Edward O. Reiter

Consensus statement on the diagnosis and treatment of children with idiopathic short stature: A summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop

OBJECTIVE Our objective was to summarize important advances in the management of children with idiopathic short stature (ISS). PARTICIPANTS Participants were 32 invited leaders in the field. EVIDENCE Evidence was obtained by extensive literature review and from clinical experience. CONSENSUS Participants reviewed discussion summaries, voted, and reached a majority decision on each document section. CONCLUSIONS ISS is defined auxologically by a height below -2 sd score (SDS) without findings of disease as evident by a complete evaluation by a pediatric endocrinologist including stimulated GH levels. Magnetic resonance imaging is not necessary in patients with ISS. ISS may be a risk factor for psychosocial problems, but true psychopathology is rare. In the United States and seven other countries, the regulatory authorities approved GH treatment (at doses up to 53 microg/kg.d) for children shorter than -2.25 SDS, whereas in other countries, lower cutoffs are proposed. Aromatase inhibition increases predicted adult height in males with ISS, but adult-height data are not available. Psychological counseling is worthwhile to consider instead of or as an adjunct to hormone treatment. The predicted height may be inaccurate and is not an absolute criterion for GH treatment decisions. The shorter the child, the more consideration should be given to GH. Successful first-year response to GH treatment includes an increase in height SDS of more than 0.3-0.5. The mean increase in adult height in children with ISS attributable to GH therapy (average duration of 4-7 yr) is 3.5-7.5 cm. Responses are highly variable. IGF-I levels may be helpful in assessing compliance and GH sensitivity; levels that are consistently elevated (>2.5 SDS) should prompt consideration of GH dose reduction. GH therapy for children with ISS has a similar safety profile to other GH indications.

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 childrens health and screening for endocrine-disrupting agents, which has led to changes in the US Environmental Protection Agencys 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.

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.

Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial.

OBJECTIVE We undertook a 1-year multicenter trial of tamoxifen treatment for precocious puberty in girls with McCune-Albright syndrome (MAS). STUDY DESIGN Girls < or =10 years with classic or atypical MAS were recruited. Pretreatment history was collected for 6 months. Patients received 20 mg tamoxifen daily. Diaries were used to record bleeding. Evaluations included physical examination, bone age, pelvic ultrasound, hormone levels, and safety assessments. RESULTS A total of 28 girls (2.9-10.9 years of age) were enrolled from 20 centers, of whom 25 completed 12 months of tamoxifen treatment. Compared with before the study, vaginal bleeding episodes decreased (3.42+/-3.36/year vs 1.17+/-1.41/year), growth velocity slowed (SDS 1.22+/-2.65 vs -0.59+/-3.06, P=.005), and rate of bone maturation decreased (1.21+/-0.78 vs 0.72+/-0.36, P=.02). Ovarian volumes were enlarged and asymmetric throughout the study, and uterine volumes were increased. No adverse events occurred. CONCLUSIONS Tamoxifen treatment of precocious puberty in MAS results in a reduction of vaginal bleeding and significant improvements in growth velocity and rate of skeletal maturation.

Responsivity of Pituitary Gonadotropes to Luteinizing Hormone-releasing Factor in Idiopathic Precocious Puberty, Precocious Thelarche, Precocious Adrenarche, and in Patients Treated with Medroxyprogesterone Acetate

Extract: One hundred micrograms synthetic luteinizing hormone-releasing factor (LRF) were administered to 13 girls and 2 boys with idiopathic precocious puberty, 3 girls with precocious thelarche, 2 girls with precocious adrenarche, and 5 children treated with medroxyprogesterone acetate (MPA). Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroid responses were assessed.The mean readily releasable LH rose to a peak of 8.4 ± 1.8 ng/ml (LER 960) in the children with idiopathic precocious puberty and was significantly greater than in normal prepubertal (1.8 ± 0.14) or pubertal children (4.9 ± 0.34). The peak plasma FSH response (8.4 ± 1.4 ng/ml) (LER 869) was higher in precocious puberty but not significantly greater than in normal prepubertal (5.3 ± 1.9) or pubertal girls (6.0 ± 1.2). The mean concentration of plasma estradiol rose significantly above resting levels after LRF in the girls with idiopathic precocious puberty. The LH response in girls with precocious thelarche and adrenarche was in the prepubertal range. In 4 of 5 children with sexual precocity treated with MPA, the LH release evoked by LRF was diminished.Speculation: Premature neural activation of hypothalamic LRF synthesis and release may occur in children with idiopathic precocious puberty. This leads to increased pituitary gonadotropin synthesis, storage, and more readily releasable LH. The higher FSH release after LRF in normal girls than boys may be a factor in the strikingly higher prevalence of idiopathic precocious puberty in girls than in boys.

