Publications by authors named "Peter A Lee"

120 Publications

Gender identity: A psychosocial primer for providing care to patients with a disorder/difference of sex development and their families [individualized care for patients with intersex (Disorders/differences of sex development): Part 2].

J Pediatr Urol 2020 Oct 2;16(5):606-611. Epub 2020 Jul 2.

Penn State College of Medicine, Hershey, PA, 17033, USA. Electronic address:

Introduction/background: Many parents of infants born with a DSD describe the process of initial sex assignment at birth as highly stressful. Parents of children with a DSD also note high distress when their children engage in behaviors that are not considered typical for their gender.

Objective: The goal of this article is to provide members of the health care team a brief overview of psychosocial facets of gender and gender identity particularly relevant to DSD for the purposes of enhancing shared decision-making and optimizing support for individuals with a DSD and their families.

Discussion: Gender identity is a multidimensional construct involving related but distinct concepts such as gender typicality, gender contentedness and felt pressure for gender differentiation, and can be assessed via standardized measures. Gender dysphoria is associated with poor psychological adjustment, and is mitigated by family and peer support. Family influences on gender identity include parental modeling of gender behavior and family composition (e.g., same-sex children vs both sons and daughters in a family). Cultural factors that may influence sex assignment include societal views on gender, and gender-related differential resource allocation within a society. In addition, religious beliefs and the presence of a "third-sex" category within a culture may also influence parental gender ideology.

Clinical Application: Health care providers who work with patients with a DSD must have a strong grasp on the construct of gender identity, and must be able to clearly and consistently communicate with patients and families about gender beliefs in order to optimize family support and gender-related decisions.
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http://dx.doi.org/10.1016/j.jpurol.2020.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890938PMC
October 2020

Individualized care for patients with intersex (disorders/differences of sex development): Part 3.

J Pediatr Urol 2020 Oct 11;16(5):598-605. Epub 2020 Jun 11.

Penn State College of Medicine, Hershey, PA, 17033, USA.

The focus of this article is to review the complex determinants of gender assignment in a child with a disorder of sex development using four different clinical cases. While the care of patients with DSD may be shared across several specialties and opinions regarding their management may vary, this may be further complicated by psychosocial, cultural and economic factors. In this regard, access to behavioral health specialists with experience and specialization in the treatment of patients with DSD should be a foundational component of the standard of care and can greatly assist in the complex decision-making regarding gender assignment. We recommend an individualized approach by a multidisciplinary team utilizing a range of evolving strategies, including outcome data (or lack thereof) to support families during the decision-making process.
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http://dx.doi.org/10.1016/j.jpurol.2020.06.004DOI Listing
October 2020

Individualized care for patients with intersex (disorders/differences of sex development): part I.

J Pediatr Urol 2020 04 4;16(2):230-237. Epub 2020 Mar 4.

Hasbro Children's Hospital, Warren Alpert School of Medicine at Brown University, Providence, RI 02903, USA. Electronic address:

The care of individuals with disorders/differences of sex development aims to enable affected individuals and their families to have the best quality of life, particularly those born with severe genital ambiguity. Two of the biggest concerns for parents and health professionals are: (1) making a gender assignment and (2) the decisions of whether or not surgery is indicated, and if so, when is best for the patient and parents. These decisions, which can be overwhelming to families, are almost always made in the face of uncertainties. Such decisions must involve the parents, include multidisciplinary contributions, have an underlying principle of full disclosure, and respect familial, philosophical, and cultural values. Assignment as male or female is made with the realization that gender identity cannot be predicted with certainty. Because of the variability among those with the same diagnosis and complexity of phenotype-genotype correlation, the use of algorithms is inappropriate. The goal of this article is to emphasize the need for individualized care to make the best possible decisions for each patient's unique situation.
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http://dx.doi.org/10.1016/j.jpurol.2020.02.013DOI Listing
April 2020

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

Horm Res Paediatr 2019 18;91(6):357-372. Epub 2019 Jul 18.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Penn State Hershey Medical Center, Hershey, Pennsylvania, USA.

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.
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http://dx.doi.org/10.1159/000501336DOI Listing
March 2020

Bacterial virulence against an oceanic bloom-forming phytoplankter is mediated by algal DMSP.

Sci Adv 2018 10 24;4(10):eaau5716. Epub 2018 Oct 24.

Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.

is a bloom-forming microalga that affects the global sulfur cycle by producing large amounts of dimethylsulfoniopropionate (DMSP) and its volatile metabolic product dimethyl sulfide. Top-down regulation of blooms has been attributed to viruses and grazers; however, the possible involvement of algicidal bacteria in bloom demise has remained elusive. We demonstrate that a strain, D7, that we isolated from a North Atlantic bloom, exhibited algicidal effects against upon coculturing. Both the alga and the bacterium were found to co-occur during a natural bloom, therefore establishing this host-pathogen system as an attractive, ecologically relevant model for studying algal-bacterial interactions in the oceans. During interaction, D7 consumed and metabolized algal DMSP to produce high amounts of methanethiol, an alternative product of DMSP catabolism. We revealed a unique strain-specific response, in which strains that exuded higher amounts of DMSP were more susceptible to D7 infection. Intriguingly, exogenous application of DMSP enhanced bacterial virulence and induced susceptibility in an algal strain typically resistant to the bacterial pathogen. This enhanced virulence was highly specific to DMSP compared to addition of propionate and glycerol which had no effect on bacterial virulence. We propose a novel function for DMSP, in addition to its central role in mutualistic interactions among marine organisms, as a mediator of bacterial virulence that may regulate blooms.
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http://dx.doi.org/10.1126/sciadv.aau5716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200362PMC
October 2018

Growth Hormone Deficiency Causing Micropenis: Lessons Learned From a Well-Adjusted Adult.

Pediatrics 2018 07;142(1)

Department of Pediatrics, College of Medicine, University of Virginia, Charlottesville, Virginia.

This report of a 46,XY patient born with a micropenis consistent with etiology from isolated congenital growth hormone deficiency is used to (1) raise the question regarding what degree testicular testosterone exposure to the central nervous system during fetal life and early infancy has on the development of male gender identity, regardless of gender of rearing; (2) suggest the obligatory nature of timely full disclosure of medical history; (3) emphasize that virtually all 46,XY infants with functional testes and a micropenis should be initially boys except some with partial androgen insensitivity syndrome; and (4) highlight the sustaining value of a positive long-term relationship with a trusted physician (R.M.B.). When this infant presented, it was commonly considered inappropriate to gender assign an infant male whose penis was so small that an adult size was expected to be inadequate, even if the karyotype was 46,XY, and testes were functional. Concomitantly, female gender assignment was considered the appropriate decision, believing that parental rearing in the assigned gender was considered the major factor determining established adult gender identity. Full disclosure of medical information was considered inappropriate. Progress in appreciating the complexities of gender identity development, which is not yet completely understood, and sexuality, coping ability, and outcome data has resulted in a change of practice in initial gender assignment. A 46,XY individual with functional testes and verified androgen responsiveness should be assigned and reared as male, regardless of penis size. Without androgen responsiveness, the multiple factors must be carefully considered and disclosed.
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http://dx.doi.org/10.1542/peds.2017-4168DOI Listing
July 2018

Gonadotropin-Releasing Hormone (GnRHa) Therapy for Central Precocious Puberty (CPP): Review of Nuances in Assessment of Height, Hormonal Suppression, Psychosocial Issues, and Weight Gain, with Patient Examples.

Pediatr Endocrinol Rev 2018 Apr;15(4):298-312

Penn State Hershey Medical Center, 500 University Drive, PO Box 850, Hershey, PA 17033, USA, E-mail:

This review suggests a central theme: that the treatment of each patient presenting with evidence consistent with central precocious puberty (CPP) needs to be individualized. This pertains to multiple factors relating to growth and growth potential, monitoring patients on treatment with gonadotropin-releasing hormone analogue (GnRHa), evaluating psychological issues with CPP and therapy, and concerns about weight gain during GnRHa therapy. Individual cases are presented. New data on adult height and rate of bone age advance are included. GnRHa treatment is effective in improving adult height in children with precocious onset of puberty, rapid progression, and good growth potential. Monitoring suppression adequacy involves a random LH level < 0.6 IU/L or a GnRHa-stimulated peak LH level < 4 IU/L as long as physical exam, growth rate, and rate of bone age progression, are also consistent with suppression. Abnormal psychosocial issues are rare with concerns primarily being related perceptions, real or perceived by others.
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http://dx.doi.org/10.17458/per.vol15.2018.kl.GnRHaforCPPDOI Listing
April 2018

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence.

Horm Res Paediatr 2017 13;88(6):371-395. Epub 2017 Nov 13.

Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania, USA.

This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.
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http://dx.doi.org/10.1159/000479371DOI Listing
October 2018

Response to Letter: "Normal Pubertal Development in Daughters of Women With PCOS: A Controlled Study".

J Clin Endocrinol Metab 2017 07;102(7):2561

Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania 17033.

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http://dx.doi.org/10.1210/jc.2017-00813DOI Listing
July 2017

Foundations of Pediatrics: Lawson Wilkins, MD (1894-1963).

Adv Pediatr 2017 08;64(1):1-11

Division of Pediatric Endocrinology, Department of Pediatrics, Penn State Hershey Medical Center, The Milton S. Hershey Medical Center, Penn State University College of Medicine, PO Box 850, Hershey, PA 17033-0850, USA.

