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Birth length has been reported to be either normal or reduced in infants with congenital GH deficiency (CGHD). We evaluated 46 infants with CGHD followed in a single regional medical center. All were born full term and had peak GH of less than 10 microg/liter after provocative stimulation. Length SD score at birth was normal but subsequently showed deceleration, at 6 months and 12 months of age, before GH treatment. The majority were delivered vaginally (83%), and delivery was uncomplicated in 61%. Four patients (9%) had breech vaginal delivery. Perinatal morbidities were found in 72% of infants and included jaundice (n = 17), hypoglycemia with or without seizure (n = 14), and hypoxemia (n = 5). Multiple pituitary hormone deficiencies were found in 85% of the subjects. Organic lesions were documented in all 22 subjects who had magnetic resonance imaging and in 4 of 11 subjects who had computed tomography scan. Only the hypoglycemic infants received early GH treatment. Growth data in hypoglycemic and normoglycemic CGHD infants were not significantly different. In our population, CGHD did not adversely affect fetal growth but is essential for normal linear growth during early infancy. Congenital developmental abnormalities in the hypothalamic-pituitary region are the most common cause of CGHD and are best diagnosed by an magnetic resonance imaging study.

We quantitated serial serum beta-hydroxybutyrate (beta-OHB) levels using the Ketosite method in 9 children with IDDM who were treated for diabetic ketoacidosis (DKA) and compared them to urinary ketone measurements by dipstick. Persistent elevations of serum beta-OHB were seen in six patients when the urine became clear of ketones; five of these patients had a recurrence of ketonuria. We conclude that many patients recovering from ketoacidosis have continuing elevations of beta-OHB after the urine is free of ketones and this unrecognized abnormality is the likely cause of recurrence of the ketonuria. We recommend that fluid therapy be continued beyond clearance of ketonuria and suggest using the Ketosite method to document restoration of normal serum beta-OHB levels in patients recovering from DKA.

The current adult heights of hypopituitary children treated with recombinant human growth hormone (rGH) now range between −1.5 and −0.7 height standard deviations (HtSDS) of control populations. These height outcomes are markedly better than the ones observed following treatment with pituitary-derived human growth hormone (pGH) (between −4.7 and −2.0 Ht SDS). Although treatment with rGH has not yielded adult heights that are equal to genetic target heights, the discrepancy is much less now than in previous decades. Higher rGH dose, longer duration of treatment, early age at diagnosis, correction of height deficit prior to onset of puberty, and daily rGH injections have had beneficial effects on final adult heights. The current dosing regimens, (0.3–0.18 mg/kg/wK) have not had an adverse effect on bone maturation and have not stimulated an earlier onset of puberty. Although height gains in puberty are less than controls, a majority of treated subjects reach heights within the normal range for adults. Higher doses of rGH during puberty have been studied in limited numbers of adolescents with positive effects; however, standard dosing will likely continue to be used because of financial considerations and safety concerns. Further improvements in adult heights are likely to be reported when the youngest children who began rGH in 1985 complete their growth. Several studies have investigated the quality of life (QOL) of GH-deficient (GHD) patients who, as children, had been treated with GH predominantly during the pGH era. Domains of functioning assessed include educational attainment, employment, and marital status. Although some studies have reported a generally positive adaptation, others have shown this group to exhibit marked deficits. Limited adult height outcomes in the pGH era of GH therapy has sometimes been used to account for poor outcomes. Variable behavioral findings are likely related to sample heterogeneity and disparate research methodologies and designs, most particularly the choice of control or comparison groups. In addition to summarizing this older literature, we report on a recently completed investigation in which the QOL adjustment of GHD patients is compared to that of same-sex siblings. Comparisons between GHD cases and norms for standardized questionnaires indicated both better and worse functioning in several domains. In contrast, very limited differences were detected between GHD cases and same-sex siblings. IGHD (isolated growth hormone deficiency) patients were functioning better than those with MPHD (multiple pituitary hormone deficiencies), but the effect sizes of these differences in most areas were relatively small. Adult height and degree of growth over the course of GH therapy were generally unrelated to QOL outcomes. Findings from the present study underscore the importance of selecting unbiased control/comparison groups in evaluating psychological outcomes among GHD adults.

The current doses of recombinant growth hormone (rGH) are two to three times those used in the pituitary growth hormone era. These rGH doses (0.025 to 0.043 mg/kg/d) are similar to or moderately greater than the physiologic requirements. Growth velocity and height gains have been shown to be greater with 0.05 mg/kg/d of rGH than with 0.025 mg/kg/d. Larger doses of GH and early initiation of treatment result in greater heights at the onset of puberty and greater adult heights. Earlier onset of puberty and more rapid maturation, as indicated by bone age, were not observed in children who were given 0.18 to 0.3 mg/kg/wk of rGH. The frequency of adverse events is very low, but diligent surveillance of all children who are treated with rGH is essential.

Several studies have investigated the quality of life (QOL) of GH-deficient (GHD) adults who, as children, had been treated with GH. Variable findings are probably related to sample heterogeneity and disparate research methodologies and designs, particularly the choice of control or comparison groups. In addition to comparing a relatively large sample to questionnaire norms, the present study is the first to compare the QOL adjustment of GHD patients to that of same sex siblings. A total of 140 former patients (76% of those eligible; mean age, 26 yr; n = 95 isolated GHD, n = 45 multiple pituitary hormone deficiencies; 117 males and 23 females) and 53 same sex siblings (84% participation), 18 yr and older, participated in the telephone questionnaire survey. The majority of interviews with GHD patients (78%) and siblings (87%) were conducted blind to the subject’s clinical status. Comparisons between GHD patients and norms for standardized questionnaires indicated both better and worse functioning in several domains. In contrast, very limited differences were detected between GHD cases and same sex siblings. Isolated GHD patients were functioning better than those with multiple pituitary hormone deficiencies, but the effect sizes of these differences in most areas were relatively small. Adult height and degree of growth over the course of GH therapy were generally unrelated to QOL outcomes. Findings from the present study underscore the importance of selecting unbiased control/comparison groups in evaluating psychological outcomes among GHD adults.

