My Mentor Quilt.

In this narrative medicine essay, a pediatric endocrinologist who is now a university president pays tribute to her many mentors who helped guide, advise, and nurture her throughout her life journey.

Treatment with a luteinizing hormone-releasing hormone agonist in adolescents with short stature.

BACKGROUND: Treatment with a luteinizing hormone-releasing hormone (LHRH) agonist increases adult height in children with LHRH-dependent precocious puberty and is prescribed by some practitioners to augment height in short adolescents. We performed a randomized clinical trial to determine whether treatment with an LHRH agonist increases adult height in short adolescents with normally timed puberty. METHODS: Fifty short adolescents (18 boys and 32 girls) with low predicted adult height (mean [+/-SD], 3.3+/-1.2 SD below the population mean) received either placebo (24 subjects) or an LHRH agonist (26 subjects). The mean (+/-SD) duration of treatment was 3.5+/-0.9 years in the LHRH-agonist group and 2.1+/-1.2 years in the placebo group (P<0.001). Adult height was measured when bone age exceeded 16 years in girls and 17 years in boys and when the rate of growth was less than 1.5 cm per year. RESULTS: Forty-seven adolescents (94 percent) were followed until they attained adult height. At the time adult height was achieved, the subjects who had been treated with an LHRH agonist were older than those who had received placebo (20.5+/-2.1 years vs. 18.0+/-2.5 years, P=0.01) and were taller (standard-deviation score, -2.2+/-1.1 vs. -3.0+/-1.2; P=0.01). Analysis of covariance showed that LHRH-agonist treatment resulted in an increase of 0.6 (95 percent confidence interval, 0.2 to 0.9) in the standard-deviation score for height, or an increase of 4.2 cm (95 percent confidence interval, 1.7 to 6.7), over the initially predicted adult height (P=0.01). Treatment with an LHRH agonist resulted in significantly greater adult height than did placebo in boys and girls, in adolescents with idiopathic short stature, and in those who had a growth-limiting syndrome. The principal adverse event in the LHRH-agonist group was decreased accretion of bone mineral density (mean lumbar vertebral bone mineral density at the time adult height was achieved, 1.6+/-1.2 SD below the population mean, vs. 0.3+/-1.2 SD below the population mean in the placebo group; P<0.001). CONCLUSIONS: Treatment with an LHRH agonist for 3.5 years increases adult height by 0.6 SD in adolescents with very short stature but substantially decreases bone mineral density. Such treatment cannot be routinely recommended to augment height in adolescents with normally timed puberty.

GNAS mutation detection is related to disease severity in girls with McCune-Albright syndrome and precocious puberty.

BACKGROUND: McCune-Albright syndrome (MAS) is characterized by a triad of gonadotropin-independent precocious puberty, café au lait skin pigmentation and fibrous dysplasia of bone. MAS is due to activating mutations of GNAS, the gene encoding Gsalpha. Interest exists in the use of GNAS mutation analysis to make a definitive diagnosis when the phenotype is not diagnostic, i.e. in partial forms of MAS. The utility of using peripheral blood for mutation analysis in this setting has not been thoroughly evaluated. OBJECTIVE: We performed a systematic analysis of genomic DNA for the detection of GNAS activating mutations in girls with MAS who presented with precocious puberty to evaluate whether identification of an activating mutation in peripheral blood is related to the presence of other features of MAS. STUDY DESIGN: Genomic DNA was isolated from blood from 13 girls with gonadotropin-independent precocious puberty. A polymerase chain reaction (PCR)-based technique was performed for GNAS mutation identification. RESULTS: GNAS activating mutations were identified in 4 patients, all of whom had classic MAS based on clinical evidence. CONCLUSIONS: Detection of activating mutations in leukocyte genomic DNA extracted from peripheral blood samples from girls with gonadotropin-independent precocious puberty was associated with the presence of other phenotypic manifestations of MAS. Until improvements in the diagnostic utility of GNAS activating mutation analysis from leukocyte genomic DNA occur, such testing in patients with atypical forms of MAS should continue to be reserved for research settings.

Limited efficacy of growth hormone (GH) during transition of GH-deficient patients from adolescence to adulthood: a phase III multicenter, double-blind, randomized two-year trial.