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http://dx.doi.org/10.1016/j.yapd.2017.03.002DOI Listing
August 2017

Pragmatic approach to intersex, including genital ambiguity, in the newborn.

Semin Perinatol 2017 06 20;41(4):244-251. Epub 2017 May 20.

Division of Pediatric Endocrinology, Department of Pediatrics, Penn State College of Medicine, 905 West Governor Rd, Suite 300, Hershey, PA 17033-0850.

The evaluation and management of a newborn with ambiguous genitalia must be undertaken as quickly as possible and with great sensitivity for the child's family. Where possible, a comprehensive team approach with a pediatric urologist, endocrinologist, geneticist, neonatologist, and child psychiatrist/psychologist should work closely with the family to establish the diagnosis and determine gender. Although the preferred gender assignment is not always clear, a thorough examination of endocrine function, karyotype, and potential for fertility should guide the determination. While some disorders of sex development (DSD) sex assignments are relatively straightforward, those with more advanced genital ambiguity and unclear gonadal function represent a major challenge. A child's phenotypic sex results from the differentiation of internal ducts and external genitalia under the influence of hormones and transcription factors. Any discordance among these processes results in ambiguous genitalia or DSD. Currently, the main categories of DSD are 46,XX DSD, 46,XY DSD, sex chromosome DSD, ovotesticular DSD, and 46,XX testicular DSD. Priority is given to rule out more immediate life-threatening disorders like salt wasting CAH. Many centers in the United States lack the comprehensive "team members" and not all conditions necessitate this team approach. This article aims to provide guidance for initial workup and identify the specific conditions for which expert guidance is needed.
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http://dx.doi.org/10.1053/j.semperi.2017.03.013DOI Listing
June 2017

Normal Pubertal Development in Daughters of Women With PCOS: A Controlled Study.

J Clin Endocrinol Metab 2017 01;102(1):122-131

Departments of Obstetrics and Gynecology.

Context: Daughters of women with polycystic ovary syndrome (PCOS) are thought to be at increased risk for developing stigmata of the syndrome, but the ontogeny during puberty is uncertain.

Objective: We phenotyped daughters (n = 76) of mothers with PCOS and daughters (n = 80) from control mothers for reproductive and metabolic parameters characteristic of PCOS.

Design, Setting, And Participants: We performed a matched case/control study at Penn State Hershey Medical Center that included non-Hispanic, white girls 4 to 17 years old.

Intervention: We obtained birth history, biometric, ovarian ultrasounds, whole-body dual-energy X-ray absorptiometry scan for body composition, 2-hour glucose challenged salivary insulin levels, and two timed urinary collections (12 hours overnight and 3 hours in the morning) for gonadotropins and sex steroids.

Main Outcome Measures: We measured integrated urinary levels of adrenal (dehydroepiandrosterone sulfate) and ovarian [testosterone (TT)] steroids. Other endpoints included integrated salivary insulin levels and urinary luteinizing hormone levels.

Results: There were no differences in detection rates or mean levels for gonadotropins and sex steroids in timed urinary collections between PCOS daughters and control daughters, nor were there differences in integrated salivary insulin levels. Results showed that 69% of Tanner 4/5 PCOS daughters vs 31% of control daughters had hirsutism defined as a Ferriman-Gallwey score >8 (P = 0.04). There were no differences in body composition as determined by dual-energy X-ray absorptiometry between groups in the three major body contents (i.e., bone, lean body mass, and fat) or in ovarian volume between groups.

Conclusions: Matched for pubertal stage, PCOS daughters have similar levels of urinary androgens and gonadotropins as well as glucose-challenged salivary insulin levels.
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http://dx.doi.org/10.1210/jc.2016-2707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413094PMC
January 2017

Monitoring treatment of central precocious puberty using basal luteinizing hormone levels and practical considerations for dosing with a 3-month leuprolide acetate formulation.

J Pediatr Endocrinol Metab 2016 Nov;29(11):1249-1257

Background: Peak gonadotropin-releasing hormone or agonist (GnRHa) stimulated luteinizing hormone (LH) testing with leuprolide acetate (LA) is commonly used to document suppression during therapy for central precocious puberty (CPP). The objective of the study was to investigate suitability of using basal LH levels to monitor GnRHa treatment and to determine optimal transition from 1-month to 3-month LA formulations via a post hoc analysis of a randomized, open-label, 6-month study.

Methods: A total of 42 children with CPP, pretreated with 7.5-, 11.25-, or 15-mg 1-month LA formulations were randomized to 11.25- or 30-mg 3-month LA. Basal LH/peak-stimulated LH levels were measured at weeks 0, 4, 8 and 12. Positive/negative predictive values and sensitivities/specificities were determined for basal LH vs. LH-stimulation results.