The goals of this presentation are to review the essential roles of aromatase, estrogens and the estrogen receptor in pubertal growth. Estrogen deficiency due to mutations in the aromatase gene (CYP19) and estrogen resistance due to disruptive mutations in the estrogen receptor gene have no effect on normal male sexual maturation in puberty. However, they lead to absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, continued growth into adulthood and very tall adult stature in both sexes. Gonadotropin and androgen levels are elevated in patients with either estrogen deficiency (aromatase deficiency) or estrogen resistance (estrogen receptor mutation). Glucose intolerance, hyperinsulinemia and lipid abnormalities are also present. Skeletal integrity is compromised. Increased bone turnover, reduced bone mineral density and osteoporosis develop in both sexes. Sexual orientation is appropriate in males and females. In females, aromatase deficiency in the ovary causes pubertal virilization and multicystic ovaries because of elevated gonadotropins and androgens. Simultaneously, secondary sexual maturation fails to occur. Placental aromatase deficiency results in virilization of the mother and her female fetus because of the accumulation of potent androgens which are not converted to estrogens. The male fetus has normal genitalia. In conclusion, estrogens are essential for normal female secondary sexual maturation, bone maturation, epiphyseal fusion, pubertal growth spurt and achievement of normal bone mineral mass. Estrogens also influence insulin sensitivity and lipid homeostasis. However, estrogens do not appear to be essential for fetal survival, placental growth, or female sexual differentiation.

A comparison was made of the growth responses of prepubertal naive GH-deficient children who were randomly assigned to receive 0.3 mg/kg.week recombinant human GH administered either daily (QD) or three times weekly (TIW) over 4 yr. The effects of the two regimens on annual growth velocity, change in height SD score, bone maturation, and age at onset of puberty are presented as the mean +/- SD. During each of the 4 yr, the annual growth velocity was significantly greater in the QD vs. TIW group. At 48 months, the mean total gain in height was 9.7 cm greater in the QD group (38.4 +/- 5.5) than that in the TIW group 28.7 +/- 3.2; P = 0.0002). The mean height SD score at the end of each year was significantly greater in the QD group. After 4 yr, the total gain in height SD score was 3.2 +/- 1.2 in the QD group compared to 1.5 +/- 0.5 in the TIW group (P = 0.0003). The height SD score at 4 yr was 0.2 in the QD group (pretreatment, -2.9) compared to -1.4 in the TIW group (pretreatment, -2.9). After 4 yr of rhGH treatment, the increment in bone age was similar in the QD (4.9 +/- 1.0 yr) and TIW (4.8 +/- 1.1 yr) groups. The change in height age minus the change in bone age was more favorable in the QD (1.2 +/- 0.8 yr) than in the TIW (0.0 +/- 0.9 yr) group (P = 0.003). The mean age at onset of puberty in boys was the same in the QD (13.2 yr) and TIW (13.0 yr) groups (P = 0.71), and the mean bone age at the start of puberty was also similar (11.5 in QD and 11.3 in TIW groups; P = 0.66). The advantages of QD rhGH treatment in prepubertal GH-deficient children after 4 yr were additional gains of 1.7 height SD score and 9.7 cm in height over those treated with the TIW regimen (P = 0.0002).

The insulin-like growth factor binding proteins (IGFBPs) are the carriers for insulin-like growth factor (IGF0-I and IGF-II. IGFBP-3 is GH-dependent and circulates associated with IGFs and an acid-labile subunit to form a 150-kilodalton (kDa) complex. In human serum, two immunoreactive molecular weight forms of IGFBP-3 have been identified. In human urine, radioimmunoassayable levels of IGFBP-3 have been detected. The objectives of this study were to characterize the molecular weight forms of IGFBP-3 in urine and serum of healthy children and adults and in children with GH deficiency (GHD), to quantify the urinary molecular weight forms of IGFBP-3, and to evaluate the relationship of these forms with GH therapy. Urine and serum were obtained from 12 prepubertal children with GHD, before and after 6 months of GH therapy, from 30 prepubertal healthy children, and from 8 healthy adults. Western immunoblotting (WIB) with IGFBP-3 antiserum (alpha IG-FBP-3g1) showed that in urine the most representative IGFBP-3 was a 17.7-kDa form. The 17.7-kDa IGFBP-3 was high in urine of healthy children compared with healthy adults and was low in children with GHD but increased after GH therapy. Urinary IGFBP-3 immunoreactive profile was determined by neutral-size exclusion chromatography, followed by IGFBP-3 RIA analysis of the fractions. Urine showed a major peak of IGFBP-3 immunoreactivity around 17 kDa. The 17-kDa urinary IGFBP-3 chromatographic peak averaged 8461 +/- 367 ng/12 h.m2 of body surface in healthy children, 3415 +/- 739 in adults (P < 0.001), 2294 +/- 354 in children with GHD before GH therapy (P < 0.001), and 7940 +/- 1874 in children with GHD after GH therapy. Urinary IGFBP-3 was also measured by RIA in unfractionated urine; healthy children showed levels significantly higher (14575 +/- 460 ng/12 h.m2) than adults (7823 +/- 1083, P < 0.001) and higher than children with GHD before GH therapy (4710 +/- 703, P < 0.001). Again, however, immunoreactive IGFBP-3 increased after GH treatment (12294 +/- 3394). In the serum of the healthy children we characterized by specific IGFBP-3 WIB analysis, a 17.7-kDa immunoreactive form of IGFBP-3 that was absent in the serum of healthy adults and low in patients with GHD, increased during GH therapy. Serum samples were subjected to neutral-size exclusion chromatography and the fractions were analyzed by WIB.(ABSTRACT TRUNCATED AT 400 WORDS)