CONTEXT: Treatment of GH-deficient adolescents in transition to adulthood remains challenging. OBJECTIVE: The objective was to assess the safety and efficacy of GH in GH-deficient adolescents in transition. PATIENTS: Fifty-eight GH-deficient adolescents (mean age, 15.8 +/- 1.8 yr; 33 males) at near completion of their linear growth participated in the study. INTERVENTION: Baseline studies were done while subjects were on GH. Subjects were retested (insulin-induced hypoglycemia) 4 wk after GH discontinuation and reclassified as persistently GH-deficient or controls (n = 18). GH-deficient subjects were randomized to GH (n = 25, approximately 20 microg/kg.d) or placebo (n = 15). SETTING: The multicenter study was conducted over a 2-yr period. MAIN OUTCOMES: Changes in body composition, bone mineral density (BMD), quality of life (QOL), cardiovascular and metabolic markers were measured. RESULTS: All groups had normal measures of lipid and carbohydrate metabolism, body composition, BMD, cardiac function, muscle strength, and QOL at baseline and after 2 yr. IGF-I concentrations decreased in all, but less so in the GH-group (P = 0.013). There was a greater increase in lean body mass (lesser adiposity) in the GH group than placebo at 12 months, but not at 24 months. CONCLUSIONS: 1) GH-deficient patients properly treated in childhood can have normal BMD, body composition, cardiac function, muscle strength, carbohydrate and lipid metabolism, and QOL when reaching adult height; and 2) continuation of GH therapy for 2 yr did not change these measures as compared to placebo-treated or control subjects. GH-deficient adolescents in good metabolic status at the time of epiphyseal fusion may safely discontinue GH for at least 2 yr. Follow-up is needed to determine whether GH therapy is eventually warranted in subjects treated with GH during childhood.

Childhood obesity.

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.

RNA interference (RNAi) for extracellular signal-regulated kinase 1 (ERK1) alone is sufficient to suppress cell viability in ovarian cancer cells.

While ovarian cancer is a leading cause of death in females today, the molecular, genetic, and environmental factors that initiate and support the progression of this disease are still only partially understood. The extracellular signal-regulated kinase (ERK) signaling pathway is a major contributor to cellular growth, differentiation and survival. Recently, we reported that this pathway is constitutively activated in ovarian cancer cells, and that by using RNA interference (RNAi) for ERK1 and ERK2, we were able to significantly suppress the number of viable tumor cells. In the present study, we have further investigated the mechanisms by which RNAi for the ERK kinases decreased viability in these cancer cells. It was determined that treatment of the cancer cells with small inhibitory RNAs (siRNAs) directed against ERK1 and ERK2 leads to the induction of apoptosis and necrosis by four hours following treatment. Additionally, we found that primary, nonmalignant ovarian cells do not respond similarly to ERK siRNA treatment and that these cells fail to die following treatment. Data presented show that ERK2 expression is more difficult to silence, depending upon cell type being examined and that silencing ERK1 expression alone is sufficient to significantly decrease tumor cell viability.

Mechanisms regulating the constitutive activation of the extracellular signal-regulated kinase (ERK) signaling pathway in ovarian cancer and the effect of ribonucleic acid interference for ERK1/2 on cancer cell proliferation.

The ERK1/2 MAPK pathway is a critical signaling system that mediates ligand-stimulated signals for the induction of cell proliferation, differentiation, and cell survival. Studies have shown that this pathway is constitutively active in several human malignancies and may be involved in the pathogenesis of these tumors. In the present study we examined the ERK1/2 pathway in cell lines derived from epithelial and granulosa cell tumors, two distinct forms of ovarian cancer. We show that ERK1 and ERK2 are constitutively active and that this activation results from both MAPK kinase-dependent and independent mechanisms and is correlated with elevated BRAF expression. MAPK phosphatase 1 (MKP-1) expression, which is involved in ERK1/2 deactivation, is down-regulated in the cancer cells, thus further contributing to ERK hyperactivity in these cells. Treatment of these cancer cell lines with the proteasome inhibitor ZLLF-CHO increased MKP-1 but not MKP-2 expression and decreased ERK1/2 phosphorylation. More importantly, silencing of ERK1/2 protein expression using RNA interference led to the complete suppression of tumor cell proliferation. These results provide evidence that the ERK pathway plays a major role in ovarian cancer pathogenesis and that down-regulation of this master signaling pathway is highly effective for the inhibition of ovarian tumor growth.

