Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium.

This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.

Earlier onset of puberty in girls: relation to increased body mass index and race.

OBJECTIVE: A recent study conducted by the Pediatric Research in Office Settings network provided evidence that girls in the United States, especially black girls, are starting puberty at a younger age than earlier studies had found, but the reasons for this are not known. Because nutritional status is known to affect timing of puberty and there is a clear trend for increasing obesity in US children during the past 25 years, it was hypothesized that the earlier onset of puberty could be attributable to the increasing prevalence of obesity in young girls. Therefore, the objective of this study was to reexamine the Pediatric Research in Office Settings puberty data by comparing the age-normalized body mass index (BMI-ZS; a crude estimate of fatness) of girls who had breast or pubic hair development versus those who were still prepubertal, looking at the effects of age and race. RESULTS: For white girls, the BMI-ZS were markedly higher in pubertal versus prepubertal 6- to 9-year-olds; for black girls, a smaller difference was seen, which was significant only for 9-year-olds. Higher BMI-ZS also were found in girls who had pubic hair but no breast development versus girls who had neither pubic hair nor breast development. A multivariate analysis confirms that obesity (as measured by BMI) is significantly associated with early puberty in white girls and is associated with early puberty in black girls as well, but to a lesser extent. CONCLUSIONS: The results are consistent with obesity's being an important contributing factor to the earlier onset of puberty in girls. Factors other than obesity, however, perhaps genetic and/or environmental ones, are needed to explain the higher prevalence of early puberty in black versus white girls.

Third-year medical student survey of office preceptorships during the pediatric clerkship.

OBJECTIVE: To assess medical students' interest in a career in pediatrics following their categorical pediatric clerkship. DESIGN: Satisfaction questionnaire to 704 third-year clerks in 5 university medical schools following the pediatric clerkship. METHODS: Analysis of the influence of the community office-based experience compared with the inpatient experience, and examination aspects of the office preceptorship most valued by the medical students. MAIN OUTCOME MEASURE: Satisfaction questionnaire addressing office-based experiences. RESULTS: Third-year pediatric clerks report that the private office setting provides a valuable learning experience, particularly when there is exposure to a wide spectrum of disease and when the preceptor had time to teach. Feelings about pediatrics as career choice rose during the clerkship from neutral to positive, and the frequency of strongly positive feelings rose from 9.2% to 28.6%. In deciding about pediatrics as a career, experiences with patients and residents in the inpatient setting still seem to count more than those experiences in the outpatient setting. CONCLUSION: Categorical pediatric clerkships provide learning environments that influence students positively toward pediatrics as a career choice. This choice is enhanced by encouraging community practitioners with students in their office to expose them to a wide variety of issues and devote time to teaching.

Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society.

In 1997 a study from the Pediatric Research in Office Settings network, based on pubertal staging of >17,000 girls between 3 and 12 years of age, indicated that breast and pubic hair development are occurring significantly earlier than suggested by our current guidelines, especially in African-American girls. In response to this article, the Lawson Wilkins Pediatric Endocrine Society undertook a comprehensive review of this topic. The primary conclusions of this review are: 1. The current recommendation that breast development before age 8 is precocious is based on outdated studies. Until 1997, no data were available on pubertal staging in US girls that could have documented a trend to earlier maturation. 2. The 1997 study indicates that stage 2 of breast and pubic hair development is being achieved ~1 year earlier in white girls and 2 years earlier in African-American girls than previous studies have shown. 3. Concerns that girls with moderately precocious puberty will be significantly short adults are overstated; most have adult height within the normal range. 4. Therapy with gonadotropin-releasing hormone agonists has not been proven to have a substantial effect on adult height in most girls whose puberty starts between 6 and 8 years of age. 5. New guidelines propose that girls with either breast development or pubic hair should be evaluated if this occurs before age 7 in white girls and before age 6 in African-American girls. No changes in the current guidelines for evaluating boys (signs of puberty at younger than 9 years) can be made at this time.normal puberty, breast development, pubic hair.

Delayed puberty in obese boys: comparison with constitutional delayed puberty and response to testosterone therapy.

