Karen Oerter Klein

An open label 12-month pilot trial on the effects of the aromatase inhibitor anastrozole in growth hormone (GH)-treated GH deficient adolescent boys.

OBJECTIVE To investigate whether 12 mo treatment with the aromatase inhibitor anastrozole can achieve sustained suppression of estrogen production and delay epiphyseal fusion in growth hormone deficient (GHD) adolescent males. STUDY DESIGN 20 adolescents with GHD were recruited (mean age +/- SE: 14.7 +/- 0.5 yr). Ten continued on GH (control group), and 10 on GH and anastrozole (Rx group) for 12 mo. RESULTS After 12 mo E2 concentrations declined 60% in the Rx group (from 1.8 +/- 0.5 to 0.7 +/- 0.3 pg/ml, p <0.05) whereas they increased in controls (from 1.2 +/- 0.7 to 1.8 +/- 0.7, p <0.05). Testosterone increased 117% in the Rx group (from 304 +/- 31 to 626 +/- 64 ng/dl), 47% in controls (from 274 +/- 89 to 398 +/- 51) (p = 0.03, ANOVA between groups). IGF-I increased 42% in controls (454 +/- 22 to 711 +/- 109 ng/ml, p <0.05), but remained invariant in the Rx group (446 +/- 29 to 540 +/- 80, p = NS). Bone markers, plasma lipids, insulin, glucose, and liver function tests were all unchanged between groups with no differences either in body composition or bone mineral density accrual. There were no differences in growth velocity, height SDS, bone age advancement, predicted adult height or testicular volumes between groups after 12 mo. CONCLUSIONS Anastrozole treatment potently decreases estrogen concentrations in adolescent males with GHD while allowing normal virilization, without deleterious effects on body composition, plasma lipids, bone metabolism or the tempo of puberty. Twelve months of treatment, however, did not increase predicted adult height. Further studies are needed to ascertain whether more prolonged estrogen blockade is helpful in the treatment of growth retardation in puberty.

Estradiol levels and secretory dynamics in normal girls and boys as determined by an ultrasensitive bioassay: a 10 year experience.

We utilized an ultrasensitive recombinant cell bioassay to measure serum estradiol in 800 normal children from birth through puberty. 105 children had repeat samples every 4 months as they approached puberty. We measured estradiol levels every hour for 24 hours in 55 children. Estradiol increased with age and pubertal stage in girls and boys, and was higher in girls than boys at each stage. Prepubertal girls have estradiol levels of 1.6 +/- 2.6 pg/ml. Prepubertal boys have estradiol levels of 0.4 + 1.1 pg/ml. Estradiol had a diurnal variation in girls and boys, with the trough occurring 08.00-20.00 h in girls, and 12.00-20.00 h in boys. We confirm that estradiol levels are higher in girls than boys even before physical signs of puberty, and that estradiol increases throughout puberty in girls and boys. This 10-year experience in 800 children shows the range and variability of estradiol by an ultrasensitive bioassay.

Estradiol levels in girls with Turner's syndrome compared to normal prepubertal girls as determined by an ultrasensitive assay.

Based on growing evidence that estradiol is produced in small amounts even in the prepubertal ovary, we hypothesized that estradiol levels in girls with Turners syndrome (TS) are lower than in normal prepubertal girls secondary to the lack of normally functioning ovaries. Estradiol levels in untreated girls with TS have not been previously well defined because of the lack of adequate sensitivity of previously available estradiol assays. We utilized an ultrasensitive assay to study estradiol levels in 34 girls with TS and 34 normal age-matched prepubertal girls between the ages of 5 and 12 years. The average estradiol level in the girls with TS (6.4 +/- 4.9 pmol/l estradiol equivalents) was significantly lower than in the normal prepubertal girls (12.7 +/- 10.8 pmol/l estradiol equivalents; p < 0.01). Girls with TS were significantly shorter, and weighed less than the normal prepubertal girls, as expected. The estradiol level was not significantly correlated with height, bone age, or degree of bone age delay. In conclusion, girls with TS have significantly lower estradiol levels than normal age-matched prepubertal girls. This report is consistent with the hypothesis that the lack of normal ovarian function in girls with TS is evident even before puberty.

Luteinizing hormone (LH) and estradiol suppression and growth in girls with central precocious puberty: is more suppression better? Are pre-injection LH levels useful in monitoring treatment?