The appropriateness of the recommended L-thyroxine dose (10-15 micrograms/kg/day) for the treatment of congenital hypothyroidism has been questioned because of the risk of iatrogenic hyperthyroidism. We report the outcome of 23 newborns with congenital primary hypothyroidism treated with 25 micrograms L-thyroxine per day (5.3-9.2 micrograms/kg/day) and followed for an average of 59 months. Serum thyroxine (T4) values increased (X = 11.4 +/- 2.7 micrograms/dL) within 4 weeks posttherapy; eight infants had T4 levelsor = 13 micrograms/dL on only half the currently recommended dose. Thyroid-stimulating hormone (TSH) values remained elevated in 18 of 21 patients for 2-21 months despite a high-normal T4. Psychometric tests were performed in 19 of the 23 patients. The mean Full Scale IQ for the congenital hypothyroid group (n = 16) was 101.4 +/- 13.2 with comparable Verbal and Performance IQ scores. Patients with a bone age (BA) ofor = 32 weeks or T42 micrograms/dL at initial evaluation had significantly Lower Verbal IQ scores. A standardized parent-report assessment of behavioral and emotional functioning revealed subgroup scale scores that were indistinguishable from nonclinical norms. We conclude that (1) average range IQ scores and positive behavioral adaptation are observed in congenitally hypothyroid children treated with L-thyroxine doses lower than currently recommended; (2) the L-thyroxine dose should be individualized to prevent iatrogenic hyperthyroidism; (3) TSH normalization should not be a primary objective of treatment, and (4) a prospective study comparing the advantages and risks of different doses of L-thyroxine is needed.

The output of urinary IGF-II was measured by RIA in 12-h overnight urine samples obtained from 22 preterm and 15 full-term infants, 40 normal children, 18 children with growth hormone (GH) deficiency, and 25 patients with idiopathic short stature. GH deficiency was defined as a peak to GH provocative tests ≤ 9.9 μUg/L during two provocative tests. The authenticity of urinary IGF-II was confirmed by size exclusion chromatography. Statistical analysis was performed by one-way analysis of variance using the Student Neuman-Keuls test to detect inter-group differences at the level of p < 0.05. The preterm and full-term infants excreted significantly higher amounts of urinary IGF-II (18.4 ± 1.7 and 5.7 ± 1.0 pmol/kg, respectively) compared with normal children (2.4 ± 0.25 pmol/ kg; P < 0.001). The output of urinary IGF-II in preterm infants was greater than that observed in full-term infants (F = 84.7, p < 0.001). The control children excreted significantly more IGF-II (2.4 ± 0.2 pmol/kg) than children with GH deficiency (0.9 ± 0.1 pmol/kg) or idiopathic short stature (1.0 ± 0.1 pmol/kg; F= 13.5; p < 0.001). Analysis of urinary IGF-II excretion based on creatinine output yielded similar results. Data on urinary IGF-I and GH previously published were correlated and compared with the excretion pattern of urinary IGF-II. Urinary GH correlates with urinary IGF-II in groups 3, 4, and 5 (0.58 and 0.46 per body weight and nmol of creatinine, respectively; p < 0.01), as well as in the preterm and full-term infants (0.51, p < 0.01; 0.54, p < 0.01) when the data were standardized for kg of body weight and nmol of creatinine, respectively. Children with GH deficiency excrete significantly less IGF-II compared with control subjects. This pattern is similar to that of urinary IGF-I. The highest urinary IGF-II output is observed in preterm infants, possibly reflecting a period of persistent elevation of IGF-II secondary to the young gestational age of these infants.

The responses of the major immunoglobulins (gamma G, gamma M and gamma A) in serum and nasal and duodenal secretions were studied in infants and children after immunization with live and inactivated poliovaccines and after natural poliomyelitis infection. The serum immunoglobulin responses to these procedures resembled each other although higher levels followed the natural infection. After immunization with live attenuated vaccine, antibody activity was found regularly in nasal and duodenal secretory gamma A immunoglobulin, but not after immunization with inactivated vaccine. To explain the alimentary immunity that follows infection with attenuated or wild poliovirus, it is proposed that orally administered live virus, which implants and replicates in the pharynx and intestinal tract, stimulates local lymphoid cells, leading to the production of immunoglobulins predominantly of the gamma A class.

Urinary growth hormone (GH) and insulin-like growth factor I (IGF-1) excretion profiles were compared in children receiving biosynthetic GH. Group 1 included 18 healthy controls. Group 2 included nine children given biosynthetic GH three times a week. Group 3 included 14 children given daily GH injections. Overnight urine samples were collected for three consecutive nights in all groups. No significant day-to-day variation in urinary GH output was observed in group 1. In group 2, urinary GH output was significantly higher on day one following injection than on days two and three. Urine GH outputs in group 2 were significantly lower on days two and three than the values observed on all days in group 3. Throughout the three-day study, subjects in group 3 excreted similar amounts of GH significantly higher than those of controls. Urinary IGF-I output (nmol/kg) was similar on all three study days in groups 1 and 3. Group 2 had significantly lower urinary IGF-I output on day three compared with day one. Urinary IGF-I output on day three was also significantly lower in group 2 than in group 3. We conclude that urinary GH and IGF-I outputs are influenced by the frequency of GH administration.