Autoimmune thyroid dysfunction in children with type 1 diabetes mellitus: screening guidelines based on a retrospective analysis.

Individuals with type 1 diabetes mellitus (DM1) have an increased risk of developing autoimmune thyroid dysfunction (AITD). We measured the prevalence of AITD in a pediatric DM1 population in order to examine the best combination of markers for predicting the development of AITD. A database of 1,254 patients with DM1 under 21 years of age was retrospectively screened for abnormalities in antithyroglobulin antibody (ATA), thyroid peroxidase antibody (TPO) and thyroid stimulating hormone (TSH). Charts on all 134 who had any of these serologic abnormalities were reviewed. 4.2% of the DM1 population was clinically diagnosed with AITD. Thirty-nine percent of the AITD diagnoses came within 1 year of DM1 diagnosis. Based upon evidence-based medicine statistics, TPO and TSH measurements are the most efficient and cost-effective combination of screening tests for AITD prediction and detection. The positive predictive value (of TPO and TSH) is 90%, with a positive likelihood ratio of 131.

Premature thelarche and granulosa cell tumors: a search for FSH receptor and G5alpha activating mutations.

Activating mutations of the Gsalpha gene are responsible for McCune-Albright syndrome and have also been identified in sporadic tumors of the pituitary and thyroid. When associated with malignancy, activating Gsalpha mutations are known as gsp-oncogenes. We hypothesized that similar activating mutations might also account for some cases of premature thelarche and/ or granulosa cell tumors. Polymerase chain reaction and DNA sequencing was used to screen for activating mutations of Gsalpha genes in children with premature thelarche and in pathologic specimens from juvenile and adult granulosa cell tumors. Because these disorders involve over-activity of the FSH-signaling pathway, we also screened for activating mutations of the FSH receptor. No mutations were detected in either the Gsalpha or the FSHR fragment studied. Previously reported polymorphisms (Ser680Asn and Ala307Thr) of the FSHR were detected in 25/27 tumor samples and 9/9 premature thelarche samples. We conclude that activating mutations in previously identified mutation 'hot-spots' in the Gsalpha and FSH receptor genes are probably not a major cause of premature thelarche or granulosa cell tumors. In contrast, polymorphisms of the FSH receptor are common.

Bicalutamide and third-generation aromatase inhibitors in testotoxicosis.

Testotoxicosis, a form of gonadotropin-independent precocious puberty, results from an activating mutation of the luteinizing hormone receptor expressed in testicular Leydig cells. Affected males experience early testosterone secretion, virilization, advancing bone age, and resultant short stature. Recently, the use of combination therapy with a potent antiandrogen agent (bicalutamide) and a third-generation aromatase inhibitor (anastrozole or letrozole) was reported to yield encouraging short-term results. We present here the results of longer-term treatment (4.5 and 5 years) with this combination therapy in 2 boys who demonstrated that it is well tolerated, slows bone-age advancement in the face of continued linear growth, and prevents progression of virilization.

No activating mutations of FSH receptor in four children with ovarian juvenile granulosa cell tumors and the association of these tumors with central precocious puberty.