Results: Pretreatment with any 1-month formulation for the most part did not affect continuation of suppression after transitioning to 3-month formulation (mean peak-stimulated LH levels remained < 4 IU/L). Basal LH predicted suppression escape (basal LH-level cutoff ≥ 0.6 IU/L predicted 70% of those failing suppression). Tolerability was similar, regardless of dose.

Conclusions: Our data indicate that a basal level of <0.60 IU/L is adequate for monitoring suppression approximately two-thirds of the time. Furthermore, the effectiveness and safety of 3-month LA treatments are not influenced by previous CPP therapies.
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http://dx.doi.org/10.1515/jpem-2016-0026DOI Listing
November 2016

Changing and Unchanging Perspectives regarding Intersex in the Last Half Century: Topics Presented in the Lawson Wilkins Lecture* at the 2015 Pediatric Endocrine Society Meeting.

Pediatr Endocrinol Rev 2016 Mar;13(3):574-84

The understanding, care and treatment of patients born with intersex or disorders of sex development conditions has evolved considerably over the last five decades. Regarding those who require evaluation before gender assignment is made, each "generation" of approach has been based upon and reflects the contemporary biological, social and psychological understanding. The most recent generation needs to consider the dramatically changed societal viewpoints regarding the acceptance and expansion beyond a binary perception of sexuality. This together with advances in genetic etiologies, surgical refinements and psychological support should result in better care and quality of life (QoL) outcomes for patients with these conditions. This paper reviews the successive generations of approach and discusses the multiple challenges facing the multidisciplinary teams caring for these patients today.
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March 2016

Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care.

Horm Res Paediatr 2016 28;85(3):158-80. Epub 2016 Jan 28.

Department of Pediatrics, Penn State College of Medicine, Hershey, Pa., USA.

The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.
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http://dx.doi.org/10.1159/000442975DOI Listing
December 2016

Preface.

Endocrinol Metab Clin North Am 2015 Dec;44(4):xvii-xviii

Georgia Prevention Center, Georgia Regents University, Health Sciences Campus, 1120 15th Street, Augusta, GA 30912, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ecl.2015.09.014DOI Listing
December 2015

Lawson Wilkins, MD, 1894-1963: A Founding Father of Pediatric Endocrinology.

Pediatr Endocrinol Rev 2015 Sep;13(1):441-3

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September 2015

Psychosexual development and quality of life outcomes in females with congenital adrenal hyperplasia.

Int J Pediatr Endocrinol 2015 15;2015:21. Epub 2015 Oct 15.

Department of Pediatrics, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850 USA.

Background/aims: Outcome information regarding females with classical congenital adrenal hyperplasia (CAH) have generally suggested poor quality of life (QoL), general maladjustment, problems regarding sexuality, and decreased fertility. The aim of this study was to assess QoL, psychosocial adaptation, and psychosexual characteristics, includingchildhood gender role behavior, gender identity, and sexual orientation in females with CAH.

Methods: Female patients with 21-hydroxylase deficiency CAH were evaluated using a questionnaire with items relating to knowledge of their condition and its therapy; consistency of medical, surgical, and psychological care; childhood friends and play behavior; and genital, pubertal, and sexual development. The subjects' perception of outcome was compared with family support and adolescent and adult QoL perspectives, including social relationships, self and body image, and gender and sexual issues.

Results: Childhood play and gender characteristics, childhood and adult genital perception, and sexual identity and orientation varied as previously reported. However, most patients indicated good family support, understanding of their condition, good quality medical care, positive self-satisfaction, indices of happiness and body image perception, and satisfaction with their sex lives.

Conclusion: The data reported here suggest that overall outcome can be very good for females with CAH and that good outcome appears to relate to quality of care and positive social support.
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http://dx.doi.org/10.1186/s13633-015-0017-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607144PMC
October 2015

Attaining genetic height potential: Analysis of height outcomes from the ANSWER Program in children treated with growth hormone over 5 years.

Growth Horm IGF Res 2015 Dec 22;25(6):286-93. Epub 2015 Aug 22.

Novo Nordisk Inc., Plainsboro, NJ, United States. Electronic address:

Objective: This study aimed to assess attainment of genetic height potential after long-term growth hormone (GH) treatment in GH-naïve children diagnosed with isolated growth hormone deficiency (IGHD), multiple pituitary hormone deficiency (MPHD), born small for gestational age (SGA), or idiopathic short stature (ISS) enrolled in the American Norditropin®

Studies: Web-enabled Research (ANSWER) Program.