CONTEXT Girls with central precocious puberty (CPP) are treated with gonadotropin releasing hormone (GnRH) analogues to suppress puberty. Gonadotropin levels are used to monitor treatment, since estradiol is difficult to measure at low levels. The optimal degree of hormonal suppression is still unknown. OBJECTIVE We hypothesized that in girls treated for CPP, estradiol levels (by ultrasensitive bioassay) would correlate with the rate of skeletal maturation and linear growth velocity. We asked whether predicted height would improve with greater luteinizing hormone (LH) and estradiol suppression. We also compared pre- and post-injection LH levels for monitoring treatment. DESIGN Thirty girls with CPP were followed for up to 2 years during treatment with leuprolide acetate depot at a dose of 0.3 mg/kg/28 days. We measured LH and estradiol levels, bone age, and growth velocity every 6 months. RESULTS Estradiol levels were suppressed to below the detection limit in three-quarters of the girls and did not correlate with the rate of skeletal maturation or linear growth. Improvement in predicted height correlated significantly with lower pre-injection LH levels. These girls have some of the lowest estradiol and LH levels, best improvement in predicted height, and least amount of bone age advancement published to date. Pre- and post-leuprolide injection LH levels were positively correlated. CONCLUSIONS Greater LH suppression may improve height outcome in girls treated for CPP with GnRH analogues. The degree of LH suppression achieved is individualized and not necessarily related to absolute dose. Pre-injection LH levels may be useful for monitoring treatment. Ultrasensitive estradiol levels were very low and usually unmeasurable, affirming the increased suppression at the higher doses of GnRH analogue used in these girls. Further investigation is needed, with longer treatment duration, a range of doses, and ultimately final height. Until such studies are completed, clinicians should be cautious when interpreting pubertal suppression.

Bone maturation along the spectrum from normal weight to obesity: a complex interplay of sex, growth factors and weight gain.

Abstract Background: The aim of the study was to define the prevalence and degree of advanced bone age (ABA) in normal vs. excessive weight children, and identify variables affecting ABA. Methods: We studied 167 children (3–18 years) with normal weight (28 F, 28 M), overweight (8 F, 12 M), and obesity (OB) (63 F, 28 M) at AI duPont Hospital for Children. We assessed bone age (BA), insulin, leptin, estradiol (E2), DHEAS, and IGF-1 levels. Results: Almost 25% of OB children have ABA>2 SDS, 33% >2 years (range 2–6.5 years advanced). ABA correlated with leptin, DHEAS and BMI z-score in girls, and with IGF-1 z-score and BMI z-score in boys (p<0.01). Girls with ABA had higher BMI z-score (p<0.001), insulin levels (p=0.02), and rates of weight gain (p=0.03). Boys with ABA had greater BMI z-score (p<0.001), but rate of weight gain did not differ. The greatest degree of ABA was found combining variables by tertiles. The top tertile of BA/CA had the highest insulin and IGF-1 z-scores. The top combined tertiles of DHEAS and BMI z-score or DHEAS and leptin in girls had the highest BA/CA. In boys, the top tertiles of BMI z-score and IGF-1 z-score produced the highest BA/CA. The lowest combined tertiles of any variables related to the lowest BA/CA. Conclusions: Multiple factors influence skeletal maturation. Almost 25% of children with OB have ABA, associated with BMI z-score, and one or more of the following: insulin, leptin, DHEAS, IGF-1, and rate of weight gain. This report delineates the prevalence and degree of ABA by sex, in children with normal versus excessive weight.

Randomized clinical trial evaluating metformin versus oral contraceptive pills in the treatment of adolescents with polycystic ovarian syndrome.

Abstract Background: Polycystic ovarian syndrome (PCOS) is characterized by irregular menses, elevated androgens, and insulin resistance. Little information is published about the treatment of adolescent PCOS. Objectives: The aim of this study was to evaluate metformin versus oral contraceptive pills (OCP) in treating adolescent PCOS. Twenty-two girls were randomized to either treatment for 6 months. The outcomes variables included body mass index (BMI) and free testosterone (FT). Results: BMI decreased in all patients (metformin p=0.004, OCP p=0.045). FT decreased significantly only with OCP. Insulin resistance measures decreased in all patients but did not reach significance. The only significant difference in any of the variables between the two groups was number of menses. BMI and FT remained less than baseline for 3 months off treatment. Conclusions: Metformin and OCP have a positive effect on BMI, which persists after treatment is discontinued. FT decreased with both treatments, but only reached significance with OCP.

Efficacy and safety of triptorelin 6-month formulation in patients with central precocious puberty

Abstract Background: Triptorelin is an established treatment for central precocious puberty (CPP) as 1- and 3-month formulations. The current triptorelin 22.5 mg 6-month formulation is approved for prostate cancer therapy. This is the first study in patients with CPP. Methods: The efficacy and safety of the triptorelin 6-month formulation in CPP were investigated. The primary objective was to evaluate the efficacy in achieving luteinizing hormone (LH) suppression to pre-pubertal levels at month 6. This was an international, non-comparative phase III study over 48 weeks. Eighteen medical centers in the US, Chile and Mexico participated. Forty-four treatment naïve patients (39 girls and five boys) aged at treatment start 2–8 years for girls and 2–9 years for boys with an advancement of bone age over chronological age ≥1 year were to be included. Triptorelin was administered im twice at an interval of 24 weeks. LH, follicle stimulating hormone (FSH) (basal and stimulated), estradiol (girls), testosterone (boys), auxological parameters, clinical signs of puberty and safety were assessed. Results: Forty-one patients (93.2%) showed pre-pubertal LH levels (stimulated LH ≤5 IU/L) at month 6 and maintained LH suppression through month 12. The percentage of patients with LH suppression exceeded 93% at each time point and reached 97.7% at month 12. No unexpected drug-related adverse events were reported. Conclusions: The triptorelin 6-month formulation was safe and effective in suppressing the pituitary-gonadal axis in children with CPP. The extended injection interval may improve compliance and increase comfort in the management of CPP.