STUDY OBJECTIVE: The stimulation of the follicle-stimulating hormone receptor (FSHR) by circulating FSH or some activating mutations of the FSHR may play a causal role in the development of granulosa cell tumors of ovaries. STUDY DESIGN: We evaluated four patients with ovarian juvenile granulosa cell tumors (age range, 2.4 to 7.2; median, 2.9 years) and five healthy pubertal girls (age range, 16 to 18.5; median, 16.8 years) for activating mutations in exon 10 of the FSHR. The patients were followed and evaluated clinically. Genomic DNA was extracted from the peripheral blood. Exon10 of the FSHR was evaluated for mutations. RESULTS: All four patients presented with signs of precocious puberty. One patient, who had markedly accelerated growth velocity and advanced bone age, developed central precocious puberty after the removal of her tumor. Another patient was diagnosed to have a left ovarian cyst without tumor recurrence approximately 3.3 years after the removal of the tumor. Activating mutations were not found, but previously reported polymorphisms (Ser680Asn and Ala307Thr) of the FSHR were detected in three of four patients and in three of five controls. The follow-up period of these four patients ranged from 4.5 to 8.8 years, with a median value of 6.7 years. CONCLUSIONS: We did not find any activating mutation in exon 10 of the FSHR in our patients, and one patient developed precocious puberty after removal of her tumor. The development of ovarian tumors in these patients may have been caused by mutations at other exons of the FSHR and G protein subunits, so the association noted between central precocious puberty and granulosa cell tumors might not be coincidental.

Role of environmental factors in the timing of puberty.

Puberty-timing measures have historically been used as indicators of adequate nutrition and growth. More recently, these measures have been examined in relation to exposure to estrogenic or antiandrogenic agents, as well as other environmental factors. The scientific community has debated whether puberty timing is occurring earlier today than in the mid-1900s in the United States and, if so, whether environmental factors play a role; however, no one has asked a multidisciplinary panel to resolve this question. Thus, a multidisciplinary expert panel jointly sponsored by the US Environmental Protection Agency, the National Institute of Environmental Health Sciences, and Serono Symposia International was convened to examine the evidence of a secular trend, identify potential environmental factors of concern, and identify research needs regarding environmental factors and puberty timing at "The Role of Environmental Factors on the Timing and Progression of Puberty" workshop. The majority of the panelists concluded that the girls' data are sufficient to suggest a secular trend toward earlier breast development onset and menarche from 1940 to 1994 but that the boys' data are insufficient to suggest a trend during this same period. The weight-of-the-evidence evaluation of human and animal studies suggest that endocrine-disrupting chemicals, particularly the estrogen mimics and antiandrogens, and body fat are important factors associated in altered puberty timing. A change in the timing of puberty markers was considered adverse from a public health perspective. The panel recommended research areas to further our understanding of the relationships among environmental factors, puberty-timing outcomes, and other reproductive and adult disease at the individual and population levels.

Environmental factors and puberty timing: expert panel research needs.

Serono Symposia International convened an expert panel to review the impact of environmental influences on the regulation of pubertal onset and progression while identifying critical data gaps and future research priorities. An expert panel reviewed the literature on endocrine-disrupting chemicals, body size, and puberty. The panel concluded that available experimental animal and human data support a possible role of endocrine-disrupting chemicals and body size in relation to alterations in pubertal onset and progression in boys and girls. Critical data gaps prioritized for future research initiatives include (1) etiologic research that focus on environmentally relevant levels of endocrine-disrupting chemicals and body size in relation to normal puberty as well as its variants, (2) exposure assessment of relevant endocrine-disrupting chemicals during critical windows of human development, and (3) basic research to identify the primary signal(s) for the onset of gonadotropin-releasing hormone-dependent/central puberty and gonadotropin-releasing hormone-independent/peripheral puberty. Prospective studies of couples who are planning pregnancies or pregnant women are needed to capture the continuum of exposures at critical windows while assessing a spectrum of pubertal markers as outcomes. Coupled with comparative species studies, such research may provide insight regarding the causal ordering of events that underlie pubertal onset and progression and their role in the pathway of adult-onset disease.

Treatment of familial male-limited precocious puberty with bicalutamide and anastrozole.

This report describes the use of bicalutamide and anastrozole in two subjects with familial male-limited precocious puberty. Clinical improvements include decreased facial acne and pubic hair. Most importantly, a marked decrease in growth velocity and skeletal advancement has been achieved.

The effect of growth hormone supplementation on late nutritional independence in pediatric patients with short bowel syndrome.