OBJECTIVE: To evaluate the results of a brief course of testosterone therapy in boys with delayed puberty and to compare the responses seen in boys with constitutional delayed puberty (CDP), boys with obesity, and boys with possible gonadotropin deficiency. DESIGN AND SETTING: A retrospective chart review was done for 36 boys aged 14 years or older, seen between 1983 and 1996 because of delayed puberty, who were given 4 monthly injections of testosterone, 100 mg/mo, and had adequate follow-up. RESULTS: There were 23 boys whose findings before and after treatment were consistent with a diagnosis of CDP. Testosterone treatment increased the growth rate from 4.3 cm/y to 11.2 cm/y (P <.00001), and mean testis length increased 0.6 to 0.8 cm in all (from a mean of 2.9 to 3.6 cm, P <.00001) in the 4 months after testosterone treatment. Serum testosterone 4 months after therapy was higher than that before therapy (P =.00003). Of 5 boys with growth hormone deficiency but unknown gonadotropin status, 2 had lack of progression after testosterone therapy and were believed to have permanent gonadotropin deficiency. Seven of the 36 boys were obese (body mass index, >25), and 6 had a response to testosterone similar to boys with CDP with clear pubertal progression. One obese boy and one nonobese boy were diagnosed as having isolated gonadotropin deficiency. CONCLUSIONS: Monitoring the growth and genital responses to a 4-month course of testosterone injections helps to differentiate CDP from gonadotropin deficiency in boys with delayed puberty. Obese boys constitute a distinct category of boys with pubertal delay in terms of their growth, but their response to testosterone is similar to that observed in boys with classic CDP.

Weight relative to height before and during growth hormone therapy in prepubertal children.

We used the Genentech National Cooperative Growth Study database to examine differences in weight relative to height (weight for height standard deviation score or WTHTZ) in 3460 patients at enrollment and after one year of therapy with recombinant human growth hormone (rhGH), and in a subset of 450 patients treated for three years with rhGH. The major diagnostic categories were idiopathic growth hormone deficiency (IGHD), organic GH deficiency (OGHD), and idiopathic short stature (ISS). Children with IGHD and ISS were underweight for height at baseline but had a progressive increase in WTHTZ during three years of rhGH therapy. The same pattern applied to children with IGHD associated with septo-optic dysplasia and CNS trauma or infection. However, children with OGHD associated with craniopharyngiomas, other CNS tumors, leukemia, or CNS irradiation were overweight when starting rhGH and showed a decrease in WTHTZ during the first year of rhGH therapy. The increase in WTHTZ during rhGH treatment in children with ISS and OGHD suggests that the GH-induced increase in muscle mass exceeded loss of fat mass. Because children with neoplasm-related OGHD were overweight at baseline, the decline in WTHTZ during the first year of rhGH therapy suggests that loss of fat mass is the predominant effect in this subgroup.

Homozygous nonsense mutation in the insulin receptor gene of a patient with severe congenital insulin resistance: leprechaunism and the role of the insulin-like growth factor receptor.

Severe congenital insulin resistance in the syndrome of leprechaunism is caused by mutations in the insulin receptor gene. We report a patient with leprechaunism who was homozygous for a mutation resulting in the absence of cell surface insulin receptors. To determine whether the receptor for Insulin-like growth factor-I (IGF-I) is involved in the phenotype of leprechaunism, we studied the effect of insulin and of IGF-I on cells from this patient. The patient had a homozygous C-->T substitution at base pair 8212 in exon 12 of the insulin receptor gene, creating a premature stop codon. This nonsense mutation is in the extracellular portion of the receptor and truncates the insulin receptor proximal to its transmembrane anchor, resulting in the absence of cell surface insulin receptors. This finding indicates that complete absence of the insulin receptor is compatible with life. Secondly, DNA synthesis was studied in skin derived fibroblasts in response to increasing concentrations of either insulin or Insulin-like growth factor-I (IGF-I), and was assessed by 3H-thymidine incorporation. In this patient's cells, both of these hormones increased 3H-thymidine incorporation, and the effect was blocked by alpha-IR3, a monoclonal antibody that blocks activation of the IGF-I receptor. These findings confirmed the absence of the insulin receptor and indicated that insulin acts here through activation of the IGF-I receptor. These data support the contention that the phenotypic and metabolic abnormalities of leprechaunism result from the combination of lack of insulin receptor action and over-activation by insulin of the type 1 IGF receptor.

The effect of the pediatric clerkship on medical student attitudes toward pediatrics at 11 medical schools.