Estrogen Suppression in Males: Metabolic Effects

We have shown that testosterone (T) deficiency per se is associated with marked catabolic effects on protein, calcium metabolism, and body composition in men independent of changes in GH or insulin-like growth factor I production. It is not clear,,however, whether estrogens have a major role in whole body anabolism in males. We investigated the metabolic effects of selective estrogen suppression in the male using a potent aromatase inhibitor, Arimidex (Anastrozole). First, a dose-response study of 12 males (mean age, 16.1 +/- 0.3 yr) was conducted, and blood withdrawn at baseline and after 10 days of oral Arimidex given as two different doses (either 0.5 or 1 mg) in random order with a 14-day washout in between. A sensitive estradiol (E2) assay showed an approximately 50% decrease in E2 concentrations with either of the two doses; hence, a 1-mg dose was selected for other studies. Subsequently, eight males (aged 15-22 yr; four adults and four late pubertal) had isotopic infusions of [(13)C]leucine and (42)Ca/(44)Ca, indirect calorimetry, dual energy x-ray absorptiometry, isokinetic dynamometry, and growth factors measurements performed before and after 10 weeks of daily doses of Arimidex. Contrary to the effects of T withdrawal, there were no significant changes in body composition (body mass index, fat mass, and fat-free mass) after estrogen suppression or in rates of protein synthesis or degradation; carbohydrate, lipid, or protein oxidation; muscle strength; calcium kinetics; or bone growth factors concentrations. However, E2 concentrations decreased 48% (P = 0.006), with no significant change in mean and peak GH concentrations, but with an 18% decrease in plasma insulin-like growth factor I concentrations. There was a 58% increase in serum T (P = 0.0001), sex hormone-binding globulin did not change, whereas LH and FSH concentrations increased (P < 0.02, both). Serum bone markers, osteocalcin and bone alkaline phosphatase concentrations, and rates of bone calcium deposition and resorption did not change. In conclusion, these data suggest that in the male 1) estrogens do not contribute significantly to the changes in body composition and protein synthesis observed with changing androgen levels; 2) estrogen is a main regulator of the gonadal-pituitary feedback for the gonadotropin axis; and 3) this level of aromatase inhibition does not negatively impact either kinetically measured rates of bone calcium turnover or indirect markers of bone calcium turnover, at least in the short term. Further studies will provide valuable information on whether timed aromatase inhibition can be useful in increasing the height potential of pubertal boys with profound growth retardation without the confounding negative effects of gonadal androgen suppression.

Importance of leuprolide acetate variable dosing for precocious puberty: a range of acceptable suppression.

AIM The effect of the variation in hormonal suppression on bone maturation, growth velocity, and adult height prediction was examined during treatment with leuprolide acetate for central precocious puberty (CPP). METHODS Ten girls on variable doses of Lupron were studied for one year. Height, weight, body mass index, luteinizing hormone (LH), estradiol, and growth velocity were measured every 3 months. Bone age and predicted height were assessed every 6 months. RESULTS LH range changed from 0.5-1.4 IU/I to 0.1-2.8 IU/I. The average Lupron dose decreased from 0.33 +/- 0.11 to 0.26 +/- 0.08 mg/kg. Predicted adult height averaged 158.33 +/- 9.5cm at the start of the study and increased to 161.45 +/- 6.26 cm (p <0.01). LH and estradiol did not correlate with the rate of bone maturation, growth velocity, predicted height, or with leuprolide dose. CONCLUSION Variable dosing of leuprolide acetate is needed to achieve similar amounts of hormonal suppression, yet small changes in dose did not significantly change LH or estradiol levels or predicted height.

Review and evaluation of patient-centered psychosocial assessments for children with central precocious puberty or early puberty

Abstract The objective of this study was to assess the current use of patient-centered psychosocial assessments for the evaluation of children with central precocious puberty (CPP). Studies evaluating the psychosocial impact of CPP were identified through searches of the PubMed and Cochrane Library databases, ClinicalTrials.gov, a drug prescribing information database, and regulatory websites. Studies were screened using prespecified inclusion and exclusion criteria. Potentially relevant patient-centered outcome assessments (including patient-, parent- or observer-reported measures) used in the identified studies were evaluated in detail for their relevance in CPP. Of the 467 studies identified, 15 met the inclusion criteria. Frequently assessed concepts included depression and anxiety, behavior and behavioral problems, body image and self-esteem and personality type/characteristics. Among the assessments used in the identified studies, the Child Behavior Checklist, Pediatric Quality of Life Inventory (PedsQL), SF-10 for Children and Child Health Questionnaire were comprehensively evaluated. The PedsQL showed promise as a patient-centered outcome measure in CPP. Although there is a lack of validated tools measuring psychosocial health and health-related quality of life in patients with CPP, the PedsQL captures issues seen in this patient population and is relatively easy to administer. Further studies using this and other tools in children with CPP are needed.