Objective To compare the urinary output of insulinlike growth factor I (IGF-I) and growth hormone (GH) in prepubertal and pubertal children with insulin-dependent diabetes mellitus (IDDM) versus nondiabetic subjects and to analyze the relationship between the urinary excretion of these peptides and degree of metabolic control. Research Design and Methods Group 1 included 30 IDDM patients who had had diabetes for 4.9 ± 0.7 yr and had normal renal function (mean age 11.6 ± 0.9 yr); group 2 consisted of 31 control subjects (mean age 9.2 ± 0.6 yr). Sensitive radioimmunoassays were used to measure IGF-I and GH in urine aliquots from 12-h timed overnight collections that had been dialyzed, concentrated 50-fold, and lyophilized. Results Significantly lower IGF-I and GH outputs per kilogram body weight per 12 h were observed in IDDM subjects compared with control subjects. When data were expressed per kilogram of body weight, no difference was observed between the urinary output of IGF-I and GH between prepubertal and pubertal subjects within group 1 or group 2. The prepubertal children had significantly lower HbA1 than the pubertal population; however, no correlation was found between urinary output of IGF-I or GH and HbA1. A positive correlation was observed between urinary IGF-I and GH (r = 0.85, P < .001). Conclusions Patients with long-standing IDDM excrete significantly lower urinary levels of IGF-I and GH compared with normal subjects. Serial measurements of these peptides from onset of IDDM are needed to define whether the changes observed are present at diagnosis or are secondary to duration of disease.

To determine whether serum 3 alpha-androstanediol glucuronide (3AG) reflects the overall effect of integrated adrenal androgen secretion in the virilizing form of congenital adrenal hyperplasia (CVAH), circadian levels (0800, 1200, 1600, and 2000 h) of serum 3AG and 17-hydroxyprogesterone (17OHP) or 11-deoxycortisol (S), androstenedione (A), testosterone (T), and 24-h urinary 17-ketosteroids (17KS) were examined in seven patients (pts) with classical 21-hydroxylase deficiency (21OHD) and one pt with classical 11 beta-hydroxylase deficiency (11 beta OHD). Hormonal studies were conducted during the second day of dexamethasone (Dex) administration (2 mg/day). In five poorly controlled CVAH pts, including the 11 beta OHD pt, highly elevated baseline morning (AM) serum 17OHP or S as well as A levels, and elevated AM T levels in three pts decreased markedly in the evening (PM), while elevated serum 3AG showed no significant circadian changes; 17KS levels were markedly elevated for age. During Dex, moderately or slightly elevated AM 17OHP, A, or T in two to four pts with 21OHD decreased to the normal range in the PM. In the pt with 11 beta OHD, S, A, and T levels were suppressed. 3AG levels were modestly elevated or normal, without circadian changes, in these pts; 17KS levels were elevated or normal. In two other 21OHD pts, modestly elevated AM baseline 17OHP and A levels decreased in the PM; elevated AM T decreased in one pt in the PM; modestly elevated 3AG levels showed no circadian changes; 17KS levels were modestly elevated. During Dex, normal or slightly elevated serum steroids and 17KS levels were associated with normal or high normal 3AG levels without circadian changes. In one postpubertal female with 21OHD, modestly elevated AM baseline 17OHP levels decreased at 2000 h; normal A and T levels throughout the day and low normal 17KS were associated with slightly low 3AG levels, without circadian variation. During Dex treatment, normal 17OHP, A, T, and low 17KS levels were associated with low 3AG levels without circadian variation. In all pts as a group, an excellent correlation (r = 0.9) was found between either 0800 h or mean, or 2000 h serum 3AG levels and 17KS. In addition, AM and PM serum 3AG levels in five normal women were similar. We conclude that the high correlation between serum 3AG and urinary 17KS and the absence of a significant circadian variation in 3AG indicate that serum 3AG, regardless of sample time, is a useful metabolic index of integrated adrenal androgen secretion in CVAH.

Twelve-h overnight urine and serum samples obtained simultaneously at 20-min intervals were assayed for growth hormone (GH). Ninety-one children, 5 to 16 y (Tanner stage 1 to 3) participated; group 1 were healthy children, group 2 were children with organic GH deficiency, and group 3 had idiopathic growth failure and normal GH stimulation tests. Serum pool GH concentrations in group 1 were similar to those in group 3 (3.3 +/- 0.3 versus 3.4 +/- 0.2 micrograms/L); group 2 had significantly lower GH concentrations (1.6 +/- 0.2 micrograms/L). Plasma IGF-I levels were significantly greater in groups 1 (14.2 +/- 2.6 nmol/L, p less than 0.001) than in groups 2 and 3 (2.6 +/- 0.5 and 5.5 +/- 0.7 nmol/L, respectively). Urinary GH (mean +/- SEM) standardized for body weight (micrograms/kg) in group 1 (0.31 +/- 0.02) was significantly greater than in group 2 (0.14 +/- 0.01) and group 3 (0.20 +/- 0.01). However, when expressed as microgram/mol creatinine, the output of GH was similar in group 1 (4.0 +/- 0.3) and group 3 (3.4 +/- 0.3); both groups had significantly greater output compared to group 2 (1.3 +/- 0.2). Urinary IGF-I (nmol/kg) in group 1 (0.22 +/- 0.02) was significantly greater than in group 2 (0.12 +/- 0.01) or group 3 (0.07 +/- 0.01). Urinary GH correlated with serum pool GH concentration (r = 0.64, p less than 0.001). Although urinary GH output reflects endogenous GH secretion, the overlap between groups 1 and 3 precludes using urinary GH measurements as a diagnostic test for GH deficiency in children with idiopathic growth failure.