PURPOSE: The use of growth hormone (GH) supplementation for intestinal adaptation among adult patients with short bowel syndrome (SBS) has provided mixed results. This report examines the effect of GH supplementation on SBS in pediatric patients. METHODS: Two girls with SBS from neonatal gastrointestinal catastrophes received exogenous GH at 0.3 mg/kg per week subcutaneously and concurrent glutamine supplementation, beginning at 6 and 6(1/2) years of age. Changes in growth (height and weight) and changes in enteral and parenteral energy requirements were evaluated. RESULTS: Treatment duration was 8 and 2.5 years, respectively. Patient weights increased from the 5th to the 41st percentile and from the 17th to the 23rd percentile, respectively. Height increased from the 1st to the 57th percentile in the former patient and increased from less than the 1st to the 17th percentile in the latter. Both patients are independent of parenteral nutrition and take enteral nutrition alone. Tolerance for enteral diets was significantly improved in each girl, with only 2 stools per day maintained in one patient. CONCLUSIONS: The data show that late exogenous treatment with GH and glutamine supplementation improved growth parameters in pediatric patients with SBS. Growth hormone and glutamine supplementation may be beneficial in promoting late intestinal adaptation in pediatric patients with SBS. These data also suggest that these adjuncts may be useful in the early phases of intestinal adaptation.

Prevalence of elevated antithyroid antibodies and antinuclear antibodies in children with immune thrombocytopenic purpura.

The prevalence and significance of autoantibodies found at the time of diagnosis of childhood ITP were studied to correlate their presence with risk for development of chronic ITP. Children presenting with acute or chronic ITP to The James Whitcomb Riley Hospital for Children between July 1993 and September 1994 were tested at study entry and followed for the presence of antithyroid antibodies (ATA), antinuclear antibodies (ANA), Coombs' reactivity, and anti-human immunodeficiency virus (HIV) antibodies. Grouped data were evaluated for significance using Fisher's exact t-test. Thirty-one patients were enrolled in the study with a median age of 8 years (range 17 months-16 years) and male-to-female ratio of 1:1.8. Forty-two percent of these children had an acute course of ITP, and 58% of children had a chronic course of ITP. Of children with acute ITP, three (23%) of the patients had an acute nonplatelet autoantibody detected. Of the children with chronic ITP, six (33%) of the children had at least one abnormal antibody value. Five children (16%) tested positive for ATA: 2 children with acute ITP and 3 with chronic ITP. Five children had positive ANA, and of these children, 4 (80%) had chronic ITP. Sixty-seven percent of patients testing positive for autoantibodies were female, and 67% of all patients were 12 years of age or older. Three patients, 1 with acute ITP and 1 with chronic ITP, had insignificant abnormal thyroid function tests (these children had minimally elevated T3 with otherwise normal thyroid function, and none of these children had autoantibodies). No patients included in the study tested positive for HIV. Our results suggest that patients with acute ITP who also have other autoantibodies may be more likely to develop chronic ITP than those lacking these autoantibodies. Larger studies are needed to determine whether the presence of ATA or ANA is predictive of clinically significant autoimmune disease.

Craniofacial and acral growth responses in growth hormone-deficient children treated with growth hormone.

OBJECTIVES: To investigate the effects of growth hormone (GH) therapy on craniofacial growth and body proportions in growth hormone deficient children. STUDY DESIGN: By using a cross-sectional study design, we investigated GH effects on craniofacial growth with photographic facial morphometrics, head circumference, and hand and foot size in 52 children with GH deficiency (GHD) treated with GH (0.27 mg/kg/wk) for 0.19 to 15.5 years, compared with untreated children with GHD and normal first-degree relatives. To detect disproportion and to correct for stature, age and height age (HA) SD scores were analyzed. RESULTS: Untreated subjects with GHD had retarded facial height and width (P values=.001) compared with normal controls; small head circumference for age and HA (P=.001); small hands for age (P<.001) that were large for HA (P=.003); and small feet for age (P<.001) that were normal for HA. When compared with normal controls, GH-treated subjects had proportional facial heights but narrower facial widths. Head circumference, however, increased disproportionately to height (P=.001), becoming large for stature, and increasing with duration of therapy and cumulative GH dose (P<.001). Hands and feet grew proportionately to height. CONCLUSION: Growth hormone treatment with conventional doses partially corrects craniofacial deficits and does not adversely affect hand and foot growth but appears to result in excessive head circumference growth.