short stature in childhood is a sign. The future predicts other clinical indications for growth hormone therapy (and perhaps other components of the GH?IGF-1 axis), longer-acting analogues and perhaps a more physiologic method of administration as virtually all methods at present are far from physiologic.

The Challenge of Defining and Investigating the Causes of Idiopathic Short Stature and Finding an Effective Therapy.

Idiopathic short stature (ISS) comprises a wide range of conditions associated with short stature that elude the conventional diagnostic work-up and are often caused by still largely unknown genetic variants. In the last decade, the improvement of diagnostic techniques has led to the discovery of causal mutations in genes involved in the function of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis as well as in growth plate physiology. However, many cases of ISS remain idiopathic. In the future, the more frequent identification of the underlying causes will allow a better stratification of subjects and offer a tailored management. GH therapy has been proposed and approved in some countries for the treatment of children with ISS. To improve the efficacy of GH therapy, trials with GH combined with GnRH agonists, aromatase inhibitors, and even IGF-I have been conducted. This review aims to revise the current definition of ISS and discuss the management of children with ISS on the basis of the most recent evidence.

Type 3 renal tubular acidosis associated with growth hormone deficiency.

BACKGROUND: We identified two boys with type 3 renal tubular acidosis (RTA) and growth hormone deficiency and we sought to differentiate them from children with classic type 1 distal RTA. METHODS: We reviewed all children <6 years of age with RTA referred over a 13-year period and compared the growth response to alkali therapy in these two boys and in 28 children with only type 1 distal RTA. RESULTS: All children with type 1 RTA reached the 5th percentile or higher on CDC growth charts within 2 years of alkali therapy. Their mean height standard deviation score (SDS) improved from -1.4 to -0.6 SDS and their mean mid-parental height (MPH) SDS improved from -0.6 to 0 SDS after 2 years. In contrast, the boys with growth hormone deficiency had a height SDS of -1.4 and -2.4 SDS after 2 years of alkali and the MPH SDS were both -2.6 SDS after 2 years of alkali therapy. Growth hormone therapy accelerated their growth to normal levels and led to long-term correction of RTA. CONCLUSIONS: A child with type 1 RTA whose height response after 2 years of alkali therapy is inadequate should undergo provocative growth hormone testing.

Can One Predict Resolution of Neonatal Hyperthyrotropinemia?

OBJECTIVE: To identify predictors of transience vs permanence of neonatal hyperthyrotropinemia. We hypothesized that infants with greater severity of perinatal stress are more likely to have transient thyrotropin elevations. STUDY DESIGN: We retrospectively studied infants diagnosed with hyperthyrotropinemia between 2002 and 2014, following them for up to 12 years after diagnosis. Patients were divided into 3 groups: transient hyperthyrotropinemia (treatment was never prescribed), transient congenital hypothyroidism (treatment started but discontinued), and permanent congenital hypothyroidism (withdrawal unsuccessful or not attempted). We performed univariate and multiple logistic regression analyses, including and excluding infants with maternal thyroid disease. RESULTS: We included 76 infants, gestational age mean (±SD) 34.2 (±5.7) weeks, evaluated for hyperthyrotropinemia. Thirty-five (46%) were never treated, and 41 (54%) received levothyroxine. Of the treated patients, 16 successfully discontinued levothyroxine, and for 25 withdrawal either failed or was not attempted. We found that male patients were almost 5 times more likely than female patients to have transient neonatal hyperthyrotropinemia (OR 4.85; 95% CI 1.53-15.37). We documented greater maternal age (31.5 ± 5.48 years vs 26 ± 6.76 years, mean ± SD, P = .02), greater rate of cesarean delivery (86.7% vs 54.2%; P = .036), and retinopathy of prematurity (37.5% vs 8%; P = .02) in the group with transient congenital hypothyroidism vs the group with permanent congenital hypothyroidism. CONCLUSION: The results show transience of neonatal thyrotropin elevations in a majority of patients and suggest a possible association of hyperthyrotropinemia with maternal and perinatal risk factors.

Timing of Puberty in Overweight Versus Obese Boys.