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 (R2 = 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.

The absence of positive feedback between estrogen and luteinizing hormone in sexually immature girls.

Extract: The development of estrogen-mediated luteinizing hormone (LH) release (positive feedback) was studied in prepubertal, pubertal, and adult females. The optimum means of eliciting positive feedback was established by administering graded doses of 17β-estradiol (E2) for 5 days to 11 women during the early follicular phase of 14 menstrual cycles. Three groups of adult subjects were formed based on the peak levels of E2 in plasma attained: 100–200 pg/ml, 200–300 pg/ml, and >300 pg/ml. In all groups, LH values in plasma fell to a nadir at a mean time of 2 days after the initiation of injections and then rose sharply while plasma E2 levels in plasma still remained elevated. The magnitude of the LH elevations appeared to relate to the levels of E2 in plasma.In contrast to the results in adult women, three prepubertal girls and an 11-year-old girl with gonadal dysgenesis did not evidence positive feedback when given similar estrogen courses. Levels of E2 in plasma in the prepubertal subjects ranged between 100 and 300 pg/ml and both LH and follicle-stimulating hormone (FSH) remained suppressed. One early pubertal girl displayed a small increment in LH in the presence of elevated exogenous estrogen levels. One midpubertal, premenarchal girl with adult levels of gonadotropins and precocious puberty due to an hypothalamic cyst revealed a large LH rise during E2 administration both before and after drainage of the cyst. Finally, a 14-year-old girl with gonadal dysgenesis and adult castrate levels of gonadotropins also displayed positive feedback.Speculation: Puberty in women is a multistage process which involves alterations in the hypothalamic-pituitary-gonadal axis. A change in sensitivity of the negative feedback system is associated with rising gonadotropin levels early in the course of sexual maturation. Ovulatory potential is dependent on the development of positive feedback, an event which occurs later in the course of pubescence.

Randomized controlled trial evaluating response to metformin versus standard therapy in the treatment of adolescents with polycystic ovary syndrome.

OBJECTIVE We evaluated the hypothesis that metformin would improve signs and symptoms of polycystic ovary syndrome (PCOS) in adolescents as compared to oral contraceptive pills (OCP) and have a favorable effect on obesity. STUDY DESIGN Thirty-five obese, post-menarchal, non-sexually active adolescents aged 12-21 years with PCOS and hyperinsulinism were randomly assigned to receive either OCP or metformin for 6 months. RESULTS There was a significant decrease in BMI in the two groups over time, from 40.1 to 38.6 in the OCP group, and 37.3 to 36.3 in the metformin group, p = 0.0026, but no significant difference in the degree of change between the two groups. Both groups had decreased free testosterone (OCP: 1.8 pg/ml to 0.96 pg/ml; metformin: 2.1 pg/ml to 1.6 pg/ml), p < 0.0001, and improvements in insulin resistance as evidenced by increased glucose/insulin (G/I) ratio (p < 0.005) and increased QUICK1 scores (p < 0.0005). No significant differences in response to treatment were found between the metformin and OCP groups in outcome variables. CONCLUSION Adolescents with PCOS treated with metformin or OCP experienced similar beneficial outcomes including reduction in androgen levels, weight loss, and increased insulin sensitivity. The choice of a treatment agent for long-term use will depend on safety profiles, therapeutic goals and patient adherence.

Medroxyprogesterone acetate in the treatment of seizures associated with menstruation

An 8-year-old girl who had a generalized seizure disorder from the age of 5 had an early onset of normal puberty and developed exacerbation of seizures and behavioral abnormalities during menstrual periods. The neurologic examination demonstrated only mild mental subnormality; a pneumoencephalogram showed slight ventricular dilatation. Oral medroxyprogesterone acetate (MPA) decreased seizure activity slightly. Subsequently following three biweekly injections of depot-MPA, the patients menses ceased, and she became seizure-free for 4 months. There was associated improvement in behavior and school performance. Serum gonadotropin values remained normal, and no side effects were observed, except for increased appetite and weight gain.

Idiopathic short stature: Management and growth hormone treatment

In the management of ISS auxological, biochemical, psychosocial and ethical elements have to be considered. In boys with constitutional delay of growth and puberty androgens are effective in increasing height and sexual characteristics, but adult height is unchanged. GH therapy is efficacious in increasing height velocity and adult height, but the inter-individual variation is considerable. The effect on psychosocial status is uncertain. Factors affecting final height gain include GH dose, height deficit in comparison to midparental height, age and first year height velocity. In case of a low predicted adult height at the onset of puberty, addition of a GnRH analogue can be considered. Although GH therapy appears safe, long-term monitoring is recommended.