Allen W. Root

Hormonal changes in puberty.

The earliest biochemical event of puberty is the appearance of intermittent serum peaks of luteinizing hormone (LH) and follicle stimulating hormone (FSH) at night, caused by a pulsatile secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus. The pituitary GnRH receptors are responsive only to pulsatile GnRH: continuous administration blocks the secretion of gonadotropins. The intermittent production of LH and FSH stimulates the gonads, leading to sex hormone secretion and the development of the germinal epithelium. Initially the sex hormone levels are raised for only part of the day. In the male the enlargement of the testes from a prepubertal 3-mL volume to 4 mL heralds the onset of puberty as the Sertoli cell volume increases. It is possible to have functioning Leydig cells and testosterone secretion in damaged testes, for instance in the Klinefelter syndrome after irradiation, without a volume increase. Testicular testosterone (via target cell conversion to dihydrotestosterone; see Ch. 8) produces pubic hair and penile growth, and is slightly augmented by androgen secretion from the adrenal gland. Acne, mood swings, the breaking of the voice, attainment of an adult body odor and sweat pattern are all androgen-mediated events. In the female the first external sign of puberty is an enlargement of the breast bud as estrogen is produced from the ovary. Some of the androgen-mediated effects seen in a girl, including pubic and axillary hair growth, are secondary to increased androgen secretion from a maturational change in the adrenal gland – adrenarche. Adrenarche is a separate event from puberty, with different regulation, and occurs in both sexes. Its androgenic features are usually subsumed in the male by testicular androgen production. In the female, along with some ovarian-derived androgens, adrenarche forms an important component of normal sexual development. Leptin produced by white fat also acts as a peripheral signal to start hypothalamic activation of gonadotroph secretion once a certain fat mass has been attained (see Ch. 5). Cyclic LH and FSH production leads to ovarian enlargement, follicle production and ultimately to maturation of the uterus and endometrium, followed by menarche. These changes can be monitored by ultrasonography (Figs 6.1–6.7). Peripheral aromatase conversion of testosterone to estrogen, especially by fatty tissue, is possible, and is

Disorders of aldosterone synthesis, secretion, and cellular function.

Purpose of review The purpose of this review is to describe the renin–angiotensin–aldosterone system and its regulatory control of sodium, potassium, chloride, hydrogen ion, and water homeostasis through its effects on the expression and activity of distal renal tubular cotransporter proteins and to discuss the gene mutations encoding these structures that disturb the function of this system. Recent findings Primary hypoaldosteronism may be the result of acquired or congenital errors in renal juxtaglomerular function (the source of renin), angiotensin generation or activity, or aldosterone synthesis. Secondary hypoaldosteronism (pseudohypoaldosteronism) occurs as a consequence of mutations in genes encoding the mineralocorticoid receptor (MR), the three subunits of the aldosterone-responsive, amiloride-sensitive nonvoltage-gated sodium channel encoded by SCNN1A, SCNN1B, and SCNN1G, the gene that regulates posttranslational phosphorylation (encoded by WNK4) of the thiazide-sensitive sodium chloride cotransporter encoded by SLC12A3, and those that regulate phosphorylation and ubiquitination of cofactors encoded by WNK1, KLH3, and CUL3 that affect WNK4 function. Summary Acquired disorders of renal function as well as mutations in many genes may adversely affect aldosterone-mediated mineral homeostasis.

Gender related differences in glucocorticoid therapy and growth outcomes among pubertal children with 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH).

Abstract Twenty-one-hydroxylase deficient congenital adrenal hyperplasia (CAH) causes glucocorticoid and mineralocorticoid deficiency, hyperandrogenism and short stature. Management of the pubertal CAH patient is particularly challenging. The purpose of this retrospective chart review study was to determine if pubertal males and females with simple virilizing CAH (SVCAH) required different glucocorticoid dosages at progressive Tanner stages. The relationship between hydrocortisone dose and height was also assessed. Twenty females and seventeen males with SVCAH were identified and followed throughout all stages of pubertal development. Males received an average hydrocortisone dose of 16.4±4.8 mg/m2/day and for females, 13.7±4.6 mg/m2/day. The glucocorticoid dosage in males was significantly higher than in females at Tanner stages 3 through 5. Higher doses were associated with a shorter (9.6 cm) achieved than anticipated adult height.

Regulation of energy balance.

Abundant data document the extraordinary increase over the past two decades in numbers of overweight children (and adults) in the United States due both to increase in caloric intake and decrease in energy expenditure [1]. The hazards to health that obesity foster are indeed costly both to the obese individual and to society. Among the consequences of obesity are insulin resistance, type 2 diabetes mellitus, hypertension, dyslipidemia, atherosclerosis, and other characteristics of the “dysmetabolic syndrome.” Conversely, eating disorders such as anorexia nervosa are also extremely common in children and adolescents. In this Commentary, selected factors that regulate energy balance are discussed.