BACKGROUND AND OBJECTIVE: Studies of the relationship of weight status with timing of puberty in boys have been mixed. This study examined whether overweight and obesity are associated with differences in the timing of puberty in US boys. METHODS: We reanalyzed recent community-based pubertal data from the American Academy of Pediatrics' Pediatric Research in Office Settings study in which trained clinicians assessed boys 6 to 16 years for height, weight, Tanner stages, testicular volume (TV), and other pubertal variables. We classified children based on BMI as normal weight, overweight, or obese and compared median age at a given Tanner stage or greater by weight class using probit and ordinal probit models and a Bayesian approach. RESULTS: Half of boys (49.9%, n = 1931) were white, 25.8% (n = 1000) were African American, and 24.3% (n = 941) were Hispanic. For genital development in white and African American boys across a variety of Tanner stages, we found earlier puberty in overweight compared with normal weight boys, and later puberty in obese compared with overweight, but no significant differences for Hispanics. For TV (≥3 mL or ≥4 mL), our findings support earlier puberty for overweight compared with normal weight white boys. CONCLUSIONS: In a large, racially diverse, community-based sample of US boys, we found evidence of earlier puberty for overweight compared with normal or obese, and later puberty for obese boys compared with normal and overweight boys. Additional studies are needed to understand the possible relationships among race/ethnicity, gender, BMI, and the timing of pubertal development.

A multicenter, open-label, observational study of testosterone gel (1%) in the treatment of adolescent boys with klinefelter syndrome or anorchia.

PURPOSE: To assess the safety and clinical outcomes of 6-month treatment with testosterone gel 1% therapy in adolescent boys with primary hypogonadism resulting from Klinefelter syndrome (KS) or anorchia. METHODS: This was a subgroup analysis of a multicenter, open-label study of adolescent boys (N = 86) with delayed puberty who received .5-5.0 g testosterone gel 1% daily for ≤6 months. Adolescent boys 12-17 years of age with KS (n = 21) or anorchia (n = 8), bone age ≥10.5 years, and baseline growth data ≥6 months were included in this analysis. Serum hormone levels (total/free testosterone, luteinizing hormone, dihydrotestosterone, follicle-stimulating hormone, and estradiol) were measured using validated assays. Safety was assessed through adverse events (AEs). RESULTS: At baseline, patients with KS were taller, weighed more, and had higher total testosterone levels (mean 174 vs. 19 ng/dL) than patients with anorchia. At 6 months, total and free testosterone and dihydrotestosterone levels increased 1.8- to 2.3-fold in the KS group and eight- to 10-fold in anorchia patients. Estradiol levels increased 1.9-fold in the anorchia group and 1.4-fold in the KS group after treatment. No clinically significant changes were noted for luteinizing hormone, follicle-stimulating hormone, and sex hormone-binding globulin concentrations in either group. Cough was the most common AE (eight of 29), followed by acne and headache (both four of 29). One anorchia and two KS patients discontinued prematurely. CONCLUSIONS: Once-daily testosterone gel application increased serum testosterone levels into the pubertal range and maintained pubertal testosterone levels during 6-month treatment. In this study, testosterone gel 1% raised testosterone levels and was associated with cough as the most common AE.

Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings Network.

BACKGROUND: Data from racially and ethnically diverse US boys are needed to determine ages of onset of secondary sexual characteristics and examine secular trends. Current international studies suggest earlier puberty in boys than previous studies, following recent trend in girls. METHODS: Two hundred and twelve practitioners collected Tanner stage and testicular volume data on 4131 boys seen for well-child care in 144 pediatric offices across the United States. Data were analyzed for prevalence and mean ages of onset of sexual maturity markers. RESULTS: Mean ages for onset of Tanner 2 genital development for non-Hispanic white, African American, and Hispanic boys were 10.14, 9.14, and 10.04 years and for stage 2 pubic hair, 11.47, 10.25, and 11.43 years respectively. Mean years for achieving testicular volumes of ≥ 3 mL were 9.95 for white, 9.71 for African American, and 9.63 for Hispanic boys; and for ≥ 4 mL were 11.46, 11.75, and 11.29 respectively. African American boys showed earlier (P < .0001) mean ages for stage 2 to 4 genital development and stage 2 to 4 pubic hair than white and Hispanic boys. No statistical differences were observed between white and Hispanic boys. CONCLUSIONS: Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were 6 months to 2 years earlier than in past studies, depending on the characteristic and race/ethnicity. The causes and public health implications of this apparent shift in US boys to a lower age of onset for the development of secondary sexual characteristics in US boys needs further exploration.

Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder.