OBJECTIVES: To investigate how the pediatric clerkship affected student attitudes toward pediatrics, and to determine if correlations existed between changes in attitudes toward pediatrics and in ratings of certain aspects of the clerkship with an increased interest in a pediatric career. METHODS: A one-page survey measuring interest in a career in pediatrics and agreement or disagreement with seven statements about pediatrics was administered at the beginning and end of the pediatric clerkship at 11 medical schools for the 1992-1993 academic year. RESULTS: The proportion of students with a strong interest in a pediatric career increased from 6.7% before the clerkship to 15.2% after the clerkship (for women, 11% to 22%; for men, 4% to 11%). Attitudes toward pediatrics were more favorable at the end vs the beginning of the clerkship. The change that correlated best with change in interest in a pediatrics career was agreement that children are enjoyable to work with. Of the eight aspects of the clerkship rated, the patients worked with on the ward received the most positive mean score. The item that correlated best with increased career interest was a positive feeling toward the ward residents. CONCLUSION: The recent trend for women to have a greater interest in careers in pediatrics than men is continuing. Finding ways to make students more comfortable when they interact with children and improving the teaching skills of residents could improve recruitment of medical students into pediatrics.

Effect of growth hormone therapy on final versus predicted height in short twelve- to sixteen-year-old boys without growth hormone deficiency.

The effect of growth hormone therapy on final height in 28 short boys without growth hormone deficiency was evaluated retrospectively. The boys had received growth hormone for at least 2 years and were close to final height when therapy was stopped. The mean estimated final height was very close to that predicted from the pretherapy bone age. The fact that bone age advanced a mean of 4.9 years during a mean of 3.5 years of therapy may account for the lack of effect on final height.

Diagnostic evaluation of short children with height 3 SD or more below the mean.

Most children who are more than 2 SD below the mean in height (less than third percentile) have no definable cause and are considered short-normal, but for children who are 3 SD below the mean (the lowest 0.13%), the prevalence of organic disease is known to be considerably greater. To better define the frequency of different diagnoses in this subgroup and to identify useful clinical findings, we reviewed the charts of all children referred for growth evaluation over a 10-year period who were > or = -3 SD in height, > 2 years old, and prepubertal. Of 60 patients (36 males and 24 females), 22% had constitutional growth delay (CGD), 23% had growth hormone deficiency (GHD), 13% had Turner syndrome, and 22% had various forms of primary growth failure (mostly associated with intrauterine growth retardation). Eight percent had very slow growth over a prolonged period but no definable cause, and 12% did not fall into any of the above groups. For differentiating GHD from CGD, a subnormal height velocity for age during a 4- to 12-month observation period, a low insulin-like growth factor-1/somatomedin C (IGF-1/Sm-C), and low total or free T4, with normal TSH, were all highly predictive of a diagnosis of GHD.

Altered blood pressure reactivity in adolescent diabetics.

OBJECTIVE: We examined hemodynamic responses to a variety of physiologic stimuli in 14 normotensive adolescents with type I diabetes and 45 healthy controls to determine whether structural vascular changes contribute to a reduced vasodilator capacity in adolescent diabetics. We asked, in adolescents with type I diabetes: (1) Are structural vascular changes present? (2) Are changes in the systemic vascular bed reflected in abnormal blood pressure regulation? and (3) Is abnormal vascular reactivity associated with either diabetes duration or control? METHODOLOGY: Diabetic subjects were outpatients treated at the Medical College of Virginia, ages 13 to 18 years. Diabetes duration averaged 7.5 years. Each subject underwent an echocardiogram, dynamic and isometric exercise testing, and forearm plethysmography. RESULTS: Compared to controls, diabetic subjects had (1) higher systolic and diastolic blood pressure during dynamic and handgrip exercise, (2) decreased forearm vasodilator capacity in response to ischemia, and (3) an increased aortic peak velocity. Group diastolic filling abnormalities were found, but these did not persist after adjustment for heart rate. The following variables were related to both diabetes duration and control (average glycosylated hemoglobin): (1) diastolic blood pressure during dynamic exercise, (2) resting forearm vascular resistance, and (3) forearm vascular reactivity. In addition, diabetes duration correlated with isometric exercise diastolic blood pressure, and diabetes control correlated with resting diastolic blood pressure. CONCLUSION: In young diabetics we found that (1) abnormalities of the resistance vessels of the forearm may be present, (2) the degree of vascular change is related to diabetes duration and control, and (3) aortic distensibility may be impaired.

Discordant metabolic actions of insulin in extreme lipodystrophy of childhood.