Design: Children with IGHD (n=2884), MPHD (n=200), SGA (n=481), or ISS (n=733) with baseline height standard deviation score (HSDS)≤-2 were assessed over 5 years of GH treatment for mean HSDS, change in HSDS (ΔHSDS), and corrected HSDS (HSDS-target HSDS).

Results: Mean HSDS and corrected HSDS significantly increased to close to target height across all diagnostic groups after 5 years of GH treatment (P<0.0001). ∆HSDS at year 5 increased for all groups (IGHD: 1.8; MPHD: 2.1; SGA: 1.8; ISS: 1.6). Among patients who continued GH for 5 years, mean insulin-like growth factor-I (IGF-I) SDS increased to within normal range across all groups. Body mass index (BMI) SDS remained relatively stable in all diagnostic groups. Bone age (BA) increased, and the mean BA to chronological age (BA/CA) ratio reached or approached 1 across diagnostic groups over 5 years of GH treatment.

Conclusions: Long-term GH therapy resulted in a significant increase in mean HSDS and corrected HSDS from baseline values in all diagnostic groups. The observed increase in mean corrected HSDS is consistent with growth that approached the patients' genetic height potential, although complete height gains will be evaluated at the attainment of final height.
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http://dx.doi.org/10.1016/j.ghir.2015.08.006DOI Listing
December 2015

Noonan syndrome and Turner syndrome patients respond similarly to 4 years' growth-hormone therapy: longitudinal analysis of growth-hormone-naïve patients enrolled in the NordiNet® International Outcome Study and the ANSWER Program.

Int J Pediatr Endocrinol 2015 8;2015(1):17. Epub 2015 Sep 8.

Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.

Background: Turner syndrome (TS) and Noonan syndrome (NS) are distinct syndromes associated with short stature and other similar phenotypic features. We compared the responses to growth hormone (GH) therapy of TS and NS patients enrolled in the NordiNet® International Outcome Study (IOS) or the American Norditropin Studies: Web-Enabled Research (ANSWER) Program, which collect information on GH therapy in clinical practice.

Methods: Repeated-measures regression analysis was performed on change in height standard deviation score (HSDS) and target-height-corrected HSDS, based on national normal references and treatment-naïve disease-specific references. Models were adjusted for baseline age and HSDS, and average GH dose. The study population was paediatric patients with TS and NS in the NordiNet® IOS and ANSWER Program. Longitudinal growth responses over 4 years were evaluated.

Results: In 30 NS patients (24 males; baseline age 8.39 ± 3.45 years) and 294 TS patients (7.81 ± 3.22 years), 4-year adjusted ΔHSDS were +1.14 ± 0.13 and +1.03 ± 0.04, respectively (national references). Based on untreated, disease-specific references, 4-year adjusted ΔHSDS for NS and TS were +1.48 ± 0.10 and +1.79 ± 0.04. The analyses showed a significant increase in HSDS over time for both NS and TS (P < 0.0001). ΔHSDS in NS was higher with younger baseline age; ΔHSDS in TS was higher for patients with younger baseline age and higher GH dose.

Conclusions: NS and TS patients responded well and similarly over 4 years of GH treatment.
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http://dx.doi.org/10.1186/s13633-015-0015-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562101PMC
September 2015

Severe Salt-Losing 3β-Hydroxysteroid Dehydrogenase Deficiency: Treatment and Outcomes of HSD3B2 c.35G>A Homozygotes.

J Clin Endocrinol Metab 2015 Aug 16;100(8):E1105-15. Epub 2015 Jun 16.

Clinic for Special Children (A.R.B., M.Y., D.R., C.H., K.A.S.), Strasburg, Pennsylvania 17579; Department of Pediatric Endocrinology (P.A.L.), Pennsylvania State University Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033; Franklin and Marshall College (K.A.S.), Lancaster, Pennsylvania 17603; and Lancaster General Hospital (K.A.S.), Lancaster, Pennsylvania 17602.

Context: 3-β-hydroxysteroid dehydrogenase (HSD3B2) deficiency accounts for less than 5% of congenital adrenal hyperplasia worldwide, but is relatively common among the Old Order Amish of North America due to a HSD3B2 c.35G>A founder mutation.

Objective: We review clinical presentation, disease course, treatment, and outcomes of a genetically homogenous population of HSD3B2-deficient patients.

Design And Participants: This was a retrospective case series: anthropometric, biochemical, and clinical data from 16 (six male) affected subjects (age, 7.2 ± 6.4 y) were compared to reference data from 12 age-matched unaffected siblings.

Setting: The setting was the Clinic for Special Children, a nonprofit rural community health center in Lancaster, Pennsylvania.

Main Outcome Measures: The main outcome measures were growth, skeletal maturation, sexual development, blood pressure, glucocorticoid dose, pituitary-adrenal homeostasis, and long-term morbidity.