The term small for gestational age (SGA) refers to infants whose birth weights and/or lengths are at least two standard deviation (SD) units less than the mean for gestational age. This condition affects approximately 3%-10% of newborns. Causes for SGA birth include environmental factors, placental factors such as abnormal uteroplacental blood flow, and inherited genetic mutations. In the past two decades, an enhanced understanding of genetics has identified several potential causes for SGA. These include mutations that affect the growth hormone (GH)/insulin-like growth factor (IGF)-1 axis, including mutations in the IGF-1 gene and acid-labile subunit (ALS) deficiency. In addition, select polymorphisms observed in patients with SGA include those involved in genes associated with obesity, type 2 diabetes, hypertension, ischemic heart disease and deletion of exon 3 growth hormone receptor (d3-GHR) polymorphism. Uniparental disomy (UPD) and imprinting effects may also underlie some of the phenotypes observed in SGA individuals. The variety of genetic mutations associated with SGA births helps explain the diversity of phenotype characteristics, such as impaired motor or mental development, present in individuals with this disorder. Predicting the effectiveness of recombinant human GH (hGH) therapy for each type of mutation remains challenging. Factors affecting response to hGH therapy include the dose and method of hGH administration as well as the age of initiation of hGH therapy. This article reviews the results of these studies and summarizes the success of hGH therapy in treating this difficult and genetically heterogenous disorder.

Metabolic syndrome in obese adolescents is associated with risk for nephrolithiasis.

OBJECTIVES: To examine the relationship between urinary pH and metabolic syndrome risk factors along with insulin resistance in obese adolescents, and to evaluate the relationship between other urinary stone-forming and -inhibiting markers and metabolic syndrome. STUDY DESIGN: A total of 46 obese adolescents were enrolled. Twenty-four hour and randomly obtained urine samples were analyzed for urinary pH, promoters of stone formation (ie, uric acid, oxalate, and relative saturation ratio of calcium oxalate [RSR-CaOx]), and inhibitors of stone formation (ie, citrate and osteopontin). Other data collected included height, weight, blood pressure, and fasting lipid, insulin, and glucose levels. RESULTS: The subjects had a mean age of 14.6±2.0 years and a mean body mass index of 36±6.3 kg/m(2). Random urine pH and the number of risk factors for metabolic syndrome were negatively correlated (r=-0.34; P=.02). RSR-CaOx was correlated with both homeostasis model assessment of insulin resistance score (r=0.38; P<.01) and number of risk factors for metabolic syndrome (r=0.47; P=.001) CONCLUSION: Decreased urinary pH and increased RSR-CaOx are associated with risk factors for metabolic syndrome in obese adolescents.

Bicalutamide plus anastrozole for the treatment of gonadotropin-independent precocious puberty in boys with testotoxicosis: a phase II, open-label pilot study (BATT).

OBJECTIVE: To evaluate the efficacy, tolerability, and pharmacokinetics of bicalutamide plus anastrozole in young males with testotoxicosis. METHODS: This was a multicenter, open-label, single-arm, 12-month, Phase II pilot trial in 14 males (2-9 years) with testotoxicosis treated with bicalutamide (12.5, 25, 50, or 100 mg) and anastrozole (0.5 or 1 mg) daily. The primary outcome was change in growth rate. RESULTS: At 1 year, the mean (standard deviation) change from baseline in growth rate was -1.6 (+/- 5.1) cm/year and -0.1 (+/- 1.8) SD units, and in bone maturation was -2.3 (+/- 0.5) years. The bone age/chronological age ratio was reduced from 2.1 (+/- 0.6) at baseline to 1.0 (+/- 0.4) (p = 0.00013). Steady-state trough R-bicalutamide and anastrozole concentrations were attained by Day 21 and 8, respectively. Gynecomastia (42.9%) and breast tenderness (12.5%) were the most common treatment-related adverse events. CONCLUSIONS: Treatment of testotoxicosis with bicalutamide plus anastrozole resulted in slower growth rate.

Results of a second year of therapy with the 12-month histrelin implant for the treatment of central precocious puberty.