Congenital lipodystrophy includes a group of disorders characterized by total or partial absence of adipose tissue and insulin resistance. In this study we investigated the nature of insulin resistance in an 11-yr-old girl with one form of congenital lipodystrophy. We examined in vivo insulin and glycemic responses to feeding and iv glucose and in vitro amino acid and thymidine incorporation responses of skin fibroblasts to insulin exposure. In addition, we used stable isotope infusions of glucose, glycerol, and amino acids to investigate the in vivo metabolic actions of insulin on carbohydrate, fat, and protein. At 5 yr of age, she first demonstrated clinical glucose intolerance. Her basal insulin levels were normal (129 and 114 pmol/L), but increased markedly (peak values, 1304 and 5045 pmol/L) after iv glucose and a mixed meal. Insulin antibodies were undetectable, and specific [125I]insulin binding to her skin fibroblasts was normal. Both [3H]aminoisobutyric acid transport and [3H]thymidine incorporation by her fibroblasts were similar to responses obtained using control cells. At 11 5/12 yr of age, while receiving an infusion of stable isotopes, infusions of insulin at doses of 0.1 and 0.3 U/kg BW.h were ineffective in reducing her blood glucose despite elevating her serum insulin level to approximately 2500 pmol/L. Resting metabolic rate, respiratory quotient, VCO2, carbohydrate and lipid oxidation rates, glucose production rate, glycerol appearance rate, and plasma glycerol concentrations were unperturbed by the insulin infusions. By contrast, the insulin infusions reduced plasma leucine concentrations (124.2 to 86.1 to 66.7 mumol/L) and 13CO2 production rates (0.034 to 0.017 to 0.011 mumol/kg/min; baseline, 0.1, and 0.3 U insulin/kg.h, respectively). The leucine appearance rate declined (1.96 to 1.72 mumol/kg.min) in response to the 0.1 U/kg.h dose, but did not decline further in response to the 0.3 U/kg.h dose. The leucine oxidation rate also declined (0.87 to 0.39 to 0.25 mumol/kg.min), and there was a dose-related reduction in most plasma amino acid concentrations. Finally, nonoxidative leucine disposal increased progressively (1.09, 1.34, and 1.48 mumol/kg.min), suggestive of an insulin-induced increase in protein synthesis. These data indicate profound metabolic resistance to the carbohydrate and lipid actions of insulin, with preservation of protein anabolism. These observations suggest that in this patient, the biological effects of insulin on carbohydrate, lipid, and protein are distinct metabolic actions, regulated independently.

Fingernail angle in girls with Ullrich-Turner syndrome.

Increased angle of insertion of the fingernails is known to be a common finding in girls with Ullrich-Turner syndrome (UTS), but there are few data on the frequency of this finding and no quantitative data that define what is a normal fingernail angle. To assess the usefulness of this measurement in evaluating patients with suspected UTS, we obtained tracings of 6 different fingernails to determine the mean fingernail angle (MFA) in 40 patients with UTS and compared the results with control girls and adults. As a group, the 24 girls with 45,X had an average MFA of 8.9 degrees, compared to 6.8 degrees for the 16 mosaics and variants, 3.0 degrees for normal children and 1.3 degrees for normal adults. Although there was overlap between the groups, 79% of 45,X girls and 56% of variants had an MFA of > 6 degrees, whereas only 8% of the combined control individuals had an MFA of > 6 degrees. Reproducibility of MFA determinations based on tracings obtained at consecutive visits was excellent (r = 0.92). There was no clear correlation between the MFA and the severity of the UTS phenotype. Determination of MFA is a simple, objective measurement which, when combined with other clinical findings, may aid the clinician in making a diagnosis of UTS.

Congenital hypopituitarism and microphthalmia. Report of two cases.

Two children are described who had microphthalmia (one with unilateral and one with bilateral) noted at birth, and whose early onset of poor linear growth and weight gain led to a diagnosis of hypopituitarism prior to two years of age. Both children had growth hormone and thyroid-stimulating hormone deficiencies, and evidence of partial ACTH deficiency. Administration of growth hormone resulted not only in rapid linear growth but it also reversed the poor weight gain and head growth noted in these children. These cases suggest that hypopituitarism and microphthalmia may be associated with each other more frequently than has been recognized previously.

Monozygotic twins discordant for Ullrich-Turner syndrome.

We describe 9-year-old twin girls who were thought to be monozygotic but who differed greatly in physical appearance and growth pattern. One twin had Ullrich-Turner syndrome (UTS), 45,X/46,XX mosaicism in peripheral blood, and only 45,X cells in skin fibroblasts. The phenotypically normal twin also had 45,X/46,XX mosaicism in blood but only 46,XX cells in cultured fibroblasts. Analysis of DNA marker patterns in blood lymphocytes and in skin fibroblasts confirmed monozygosity with a probability of 99.97%. This case is compared with other reported cases of discordance for UTS in twins. It is concluded that essentially all of the differences between the two twins can be explained by loss of an X chromosome early in embryogenesis with complete separation of 45,X and 46,XX cell lineages at the time of the twinning event. The presence of mosaicism in the peripheral blood of both twins is presumably due to anastomoses between the placentae resulting in a mixture of the two cell populations in the hematopoietic tissue.