Results: Exogenous glucocorticoid requirement was dichotomous: a standard-dose group (n = 9) required 15.4 ± 4.9 mg/m(2)/d hydrocortisone equivalent, whereas a high-dose group required much larger and more variable doses (hydrocortisone equivalent, 37.8 ± 15.4 mg/m(2)/d) (P < .0001). Despite glucocorticoid doses 2-fold higher than the standard-dose group, high-dose patients: 1) had ACTH, 17-hydroxypregnenolone, and dehydroepiandrosterone levels that were 10-fold, 20-fold, and 20-fold higher, respectively; 2) were exclusively affected by signs of sex steroid excess; and 3) tended to have more iatrogenic complications.

Conclusions: Patients with HSD3B2 deficiency and 21-hydroxylase deficiency suffer similar morbid complications from under- and overtreatment, but HSD3B2 deficiency is associated with a distinctive pattern of sex steroid dysmetabolism. Disease- and treatment-related morbidities are almost exclusively observed among subjects who have a high exogenous glucocorticoid requirement.
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http://dx.doi.org/10.1210/jc.2015-2098DOI Listing
August 2015

Increased height standard deviation scores in response to growth hormone therapy to near-adult height in older children with delayed skeletal maturation: results from the ANSWER Program.

Int J Pediatr Endocrinol 2015 15;2015(1). Epub 2015 Jan 15.

Department of Clinical Development, Medical and Regulatory Affairs, Novo Nordisk, Inc., 800 Scudders Mill Road, Plainsboro, NJ 08536 USA.

Background: A primary goal of recombinant human growth hormone therapy (GHT) in children is attaining normal adult height. In this study, children with growth hormone deficiency (GHD) (including isolated idiopathic growth hormone deficiency [IGHD] and multiple pituitary hormone deficiency [MPHD]), idiopathic short stature (ISS), and Turner syndrome (TS) were evaluated for near-adult height (NAH) and percent achieving NAH within the normal range after approximately 4 years of GHT.

Methods: Data from the American Norditropin®

Studies: Web-Enabled Research (ANSWER) Program were analyzed for NAH from age at treatment start (ATS) (i.e., referral age as defined by age at enrollment in the study) to last clinic visit using one of the following two criteria: 1) age ≥18 years, or 2) if male: ≥16 years and height velocity (HV) <2 cm/year; if female: ≥15 years and HV <2 cm/year. All patients had a baseline height standard deviation score (HSDS) ≤ -2, and either GHD (n = 201), ISS (n = 19), or TS (n = 41). The main outcome measures included HSDS and corrected HSDS (HSDS-target HSDS) in response to GH treatment, and correlation of ATS with NAH HSDS.

Results: Mean (± SD) chronological and bone ages at baseline were 14.0 ± 2.1 years and 11.7 ± 2.0 years, respectively, and mean GHT duration was 4.0 ± 1.6 years. Mean HSDS (baseline to NAH; GHD: -2.7 to -1.0; ISS: -2.8 to -1.4; TS: -3.0 to -1.8) and mean corrected HSDS (baseline to NAH; GHD: -2.1 to -0.3; ISS: -2.1 to -0.6; TS: -1.8 to -0.6) increased across diagnostic indications. Percentages of patients reaching near-adult HSDS > -2 were GHD: 87.6%; ISS: 78.9%; TS: 65.8%. Significant negative correlations were found between ATS and NAH HSDS when analyzed by sex.

Conclusions: Despite a relatively advanced childhood age, the majority of GH-treated patients attained mean near-adult HSDS within the normal range (HSDS > -2). Negative correlations of ATS with near-adult HSDS indicate that an earlier age at treatment start would likely have resulted in greater adult height achieved in both male and female patients.
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http://dx.doi.org/10.1186/1687-9856-2015-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405836PMC
April 2015

The Diagnosis of Polycystic Ovary Syndrome during Adolescence.

Horm Res Paediatr 2015 Apr 1. Epub 2015 Apr 1.

Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pa., USA.

Background/aims: The diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescence are controversial, primarily because the diagnostic pathological features used in adult women may be normal pubertal physiological events. Hence, international pediatric and adolescent specialty societies have defined criteria that have sufficient evidence to be used for the diagnosis of PCOS in adolescents.

Methods: The literature has been reviewed and evidence graded to address a series of questions regarding the diagnosis of PCOS during adolescence including the following: clinical and biochemical evidence of hyperandrogenism, criteria for oligo-anovulation and polycystic ovary morphology, diagnostic criteria to exclude other causes of hyperandrogenism and amenorrhea, role of insulin resistance, and intervention.