Background. Gonadotropin releasing hormone analogs (GnRHas) are standard of care for central precocious puberty (CPP). The histrelin subcutaneous implant is safe and effective in the treatment of CPP for one year. Objective. The study evaluates a second year of therapy in children with CPP who received a new implant after one year of treatment. Methods. A prospective one-year study following an initial 12-month treatment period was conducted. Results. Thirty-one patients (29 girls) aged 7.7 +/- 1.5 years received a second implant. Eighteen were naïve to GnRHa therapy at first implantation. Peak LH declined from 0.92 +/- 0.58 mIU/mL at 12 months to 0.51 +/- 0.33 mIU/mL at 24 months (P < .0001) in naïve subjects, and from 0.74 +/- 0.50 mIU/mL at 12 months to 0.45 +/- 0.35 mIU/mL at 24 months (P = .0081) in previously treated subjects. Predicted adult height increased by 5.1 cm at 24 months (P = .0001). Minor implant site reactions occurred in 61%, while minor difficulties with explantation occurred in 32.2% of subjects. Conclusion. The histrelin implant demonstrates profound hypothalamic-pituitary-gonadal axis suppression when a new implant is placed for a second year of treatment. Prospective follow-up of this therapeutic modality for the treatment of CPP is needed.

Metabolic abnormalities in human immunodeficiency virus-infected children: two-year follow-up.

BACKGROUND: HIV-associated lipodystrophy (LD) manifests with fat maldistribution, dyslipidemia, and insulin resistance in some HIV-infected children on antiretroviral therapy. AIM: To assess whether lipid abnormalities in patients with HIV are stable over time. PATIENTS: The perinatally HIV-infected cohort at a medium-sized urban US teaching hospital. METHODS: This prospective, observational study consisted of five visits (at entry and 3, 6, 24, and 30 months after entry) during which fasting venous blood samples were drawn for HIV-1 RNA, CD4 lymphocytes, lipid profile, free fatty acids (FFA), glucose, insulin, and adiponectin. IGF-I/IGFBP-3 levels were measured at the first and fifth visits. RESULTS: Of 36 study participants, seven were lipodystrophic, and 30 patients completed all five study visits. LDL-cholesterol, total cholesterol (TC), triglycerides (TG), and FFA levels were significantly higher in patients taking protease inhibitors (PIs). Patients with LD had higher TC and TG levels (both p < 0.05), and higher FFA (p = 0.0532). Adiponectin levels did not differ between PI/non-PI and LD/non-LD groups. HDL-cholesterol seemed to decrease, and FFA to increase over time. All IGF-I and all but one IGFBP-3 level were within normal range for age and Tanner stage. CONCLUSION: Dyslipidemia remained relatively constant over our study period. Adiponectin was not useful as a marker of LD in our population.

Public health implications of altered puberty timing.

Changes in puberty timing have implications for the treatment of individual children, for the risk of later adult disease, and for chemical testing and risk assessment for the population. Children with early puberty are at a risk for accelerated skeletal maturation and short adult height, early sexual debut, potential sexual abuse, and psychosocial difficulties. Altered puberty timing is also of concern for the development of reproductive tract cancers later in life. For example, an early age of menarche is a risk factor for breast cancer. A low age at male puberty is associated with an increased risk for testicular cancer according to several, but not all, epidemiologic studies. Girls and, possibly, boys who exhibit premature adrenarche are at a higher risk for developing features of metabolic syndrome, including obesity, type 2 diabetes, and cardiovascular disease later in adulthood. Altered timing of puberty also has implications for behavioral disorders. For example, an early maturation is associated with a greater incidence of conduct and behavior disorders during adolescence. Finally, altered puberty timing is considered an adverse effect in reproductive toxicity risk assessment for chemicals. Recent US legislation has mandated improved chemical testing approaches for protecting children's health and screening for endocrine-disrupting agents, which has led to changes in the US Environmental Protection Agency's risk assessment and toxicity testing guidelines to include puberty-related assessments and to the validation of pubertal male and female rat assays for endocrine screening.

Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial.