Puberty is the transitional period between childhood and adulthood when physical, sexual, and psychosocial maturation occurs. The onset of puberty is controlled by the gonadotropin-releasing hormone (GnRH) neuron and is triggered when inhibition of the neuron is lifted. Subsequently, GnRH induces secretion of other hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which in turn stimulate the gonads. Concurrently, increases in estrogen levels in both boys and girls stimulate growth hormone (GH) and insulin-like growth factor-I (IGF-I) secretion, which are responsible for the pubertal growth spurt. In hypogonadal children, however, hypothalamic/pituitary defects or gonadal diseases preclude the production of these hormones, preventing the onset of puberty. Hormone replacement therapy with either estrogen or testosterone is a viable treatment option for hypogonadal children. These should be administered with consideration of sexual maturation rates, statural and bone growth rates, and occurrence of adverse effects. The merits and disadvantages of various hormone replacement therapies for girls and for boys are discussed.

We assessed the adult quality of life of five medical chart-selected genetic males (ages 29-34 years) assigned and reared as females due to ambiguity of the external genitalia. All five were treated following the traditional method proposed by John Money and colleagues in 1955, commonly referred to as the "optimal gender policy". The adult follow-up assessment included physical and endocrinological evaluation, completion of self-report questionnaires, and a semi-structured interview assessing gender identity, sexual experience and orientation. Quality of life domains assessed by questionnaire included health-related issues, satisfaction with health-care management, emotional distress, and relationship satisfaction. Vaginoplasty in four out of five patients was initially unsuccessful. Four patients had periodic lapses in adherence to hormone replacement therapy. Gender role behavior across development was masculine relative to norms for women. All participants reported a female gender identity without a history of gender dysphoria. The majority of participants (four of five) reported being sexually active and in long-term relationships (three heterosexual, one homosexual). Current emotional adaptation and health-related quality of life are within the normal range for four participants. Sex assignment of 46,XY individuals with ambiguous genitalia as females is compatible with a positive quality of life.

In healthy boys, puberty is the transitional period between childhood and adulthood that results from a resurgence of augmented pulsatile secretion of gonadotropin-releasing hormone, a hypothalamic decapeptide that controls gonadotropin biosynthesis and eventually reproduction.

Comprehensive guidelines for optimizing the outcomes for girls with Turner syndrome (TS) have been proposed (1–8). Much credit is owed to the advocacy positions taken by the TS Societies and their strong endorsement of clinical studies carried out by pediatric endocrinologists, psychologists, and geneticists. These collaborative efforts have resulted in significant advances in our understanding of the scope of the problems that may be encountered by girls with TS. They have also, led to the development of effective new treatment strategies. Credit must also be given to the parents of these children without whom our knowledge base would be incomplete.

The endocrine management of growth failure and short stature has changed dramatically since the introduction of biosynthetic growth hormone (GH). To date, however, there are no published studies concerning the behavioral outcomes of individuals who had been treated entirely within the new era of biosynthetic GH therapy. Insofar as improvements in the treatment regimen have resulted in better growth and adult height outcomes (1), there is good reason to speculate that the psychosocial adjustment of individuals treated entirely in this new era will also be superior to that of patients who were treated when supplies of GH were limited. This belief is so pervasive that it has contributed to the expanded prescribing of GH to non-GH-deficient patient groups with short stature (2,3). Until behavioral outcome studies of these newer cohorts are completed, there remains much to be learned from the experiences and quality of life (QOL) outcomes of patients, now young adults or older, who have completed treatment, regardless of treatment era.

A 16½-year old girl with mixed gonadal dysgenesis was born with ambiguous genitalia and had undergone bilateral gonadectomy in infancy. She developed a right adnexal mass and recurrent right lower abdominal pain after starting cyclical replacement estrogen and progesterone therapy. The location and characteristics of the mass raised concern that a neoplasm had developed from a portion of the dysgenetic gonad which might not have been removed during the original surgery. Upon exploratory laparotomy, the right adnexal mass was observed to be a hematometra of a rudimentary uterine horn that had become distended with blood. The uterine horn was removed and the uterus was left undisturbed.

We measured adult heights (Ht) of 94 healthy GH-sufficient children (peak GH10 ng/mL, polyclonal RIA) whose Ht at presentation were more than 2 SD below the mean for chronological age, with normal weight-to-Ht ratios, normal body proportions, and pathologic growth velocity for chronological age. Group 1 (n 36, 6 females) received standardized doses (0.3 mg/kg x week) of GH (mean duration = 41 months), while group 2 (n = 58, 17 females) received no treatment. Our conclusion was that the mean final Ht SD score in the GH-treated group (-1.5) was significantly greater than in the untreated group (-2.1); P.001. Genetic predisposition to short stature was evident in both groups: the midparental Ht SD score was -1.1 in the treated and -1.0 in the untreated group. Midparental Ht was met or exceeded by 42% of the GH-treated group but only 15% of the untreated group. Final Ht was not significantly different from predicted Ht, except from GH-treated girls, who exceeded their predicted Ht. Although the mean Ht gains (6.8 cm in girls and 3 cm in boys) were modest and variable, GH treatment provided significantly better Ht outcomes for the majority of children with idiopathic growth failure.

