John S. Fuqua

Treatment and Outcomes of Precocious Puberty: An Update

Precocious puberty is a common problem affecting up to 29 per 100,000 girls per year. The earliest identified neuroendocrine change in early puberty thus far is increased kisspeptin secretion from the arcuate nucleus and the anteroventral paraventricular nucleus of the hypothalamus. The regulation of kisspeptin secretion is not well understood, but neurokinin B and dynorphin provide autocrine regulation. The etiologies of precocious puberty may be subdivided into GnRH-dependent and GnRH-independent causes. GnRH-dependent precocious puberty, often called central precocious puberty (CPP), is usually treated with GnRH analogs. Newer developments in the treatment of CPP include expanded data on the safety and efficacy of the subdermal histrelin implant, which is useful for long-term treatment, although removal may be difficult in some cases. Preliminary data suggest that the implant may be left in place for up to 2 years without loss of biochemical suppression. In the last 2 years, more data have been published concerning extended-release leuprolide acetate injections that indicate that the 11.25-mg dose may not provide full biochemical suppression but may clinically suppress signs of puberty, including the accelerated growth velocity and advanced skeletal maturation seen in CPP. Treatment options for familial male-limited precocious puberty and McCune-Albright syndrome are expanding as well, although data are preliminary. Long-term outcome studies of CPP indicate overall good menstrual and reproductive function, but the prevalence of polycystic ovary syndrome may be higher than in the general population. Remarkably few studies have evaluated the behavioral and psychological outcomes of precocious puberty, in contrast to early normal maturation. Additional outcome studies of endocrine, metabolic, and psychological effects of CPP are clearly needed.

GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults.

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that ‘for approved indications, GH is safe’; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.

Characteristics of Referrals for Gender Dysphoria Over a 13-Year Period

PURPOSE Our Pediatric Endocrinology Clinic has seen a sharp increase in referrals for gender dysphoria (GD) during recent years. However, the frequency and characteristics of referrals have not been objectively examined. METHODS A retrospective chart review of referrals for GD during the past 13 years was performed. Variables analyzed included numbers of referrals per year, patient characteristics, comorbid conditions, and hormonal therapy. Timing of referral and eligibility for treatment were measured against established recommendations. RESULTS Of 38 patients, 74% were referred during the last 3 years. Most patients presented late in puberty before a GD-specific psychological evaluation and few were eligible for hormonal treatment at baseline. Over half had psychiatric and/or developmental comorbidities. CONCLUSIONS A dramatic increase in referrals for GD since 2002 was confirmed. Enhanced provider education and outreach regarding care of patients with GD are needed.

Neuroendocrine alterations in the exercising human: Implications for energy homeostasis

Complex mechanisms exist in the human to defend against adverse effects of negative energy balance. These include alterations of hormone secretion affecting the growth hormone/insulin-like growth factor system, the adrenal axis, and the reproductive system, particularly in females. Energy deficits are least partially offset by neuroendocrine mechanisms regulating appetite and satiety. The complex feedback mechanisms reporting peripheral fat and energy stores to the central nervous system involve secretion of the peptide hormones leptin and ghrelin, which act centrally on neurons in the arcuate nucleus and anteroventral periventricular area. In addition to appetite regulation, these hormones exert influences on spatially and functionally-related mechanisms regulating reproductive function, such as the kisspeptin-gonadotropin releasing hormone system. Negative energy balance often occurs partially as a result of strenuous and repetitive physical exercise. Exercise stress leads to increased cortisol secretion, but this action is mediated through the induced negative energy balance. In healthy adults with energy deficits, this exercise-induced stress appears to be more important than pure psychological stress in impairing reproductive function. Estrogen deficiency resulting from negative energy balance has important adverse effects on bone density as well as bone microarchitecture, and it may also adversely affect markers of cardiovascular disease.

Identification of a Novel Heterozygous IGF1 Splicing Mutation in a Large Kindred with Familial Short Stature

Background/Aims: Insulin-like growth factor (IGF)-I is critical for normal human growth. Extremely rare homozygous mutations of the IGF1 gene severely impair intrauterine growth, intellectual development and postnatal growth. Case/Method: A young male presented with postnatal growth retardation (–4.0 height SDS). His serum IGF-I concentration was low (115 µg/l, –2.21 SDS) and increased minimally to 130 µg/l (–1.82 SDS) on GH therapy, and he was analyzed for defect(s) in the GH-IGF-I axis. Severe short stature could be traced back several generations. Results: From the proband and 4 other severely short-statured family members, two novel, heterozygous, variants were identified in the IGF1 gene: c.207G>A in exon 3 and c.402+1G>C in the donor splice site of intron 4. The IGF1 gene was normal in 11 normal stature family members, and, interestingly, in 5 other short-statured family members. Study of IGF1 mRNA indicated c.402+1G>A induced splicing out of exon 4, leading to a predicted frameshift and protein truncation. Conclusions: A novel heterozygous IGF1 splicing variant is associated with familial short stature in an extended family. Although it remains unclear whether this heterozygous mutation is the cause of the growth failure, the extreme rarity of IGF1 gene defects makes these cases of considerable interest.

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.