CONTEXT: GnRH analog (GnRHa) therapy for central precocious puberty (CPP) typically involves im injections. The histrelin implant is a new treatment that provides a continuous slow release of the GnRHa histrelin. OBJECTIVE: The objective of the study was to investigate the safety and efficacy of the subdermal histrelin implant for the treatment of CPP in treatment naive and previously treated children. DESIGN: This was a phase III, open-label, prospective study of 1-yr duration. SETTING: The study was conducted at nine U.S. medical centers. PATIENTS: Girls ages 2-8 yr (naive) or 2-10 yr (previously treated) and boys 2-9 yr (naive) or 2-11 yr (previously treated) with clinical evidence of CPP and a pretreatment pubertal response to leuprolide stimulation were eligible. INTERVENTION: A 50-mg histrelin implant was inserted sc in the inner upper arm. MAIN OUTCOME MEASURES: Peak LH after GnRHa stimulation testing and estradiol (girls) and testosterone (boys) were the main outcome measures. RESULTS: Thirty-six subjects (20 naive) were enrolled. By 1 month, peak LH fell from 28.2 +/- 19.97 (naive) to 0.8 +/- 0.39 mIU/ml (P < 0.0001) and from 2.1 +/- 2.15 (previously treated) to 0.5 +/- 0.32 mIU/ml (P < 0.0056). Estradiol suppressed from 24.5 +/- 22.27 (naive) to 5.9 +/- 2.37 pg/ml (P = 0.0016) and remained suppressed in previously treated subjects, as did testosterone. Suppression was maintained throughout the study. No significant adverse events occurred. CONCLUSIONS: The subdermal histrelin implant achieves and maintains excellent suppression of peak LH and sex steroid levels for 1 yr in children with CPP. The treatment is well tolerated. Long-term studies are needed to confirm these results.

Small for gestational age: short stature and beyond.

Depending on the definitions used, up to 10% of all live-born neonates are small for gestational age (SGA). Although the vast majority of these children show catch-up growth by 2 yr of age, one in 10 does not. It is increasingly recognized that those who are born SGA are at risk of developing metabolic disease later in life. Reduced fetal growth has been shown to be associated with an increased risk of insulin resistance, obesity, cardiovascular disease, and type 2 diabetes mellitus. The majority of pathology is seen in adults who show spontaneous catch-up growth as children. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation in children born SGA can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain. Implicitly, this argument questions current infant formula feeding practices. The risk is less clear for individuals who do not show catch-up growth and who are treated with GH for short stature. Recent data, however, suggest that long-term treatment with GH does not increase the risk of type 2 diabetes mellitus and the metabolic syndrome in young adults born SGA.

Age at growth hormone therapy start and first-year responsiveness to growth hormone are major determinants of height outcome in idiopathic short stature.

AIM: To develop methods to identify factors associated with a favorable outcome in GH-treated children with idiopathic short stature (ISS). METHODS: From 4,685 children listed as having ISS within KIGS (Pfizer International Growth Database), we studied (a) the prediction model group (n = 657) to develop the first-year prediction model, and (b) the near adult height group (NAH; n = 256) which received GH for >4 years to develop descriptive models for adult height and overall height gain. RESULTS: NAH group at GH start: age was 10.0 years, height -2.5 SD score (SDS), weight -2.3 SDS, height minus mid-parental height (MPH) -1.5 SDS; GH dose 0.19 mg/kg/week. Height gain was 1.1 SDS at a median age of 17.2 years. Growth response correlated positively with GH dose and weight at the start of GH treatment, and negatively with age and height SDS minus MPH SDS. The model explains 39% (error SD 1.2 cm) of the variability. Adult height correlated (R(2) = 0.64) positively with height at GH start, MPH and the first-year responsiveness to GH, and negatively with age. CONCLUSIONS: Prepubertal children with ISS who show an appropriate first-year response to GH are likely to benefit from long-term treatment, even on low GH dosages.

Major determinants of height development in Turner syndrome (TS) patients treated with GH: analysis of 987 patients from KIGS.

Little is known about factors determining height outcome during GH treatment in Turner syndrome (TS). We investigated 987 TS children within the Kabi International Growth Study (KIGS) who had reached near adult height (NAH) after >4 y GH treatment (including >1 y before puberty). Through multiple regression analysis we developed a model for NAH and total gain. Our results were as follows (median): 1) At start, age 9.7 yrs, height (HT) 118.0 cm (0.0 TS SDS), projected adult height 146.1 cm, GH dose 0.27 mg/kg wk; 2) NAH HT 151.0 cm (1.5 TS SDS); 3) Prepubertal gain 21.2 cm (1.6 TS SDS); 4) Pubertal gain 9.4 cm (0.0 TS SDS). NAH correlated (r = 0.67) with (ranked) HT at GH start (+), 1 year responsiveness to GH (+), MPH (+), age at puberty onset (+), age at GH start (-), and dose (+). The same factors explained (R = 0.90) the total HT gain. However, HT at GH start correlated negatively. Karyotype had no influence on outcome. Evidently, height at GH start (the taller, the better), age at GH start (the younger, the better), the responsiveness to GH (the higher, the better) and age at puberty (the later, the better) determine NAH.