Growth hormone prepared by recombinant DNA technology (somatropin) has been commercially available for over 11 years. More than 38 000 children have been treated with different growth hormone products. While the best response to treatment occurs in children with severe growth hormone deficiency, therapy with growth hormone will increase the rate of statural growth in children with short stature of many different aetiologies. There are few studies of the effect of growth hormone treatment on final adult height, and the magnitude of this effect is harder to gauge, particularly in children with idiopathic short stature. Other benefits of growth hormone treatment in children include improvement in psychosocial functioning and physiological parameters, such as bone mineral density. Adverse effects associated with growth hormone treatment have been relatively uncommon. Most of the safety data on growth hormone have come from large postmarketing databases maintained by 2 pharmaceutical companies. The adverse event profile reported in children treated with growth hormone is different from that found in adults. Peripheral oedema and carpal tunnel syndrome, which are common in adults treated with growth hormone and frequently result in treatment discontinuation, are rare in children. Intracranial hypertension is rare, but can occur in children with growth hormone deficiency, Ullrich-Turner syndrome or renal insufficiency during the first 8 to 12 weeks after the start of growth hormone treatment; it has seldom been reported in adults with growth hormone deficiency. Children with growth hormone deficiency, Ullrich-Turner syndrome or renal insufficiency are prone to develop slipped capital femoral epiphyses both before and during growth hormone treatment. Therefore, limping and complaints of hip or knee pain should be carefully investigated.

Dehydroepiandrosterone sulfate (DHEAS) concentration levels were measured by a specific RIA in 23 female and 7 male patients with classical congenital adrenal hyperplasia (CAH) salt-losing type due to steroid 21-hydroxylase (21-OH) deficiency. The patients were divided into four groups by age and the DHEAS concentrations (mean +/- SD; micrograms/dl) for each age group were: 5 to 8 years (10.2 +/- 6.5; range 5-23 micrograms/dl); 8 to 10 years (18.3 +/- 14.9; range 5-44 micrograms/dl); 10 to 18 years (41.9 +/- 40; range 5-160 micrograms/dl); and above 18 years (49.7 +/- 65.9; range 9 to 242 micrograms/dl). These DHEAS levels were compared to age-matched normal values and it was found that DHEAS concentrations in 29 of the 30 patients were less than or in the lower part of the normal range for all age groupings. The DHEAS levels did not correlate with 17 alpha-hydroxyprogesterone (17-OHP), androstenedione, and testosterone values. The data indicate that blunted adrenarche occurs in classical CAH patients with 21-OH deficiency.

We examined excised gonadal tissue obtained from two 45,X patients for evidence of Y chromosomal material. Both patients had features atypical for individuals with Turner syndrome, a large dysgerminoma in patient 1 and clitoromegaly in patient 2. Southern blot analysis of polymerase chain reaction (PCR)-amplified DNA was performed for five Y chromosome-specific probes (SRY, ZFY. DYZ3, KALY, and DYZ1). Fluorescence in situ hybridization (FISH) with a combination probe specific for the DYZ1/DYZ3 loci was utilized. For both patients, Southern blot analysis of PCR-amplified DNA with primers for the SRY gene was positive. No signals were detected with the other Y chromosome-specific probes for patient 1. For patient 2, positive signals were obtained for all-Y-specific probes. FISH was negative in the gonadal specimen from patient 1, while rare cells were positive in the sections from patient 2. Turner syndrome and mixed gonadal dysgenesis may represent different points on a continuum of disorders of sexual differentiation. Although the risk for gonadal tumors is considered to be low in patients with Turner syndrome, prospective evaluation is critical to ascertain: The frequency of somatic cell mosaicism for cell lines carrying Y chromosomal material, and how the presence of Y chromosomal material in patients with Turner syndrome affects the propensity for virilization and gonadal neoplasms.

Recent studies in our laboratories have shown that urine from healthy adults contains immunoreactive and intact insulin-like growth factor-binding protein-3 (IGFBP-3). The aim of this study was to assess urinary IGF-I, IGF-II, and IGFBP-3 in a cross-sectional study of healthy subjects, as well as characterize urinary IGFBPs (uIGFBps) in patients with GH deficiency (GHD) and renal disease, such as, Alport syndrome, immunoglobulin A nephropathy, focal segmental glomerulosclerosis, and systemic lupus erythematosus. Urinary concentrations of IGF-I and IGF-II in pooled spot morning urines of healthy subjects, measured by RIA, were low and relatively unaltered throughout age, when expressed as either nanograms per milliliter or nanograms per milligram creatinine. To determine the complement of IGFBPs in urine of healthy subjects, spot morning urine samples were subjected to Western ligand blot and immunoblot analysis. IGFBP-3 was detected at 40-50 kDa, possibly due to variable glycosylation of uIGFBP-3. In addition, a 32-kDa IGFBP-2 and smaller unclassified IGFBPs were detected. Unlike uIGFs, urinary concentrations of IGFBP-3 (uIGFBP-3; nanograms per milligram creatinine) were age-, but not sex-related. Levels of uIGFBP-3 ranged from 40-60 ng/mL in children between 4 and 10 yr of age. After 11 yr, immunoreactive uIGFBP-3 progressively declined, attaining a plateau after 26 yr of age to approximately 18 ng/mg creatinine. uIGFBP-3 did not correlate with uIGF levels. Regulation of IGFBP-3 in the urine of normal subjects and of renal disorders was examined by RIA, Western ligand blot (WLB), and protease assay. Intact uIGFBP-3 was consistently found in normal urine and little urinary protease was identified. In GHD patients, IGFBP-3 by WLB was low or undetectable, whereas RIA levels of uIGFBP-3 were normal or high, consistent with the presence of IGFBP-3 proteolytic activity. In Alport syndrome, both RIA measures and WLB analysis were high, as was the IGFBP-3 proteolytic activity. Patients with immunoglobulin A nephropathy, focal segmental glomerulosclerosis and systemic lupus erythematosus measured low-normal levels of IGFBP-3 by WLB and RIA, and displayed little protease activity. This study provides normative data concerning radioimmunoassayable levels of IGFBP-3 in urine. The presence of normal-elevated levels of uIGFBP-3 by RIA in GHD indicates that uIGFBP-3 levels are not under GH control and are unlikely to represent filtered serum IGFBP-3.(ABSTRACT TRUNCATED AT 400 WORDS)