Steroid cell tumor of the ovary in a child.

An 8-year-old girl exhibited severe, progressive virilization of 2 years' duration associated with markedly elevated circulating testosterone concentrations. Based on her initial clinical presentation and results of a chemical evaluation, she was originally thought to have non-classic 21-hydroxylase deficiency, but her condition did not respond to corticosteroid therapy. Further evaluation confirmed the presence of an ovarian neoplasm. The excised ovary contained an attached gray-brown mass. Light microscopic and ultrastructural examination revealed the mass to be a steroid cell tumor. Because Reinke's crystals were not present, it was designated to be a steroid cell tumor not otherwise specified. This case represents one of 22 reported cases of steroid cell tumor occurring in children described in the literature, most of which have been associated with heterosexual precocity. To our knowledge, steroid cell tumors are benign when they occur in prepubertal children. Although they are rare, steroid cell tumors of the ovary should be considered in cases of childhood virilization.

Diagnostic value of testosterone therapy in boys with delayed puberty.

A brief course of testosterone injections is known to be an effective treatment for boys with constitutional delayed puberty. In this study, data from seven boys at least 14 years old who received testosterone enanthate (100 mg intramuscularly monthly for four months) were analyzed to see if linear and testicular growth responses could be useful diagnostically in excluding growth hormone deficiency (GHD) and isolated gonadotropin deficiency, two conditions that are often difficult to distinguish from constitutional delayed puberty. During four months of testosterone therapy, growth rate increased from 4.0 +/- 1.0 cm/y to 10.7 +/- 2.3 cm/y, and was greater than 8 cm/y in all patients. Since testosterone-induced stimulation of linear growth is largely GH-mediated, the large increase in growth rate in all boys is considered indicative of GH sufficiency. Testis length, which did not increase during testosterone therapy, increased by 0.6 to 0.8 cm in every patient (from 2.7 +/- 0.3 cm to 3.4 +/- 0.4 cm) over the following four months, indicating normal gonadotropin secretion and normal pubertal progression; in contrast, the increase in serum testosterone concentrations after discontinuation of testosterone treatment was more variable. It is concluded that the growth response to a four-month course of testosterone is helpful in excluding GHD in boys with delayed puberty, and an additional four months of follow-up is sufficient to document the onset of puberty, thereby eliminating the possibility of isolated gonadotropin deficiency.

Antimitogenic actions of lectins in cultured human fibroblasts.

It was previously reported that the lectins wheat germ agglutinin (WGA) and concanavalin A (Con A) inhibit the mitogenic actions of multiple peptide growth factors in human fibroblasts without having a significant effect on mitogen binding. The current studies were designed to further examine the mechanisms of this antimitogenic action of lectins. Addition of WGA at progressively later times after stimulation of fibroblasts with peptide mitogens revealed significant inhibition of DNA synthesis even when the lectin was added 16-20 h after growth factors. This suggests an inhibitory effect on a pathway occurring late in G1, or close to the G1/S boundary. WGA also inhibited stimulation of DNA synthesis by non-peptide agents such as colchicine and vanadate ion, indicating that the lectin inhibits a common distal step in the mitogenic response, rather than acting primarily on events occurring at the level of the growth factor-receptor interaction. WGA had a rapid (within 30 min) inhibitory effect on insulin-stimulated amino acid uptake, but Con A, which like WGA blocked mitogen-stimulated 3H-dT incorporation, had little effect on stimulation of amino acid uptake. Thus the inhibition of DNA synthesis and amino acid uptake by lectins appear to be mediated by distinct mechanisms. WGA binding to fibroblasts persisted even when the lectin was removed from the incubation medium, but unlike 125I-EGF, which was rapidly internalized at 24 degrees C, little 125I-WGA was internalized. Incubation of fibroblasts for 20 h with WGA or Con A was not toxic to cells, since reversal of lectin binding by the appropriate saccharide allowed normal subsequent stimulation of DNA synthesis by EGF and insulin. However, the observation that cells exposed to antimitogenic lectins undergo a marked decrease in cell spreading suggests that changes in cell shape may be relevant to the mechanism by which lectin-treated fibroblasts become unresponsive to mitogenic stimulation.