The impact of assay sensitivity in the assessment of diseases and disorders in children

Accurate measurement of the low levels of testosterone (T) and estradiol (E(2)) present in normal children and in children with disorders of puberty and sexual development is critical both for appropriate diagnosis and treatment and for clinical research studies. However, measurement of these levels lacks needed precision because of inadequate sensitivity of most commercially available assays and poor accuracy at the low levels found in normal childhood and most disorders. While immunoassays presently do not appear to have the potential to provide more accurate measurements, isotope dilution-gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry techniques offer promise to meet this need to improve clinical care and research.

Predictors of First-Year Growth Response to a Fixed-dose Growth Hormone Treatment in Children Born Small for Gestational Age: Results of an Open-Label, Multicenter Trial in the United States

BACKGROUND Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.

Lawson Wilkins: portrait of a pioneer

Foreword September 27, 2013 was the 50 anniversary of Lawson Wilkins’ death. After reading the two articles by his daughter, Betsy McMaster, and his devoted protegee, Claude Migeon, we can’t help but wonder what Dr. Wilkins would have thought if he could see how we practice Pediatric Endocrinology today. Lawson Wilkins was born in 1894, and his father (also a physician) would take him along on his rounds in a horse and buggy. After serving in World War I and graduating from Johns Hopkins School of Medicine, Dr. Wilkins completed his pediatric residency at Yale and then settled down in his home town of Baltimore to practice general pediatrics. However, he quickly distinguished himself from other practitioners by his insatiable curiosity and careful attention to measurable physical parameters and the information they provided for diagnosis and clinical management. He became renowned for the meticulous graphs and charts that he hand-prepared as illustrated in the famous portrait. (Figure 1) As he studied growth and development of normal children and contrasted these with patterns in children with hypothyroidism, his interest in endocrinologic disorders increased. He developed a relationship with Dr. Edwards Park, Chief of Pediatrics at Hopkins. Dr. Park was eventually able to recruit Dr. Wilkins to a part time and then a full time faculty position. But much of his early work in hypothyroidism was conducted while he was working diligently in his pediatric practice. After giving up his practice in 1946, he devoted himself full time to endocrinology, resulting, with the help of his fellows and associates, in a rapid expansion of scientifically validated knowledge. No doubt that Dr. Wilkins saw tremendous changes over the course of his medical career, perhaps the most important one being the development of antibiotics, which saved the lives of countless children. But Dr. Wilkins himself was the driver of changes in endocrine practice. In fact, while trying to learn from his predecessors about endocrinology in children, he ended up throwing an existing text of endocrine disease against the wall in frustration and decided to write his own based on his collection of painstakingly-developed case observations. This work eventually led to the first textbook of Pediatric Endocrinology and stimulated interest in the subspecialty around the world. But if he could have travelled forward in time to 2013, what would he think of where we are now? He would certainly have been amazed by the technology. Measurement of hormones in his day relied on relatively primitive time and labor-intensive chromatographic and colorimetric techniques. Radioimmunoassays were perfected after his death, and platform-based immunoassays and tandem mass spectrometry were not even dreams. He might have been jealous of our ability to draw a blood sample and know the 17-hydroxyprogesterone or T4 concentration on the same day! As noted above, much of Dr. Wilkins’ early work in Pediatric Endocrinology was in the area of hypothyroidism, particularly congenital Indiana University School of Medicine, Indianapolis, IN, USA Full list of author information is available at the end of the article Figure 1 Lawson Wilkins portrait. Fuqua and Lee International Journal of Pediatric Endocrinology 2014, 2014(Suppl 1):I1 http://www.ijpeonline.com/content/2014/S1/I1

Reply to: Zucker et al., “Comment on Chen, Fuqua, and Eugster's (2016) ‘Characteristics of Referrals for Gender Dysphoria Over a 13-Year Period’”

however, over the entire period, the number of children (n 1⁄4 502) referred for gender dysphoria was substantially higher than the number of referred adolescents. Wood et al. [3] updated these findings, reporting on a new cohort from 2008 to 2011. The number of adolescents who were referred continued to increase and, during this period, the number of referred adolescents (n 1⁄4 103) exceeded the number of referred children (n 1⁄4 75) for the first time in the history of their gender identity clinic. Aitken et al. [4] reported data on referred adolescents with gender dysphoria consistent with Chen et al.’s observation of the recent increase in referred patients. Between 1976 and 2013, Aitken et al. reported a correlation of .76 between calendar year and number of referrals/year, with calendar year accounting for 68% of the variance. Aitken et al. also documented an inversion in the sex ratio of adolescent referrals for gender dysphoriadfrom one favoring natal males to one favoring natal femalesdthat was consistent with Chen et al. Aitken et al. reported that, before 2006, the male:female sex ratio was 2.11:1, but between 2006 and 2013, the sex ratio was 1:1.76. Finally, Aitken et al. reported on a similar inversion in the sex ratio of adolescents referred for gender dysphoria at a gender identity clinic in the Netherlands: Between 1989 and 2005, the sex ratio was 1.41:1 (n 1⁄4 186), but between 2006 and 2013, the sex ratio was 1:1.72 (n 1⁄4 148). We think that Chen et al.’s data, albeit based on a small sample, are consistent with trends that have been observed internationally, including speciality gender identity clinics that see large numbers of patients.