Nine gonadotropin-deficient hypopituitary men were cycled through periods of treatment with testosterone (T), gonadotropin (Gn), and placebo (Pl) using a blind cross-over design. Self-reports of sexual behavior, recordings of nocturnal penile tumescence (NPT), and sex steroid levels were obtained during each treatment period. Subjects had significantly higher plasma T during the T and Gn treatments than during the control periods. Similarly, self-reported frequency of ejaculation and ratings of libido as well as duration measures of NPT were significantly higher on T and Gn. Two thirds of the sample had no sociosexual experience. Behavioral differences between the T and Gn periods were minimal. These data support the hypothesis that Gn and T are equally effective in stimulating specific aspects of male psychosexual behavior.

The output of urinary growth hormone (GH) and IGF-I were quantitated by RIA in 12-h urine collections obtained from infants who were preterm, small for gestational age (PT-SGA, n = 13); preterm, appropriate for gestational age (PT-AGA, n = 27); full term, small for gestational age (FT-SGA, n = 13); and full term, appropriate for gestational age (FT-AGA, n = 29); and from normal children (n = 33). The amounts of GH and IGF-I (mean +/- SEM) excreted by the PT-SGA and FT-SGA infants were not significantly lower than those excreted by the PT-AGA and FT-AGA groups, respectively [GH (micrograms/kg): PT-SGA 13.7 +/- 3.1 versus PT-AGA 14.0 +/- 2.2, FT-SGA 7.8 +/- 2.4 versus FT-AGA 6.6 +/- 1.8; IGF-I (nmol/kg): PT-SGA 0.52 +/- 0.09 versus PT-AGA 0.53 +/- 0.04, FT-SGA 0.31 +/- 0.05 versus FT-AGA 0.35 +/- 0.04]. All infant groups exhibited significantly greater outputs of urinary GH and IGF-I compared with the children (p less than 0.01). The plasma concentrations of GH in all infant groups were high, whereas the plasma IGF-I levels were low. Microalbumin and beta-2 microglobulin excretion did not correlate with urinary GH and IGF-I output. Despite the higher microalbumin output in FT babies, urinary GH and IGF-I excretion was lower in these groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Linear Growth Characteristics of Untreated Congenitally Growth Hormone Deficient (CGHD) Infants from Birth to One Year of Age

The goal of this study was to compare the adult height outcomes of 201 hypopituitary children treated at CHOB with standardized doses of either pGH (n=106, 0.3u/kg/week = 0.15 mg/kg/wk rGH approximately, three times weekly (TIW), IM or SC) or rGH (n=95, 0.3 mg/kg/wk TIW or daily SC). During the pGH era (1964-1985) GH treatment was given 9 -12 months each year in contrast to the rGH era when treatment was continuous. All patients exhibited a peak GH response to two provocative tests of

COMPARISON OF FINAL HEIGHTS OF GH TREATED VERSUS UNTREATED CHILDREN WITH IDIOPATHIC GROWTH FAILURE. † 494

In Reply. —The focus of our study was to assess the role of gonadal steroids in the growth of prepubertal children. Growth following replacement sex steroid therapy and adult heights were of secondary importance. Projected adult heights based on chronologic bone age at the start of sex steroid therapy are less meaningful than actual final heights because of inherent errors in estimating final heights from bone age films.

Purified human growth hormone (hGH) was iodinated with 131I ([131I]iodo-hGH) and purified on Sephadex G-100. The monomeric [131I]iodo-hGH (mol wt about 20,000 daltons) was injected as a bolus iv in healthy volunteers and plasma obtained at 10, 20, and 40 min. Then continuous infusion with [131I]-iodo-hGH was started and further plasma samples obtained after 120 min when a plateau of immunoreactive hGH (IR-hGH) had been attained. In one individual the bolus injection was followed further to 60 and 120 min. Fresh plasma was immediately chromatographed on Sephadex G-100 and the IR-hGH profiles evaluated. In all instances following iv injection, larger and occasionally smaller immunoreactive moieties than the injected [131I]iodo-hGH appeared. When [131I]iodo-hGH was incubated at 37 C with fresh human plasma from 4 different individuals from 10 to 120 min, the larger molecular weight forms, noted in the in vivo studies, were again demonstrable. Only the monomeric [131I]iodo-hGH was found when [131I]iodo-hGH was incubated at 37 C for 120 min with human serum albumin or gamma globulin.

Gonadal function was assessed by determination of the serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in 24 children and adolescents 6-98 months after completion of treatment for Hodgkin disease that included pelvic irradiation and/or combination chemotherapy. Four of the five women and six of the nine men who received pelvic irradiation had elevations of serum FSH. Nine of these patients with an elevated FSH received combination chemotherapy in addition to pelvic irradiation. Five of seven males who received combination chemotherapy but no pelvic irradiation and were postpubertal at the time of evaluation had an elevated FSH level. Three of these five were prepubertal at the time of treatment. These results suggest that gonadal dysfunction occurred frequently among children and adolescents following treatment that included combination chemotherapy for Hodgkin disease.