Results And Conclusion: Features of PCOS overlap normal pubertal development. Hence, caution should be taken before diagnosing PCOS without longitudinal evaluation. However, treatment may be indicated even in the absence of a definitive diagnosis. While obesity, insulin resistance, and hyperinsulinemia are common findings in adolescents with hyperandrogenism, these features should not be used to diagnose PCOS among adolescent girls. © 2015 S. Karger AG, Basel.
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http://dx.doi.org/10.1159/000375530DOI Listing
April 2015

In utero exposure to cigarette smoking, environmental tobacco smoke and reproductive hormones in US girls approaching puberty.

Horm Res Paediatr 2015 24;83(1):36-44. Epub 2015 Jan 24.

Public Health Program, College of Arts and Sciences, Shenandoah University, Winchester, Va., USA.

Background/aims: Evidence is unclear whether prenatal smoking affects age at menarche and pubertal development, and its impact upon hormones has not been well studied. We aim to identify potential pathways through which prenatal smoking and environmental tobacco smoke (ETS) affect reproductive hormones in girls approaching puberty.

Methods: We examined the association between prenatal smoking, current ETS and luteinizing hormone (LH) and inhibin B (InB) in 6- to 11-year-old girls in the 3rd National Health and Nutrition Examination Survey, 1988-1994. Parents/guardians completed interviewer-assisted questionnaires on health and demographics at the time of physical examination. Residual blood samples were analyzed for reproductive hormones in 2008.

Results: Of 660 girls, 19 and 39% were exposed to prenatal smoke and current ETS, respectively. Accounting for multiple pathways in structural equation models, prenatally exposed girls had significantly lower LH (β = -0.205 log-mIU/ml, p < 0.0001) and InB (β = -0.162, log-pg/ml, p < 0.0001). Prenatal smoking also influenced LH positively and InB negatively indirectly through BMI-for-age. ETS was positively associated with LH, but not with InB.

Conclusion: Exposure to maternal smoking may disrupt reproductive development manifesting in altered hormone levels near puberty.
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http://dx.doi.org/10.1159/000369168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348220PMC
December 2015

Age at hormonal onset of puberty based on luteinizing hormone, inhibin B, and body composition in preadolescent U.S. girls.

Pediatr Res 2014 Dec 5;76(6):564-70. Epub 2014 Sep 5.

Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota.

Background: Hormonal indicators could be useful for detecting early pubertal onset, but there is little research on how they are related to puberty in U.S. girls. We determined median age at hormonal onset of puberty based on luteinizing hormone (LH) and inhibin B (InB) and explored the extent to which body composition moderates this timing process.

Methods: We analyzed anthropometric and hormone data of 698 US peri-pubertal girls ages 6-11.99 y who had participated in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994.

Results: Median age of hormonal onset of puberty was 10.43 y by LH and 10.08 y by InB cut-offs (1.04 mIU/ml for LH and 17.89 pg/ml for InB). Postnatal weight gain modulated onset, making it earlier by 10-11 mo among the highest (greater than +1 SD) relative to normal weight gainers. Onset occurred first in non-Hispanic black (NHB) girls, 10.08 y (95% confidence interval (CI): 10.07-10.09), followed by Mexican-American (MXAM) at 10.64 y (95% CI: 10.63-10.65), and at 10.66 y (95% CI: 10.66-10.67) for non-Hispanic white (NHW) girls using LH. With InB, onset occurred first in MXAM girls at 9.9 y, and at 10.3 y and 10.4 y for their NHB and NHW peers, respectively.

Conclusion: Preadolescent weight gain lowers the age at hormonal onset as defined by LH concentrations. Preventing obesity in childhood may also avert the earlier initiation of the maturation process even at the hormonal level.
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http://dx.doi.org/10.1038/pr.2014.131DOI Listing
December 2014

Lawson Wilkins: portrait of a pioneer.

Int J Pediatr Endocrinol 2014 ;2014(Suppl 1):I1

Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.

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http://dx.doi.org/10.1186/1687-9856-2014-S1-I1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080265PMC
May 2015

36-month treatment experience of two doses of leuprolide acetate 3-month depot for children with central precocious puberty.

J Clin Endocrinol Metab 2014 Sep 13;99(9):3153-9. Epub 2014 Jun 13.

Penn State School of Medicine (P.A.L.), Hershey, Pennsylvania 17033; Indiana University School of Medicine (P.A.L.), Indianapolis, Indiana 46202; University of California San Diego (K.K.), San Diego, California 92093; Nemours Children's Clinic (N.M.), Jacksonville, Florida 32207; and AbbVie (T.L.-V., P.B.), North Chicago, Illinois 60064.

Context: We have recently demonstrated short-term (6-month) efficacy and safety of leuprolide acetate 3-month depot 11.25 and 30 mg in children with central precocious puberty (CPP).