Endocrinology and metabolism 2014.

All Childrens Hospital/Johns Hopkins Medicine, St Petersburg, Florida Correspondence to Allen W. Root, MD, Division of Endocrinology & Diabetes, All Childrens Hospital/Johns Hopkins Medicine, 501 Sixth Avenue South, St Petersburg, FL 33701, USA. e-mail: roota@allkids. org Curr Opin Pediatr 2014, 26:472–474 DOI:10.1097/MOP.0000000000000115 In the August 2014 Endocrine and Metabolism section of Current Opinion in Pediatrics, Drs Nambam, Winter, and Schatz examine the autoimmune polyglandular syndromes, describing those associated with deleterious mutations in AIRE (autoimmune polyglandular syndrome type 1) and FOXP3 (X-linked immunodysregulations, polyendocrinopathy, and enteropathy) and those related to abnormalities of IgG4. Drs Marini, Smith, and Reich discuss the variants of genes required for mineral and bone homeostasis that lead to forms of osteogenesis imperfecta. Drs Levitsky, Ardestani, and Rhoads review the role of betatrophin, a recently identified product of liver and fat cells that stimulates pancreatic b-cell proliferation, and considers the possible impact of this or a related protein(s) in the management of patients with insulin deficiency in humans. Drs Patwari and Wolfe discuss the syndrome of ‘Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD)’, a disorder characterized in addition bymultiple pituitary hormone deficiencies including those of growth, luteinizing, follicle-stimulating, and thyroid-stimulating hormones. Finally, the editor reviews the regulation of aldosterone synthesis and its functional effects on sodium, potassium, chloride, and water homeostasis while discussing gene mutations that result in decreased aldosterone synthesis (hypoaldosteronism) and those related to abnormalities in the cellular components (mineralocorticoid receptor, sodium channel, thiazide-sensitive sodium chloride co-transporter) that mediate the effects of this mineralocorticoid, defects in which lead to pseudohypoaldosteronism. An immmunoglobulin or antibody is a glycoprotein that recognizes another structure or antigen as ‘foreign’ to the human body. Antibodies bind to and enhance removal and destruction of antigens. There are five antibody classes, IgA, IgD, IgE, IgM, and IgG, whose designation depends on location and function (e.g., IgA is found in the intestinal and urinary tracts and in respiratory mucosa; IgG accounts for the bulk of circulating antibodies).

Endocrinology and metabolism 2011.

In the 2011 Endocrine and Metabolic Section are discussions concerning pituitary–thyroid function in obese children and adolescents by Professor Thomas Reinehr (pp. 415–420); the genetic errors that lead to the biochemical defects in thyroxine biosynthesis that are of pathophysiologic significance in congenital primary hypothyroidism due to dyshormonogenesis by Drs Helmut Grasberger and Samuel Refetoff (pp. 421–428); the functional role of selenium and its importance in normal thyroid homeostasis by Drs Ulrich Schweitzer, Nora Dehina, and Lutz Schomburg; the long-term status of adult women with 21-hydroxylase deficient congenital adrenal hyperplasia (CAH) by Dr Anna Nordenström; the complex clinical manifestations of patients with Noonan syndrome and related disorders and their corresponding genetic aberrations by Dr Martin Zenker; and the natriuretic hormones, their cell membrane receptors, and their clinical usefulness by Dr Anne Lenz (pp. 452–459).

Endocrinology and metabolism.

The 2008 Endocrine and Metabolic Section contains discussions concerning hyponatremia in the child who has sustained an insult to the central nervous system, the roles of 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1) and hexose 6-phosphate dehydrogenase (H6PD) in the genesis of insulin resistance and type 2 diabetes mellitus, genes that regulate the onset of pubertal development in humans, gynecomastia in the prepubertal and adolescent boy, and abnormalities of mitochondrial function. Dr Rivkees (pp. 448–452) rationally dissects the pathophysiology of hyponatremia that may occur in children with traumatic, surgical, or infectious insults to the central nervous system. He distinguishes between hyponatremia associated with appropriate secretion of antidiuretic hormone (ADH) that develops when the patient is volume depleted and that in response to inappropriate secretion of ADH, which occurs despite normovolemia or hypervolemia, designated by Dr Rivkees as the Syndrome of Appropriate ADH Secretion (SAADH) and the Syndrome of Inappropriate ADH Secretion (SIADH), respectively. Dr Rivkees also critically analyzes the entity entitled the ‘cerebral salt-wasting syndrome’ and concludes that only very rarely hyponatremia may be attributed to a brain-derived ‘hyponatremic factor’.