Urinary GH and somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) excretion were measured in 12-h urine collections obtained from 43 infants (27 stable preterm infants and 16 healthy fullterm infants) and 31 normal children, aged 3-17 yr. Urinary Sm-C/IGF-I was excreted as the free hormone, since no binding of radiolabeled Sm-C/IGF-I to any urine protein with a mol wt similar to those described for plasma Sm-C/IGF-I-binding proteins was found. The preterm infants excreted significantly more urinary GH [13.5 +/- 2.1 (+/- SE) ng/kg.12 h] than either the fullterm infants (5.3 +/- 1.6 ng/kg.12h) or the children (0.27 +/- 0.02 ng/kg.12 h; P less than 0.01). The mean urinary Sm-C/IGF-I excretion in the preterm infants (98.9 +/- 7.5 mU/kg.12 h) was comparable to that in fullterm infants (87.6 +/- 9.7 mU/kg.12 h); both groups excreted significantly more urinary Sm-C/IGF-I than children (28.4 +/- 2.1 mU/kg.12 h; P less than 0.01). The group differences were similar when the results were expressed in terms of creatinine excretion. Urinary GH excretion correlated positively with urinary Sm-C/IGF-I excretion (r = 0.68). The higher output of these peptides in rapidly growing infants and their positive correlation in urine provide additional support for the Sm hypothesis.

A 19-year-old woman with the Ullrich-Turner syndrome presented with a mass filling her entire pelvis. The tumor was a dysgerminoma. Only one other patient with a 45,X chromosome constitution has been reported with this form of malignancy.

The diagnosis of congenital adrenal hyperplasia due to a deficiency of the enzyme 17 alpha-hydroxylase was made in a genetic male and female sibling pair born of parents who were first cousins. The genetic male was a phenotypic female who presented with primary amenorrhea and mild hypertension. The genetic female exhibited absence of secondary sexual characteristics and severe hypertension. The plasma steroid data confirmed the diagnosis of 17 alpha-hydroxylase deficiency in both subjects: low 17 alpha-hydroxyprogesterone, elevated desoxycorticosterone, elevated corticosterone and elevated progesterone. These are the first case reports of 17 alpha-hydroxylase deficiency in a male-female sibling pair, and they add support to the hypothesis that this is an autosomal recessive disorder.

Skin fibroblasts derived from either a normal child or from untreated hypopituitary children become progressively more rounded and finally detach and float free when cultured in medium containing serum from growth hormone (GH)-deficient patients. In contrast, human fibroblasts cultured in medium supplemented with serum obtained from hypopituitary children during successful treatment withgrowth hormone exhibit normal monolayer confluency. These observations are compatible with the explanation that serum from GH-deficient children lacks a GH-dependent component which is essential for the normal in vitro growth of human skin fibroblasts.

Plasma beta-hydroxybutyrate (beta-OHB) concentrations and simultaneous urine tests for ketonuria (nitroprusside reaction) were evaluated every 4 h throughout a 24-h study in 10 healthy insulin-dependent diabetics who had poor control based on home urine tests and elevated hemoglobin A1C. Concurrent measurements of the major carbohydrate regulatory hormones were made in the diabetic group and in a control population of 20 age-matched subjects. In the diabetics, 73% of the beta-OHB measurements were elevated. Only 43% of the abnormal beta-OHB values were associated with ketonuria. The diabetic subjects also showed exaggerated diurnal patterns for plasma beta-OHB and cortisol. There were no significant differences for the other regulatory hormones in the diabetic and normal groups. We conclude that 1) abnormal plasma beta-OHB levels without ketonuria are prevalent in poorly controlled diabetics; 2) negative nitroprusside tests for ketonuria underestimate the presence of ketonemia due to increased beta-OHB concentrations; 3) both insulin deficiency and glucocorticoid excess may influence ketone body metabolism in insulin-dependent diabetic patients.

Growth hormone (GH) responses to growth hormone-releasing factor (GRF) were evaluated in 55 children with growth failure. The study groups consisted of group 1, severe GH deficiency; group 2, partial GH deficiency; group 3, patients with prior cranial radiation for nonpituitary brain tumors; and group 4, children with idiopathic growth failure. Children in group 1 were unresponsive to GRF (mean GH peak +/- SEM, 1.6 +/- 0.5 ng/ml). Higher GH responses to GRF were observed in both groups 2 (17.2 +/- 4.1 ng/ml) and 3 (10.4 +/- 2.8 ng/ml). The highest GH responses to GRF were observed in group 4 (35.9 +/- 4.3 ng/ml). ANOVA revealed a significant difference between groups (F = 12.9; df = 3; p less than 0.01), and further analysis by the Scheffe and Student-Newman-Keuls tests revealed that group 4 was significantly higher than groups 1, 2, or 3 (p less than 0.05). These data suggest that GRF unresponsiveness is a reliable predictor of severe GH deficiency. In patients with partial GH deficiency or idiopathic growth failure, the GRF gives semiquantitative information about somatotrope responsivity to exogenous stimulation.

Fourteen children with brain tumors received endocrine evaluations at least one year following completion of cranial irradiation. Treatment consisted of operation (13 patients), craniospinal irradiation (6), whole brain irradiation (5), posterior fossa irradiation (3), and chemotherapy (10). Endocrine evaluation included bone age roentgenography and measurement of growth hormone (using sequential arginine and insulin stimulation), thyroxine, thyroid-stimulating hormone, plasma cortisol, testosterone, prolactin, and urinary follicle-stimulating hormone and luteinizing hormone. Ten of 12 children (83%) had abnormal responses to both tests of growth hormone stimulation. All growth hormone-deficient patients treated prior to puberty and tested at least 2 years following completion of cranial irradiation had decelerated linear growth. Results of thyroid function tests were abnormal in 4 patients: 2 patients had evidence of primary hypothyroidism, and 2 showed secondary or tertiary hypothyroidism. Two patients had inadequate cortisol responses to insulin hypoglycemia. Urinary follicle-stimulating hormone and luteinizing hormone, serum prolactin, and serum testosterone levels were appropriate for age in all patients.