Objective: To assess long-term (36-month) hypothalamic-pituitary-gonadal axis suppression and safety of leuprolide acetate 3-month depot 11.25 and 30 mg in children with CPP.

Design: Open-label, 36-month extension.

Setting: Twenty pediatric endocrine centers.

Patients: Seventy-two children (mean age, 8.5 ± 1.6 y; 65 females) with CPP completed and showed maintenance of LH suppression after a 6-month lead-in study.

Intervention: Leuprolide acetate depot (11.25 or 30 mg) administered im every 3 months.

Main Outcome Measures: Peak-stimulated LH, estradiol, T, growth rate, pubertal progression, and adverse events (AEs).

Results: Twenty-nine of 34 subjects in the 11.25-mg group and 36 of 38 subjects in the 30-mg group had LH values < 4 mIU/mL after day 1 at all time points. All seven subjects who escaped LH suppression at any time still maintained sex steroid concentrations at prepubertal levels and showed no signs of pubertal progression. AEs were comparable between groups, with injection site pain being the most common (26.4% overall). No AE led to discontinuation of study drug. The safety profile over 36 months was comparable to that observed during the 6-month pivotal study.

Conclusions: The two doses of leuprolide acetate 3-month depot were associated with an acceptable safety profile and provided maintenance of LH suppression in the majority of children with CPP during the 36 months of the study or until readiness for puberty.
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http://dx.doi.org/10.1210/jc.2013-4471DOI Listing
September 2014

Evaluation and treatment of cryptorchidism: AUA guideline.

J Urol 2014 Aug 20;192(2):337-45. Epub 2014 May 20.

American Urological Assocation Education and Research, Inc., Linthicum, Maryland.

Purpose: Cryptorchidism is one of the most common pediatric disorders of the male endocrine glands and the most common genital disorder identified at birth. This guideline is intended to provide physicians and non-physician providers (primary care and specialists) with a consensus of principles and treatment plans for the management of cryptorchidism (typically isolated non-syndromic).

Materials And Methods: A systematic review and meta-analysis of the published literature was conducted using controlled vocabulary supplemented with key words relating to the relevant concepts of cryptorchidism. The search strategy was developed and executed by reference librarians and methodologists to create an evidence report limited to English-language, published peer-reviewed literature. This review yielded 704 articles published from 1980 through 2013 that were used to form a majority of the guideline statements. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence-based data.

Results: Guideline statements were created to inform clinicians on the proper methods of history-taking, physical exam, and evaluation of the boy with cryptorchidism, as well as the various hormonal and surgical treatment options.

Conclusions: Imaging for cryptorchidism is not recommended prior to referral, which should occur by 6 months of age. Orchidopexy (orchiopexy is the preferred term) is the most successful therapy to relocate the testis into the scrotum, while hormonal therapy is not recommended. Successful scrotal repositioning of the testis may reduce but does not prevent the potential long-term issues of infertility and testis cancer. Appropriate counseling and follow-up of the patient is essential.
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http://dx.doi.org/10.1016/j.juro.2014.05.005DOI Listing
August 2014

Varicocele: a dilemma in adolescent males.

Pediatr Endocrinol Rev 2014 Feb;11 Suppl 2:274-83

Varicoceles are the most common cause of infertility in men. Despite the high prevalence of varicoceles, only a small percentage of men with varicoceles have subfertility or infertility. In adolescents, the prevalence of varicoceles increases dramatically during puberty to reach adult prevalence rates. The development of varicoceles during puberty can impair testicular growth and function. Data on hormonal and semen parameters in adolescents with varicoceles are limited, making it harder to determine which varicoceles are associated with infertility and which may benefit from surgery. The main indications for varicocelectomy in adolescents with varicoceles include a volume differential between unaffected and affected testes or abnormality in semen analysis.
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February 2014

Treatment of hypogonadism in males.

Pediatr Endocrinol Rev 2014 Feb;11 Suppl 2:230-9

The treatment of adolescent males with hypogonadism using testosterone is dependent on the underlying diagnosis as well as the patient's and family's preferences. Those with testicular failure, always a pathologic condition, begin lifelong therapy, while short-term therapy is often begun for those who have a delayed puberty. There is a wide variety of testosterone formulations available, with differences in adverse events sometimes associated with the method of administration. The goals of treatment involve stimulating physical puberty, including achievement of virilization, a normal muscle mass and bone mineral density for age, and improvement in psychosocial wellbeing. While androgen therapy results in physical changes of puberty, the potential for fertility must be considered for those with permanent gonadotropin deficiency. in this population, therapy with gonadotropins or gonadotropin releasing hormone may be effective. For those with testicular failure, fertility may be possible but requires assisted reproductive procedures.
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February 2014