Pediatric endocrinology is a fascinating branch of pediatrics that allows physiology-based logical deduction of etiology, presentation, workup, and management. Unfortunately lack of understanding of nuances of endocrine physiology complicates its understanding. This has resulted in incorrect labeling of pediatric endocrinology as an exotic specialty dealing with rare disorders requiring expensive workup and exorbitant treatment. Physiology-based understanding of pediatric endocrinology provides the framework of targeted evaluation and management.
WHAT IS A HORMONE?
Hormones are substances that act on organs distant from their source of production. They are secreted by endocrine (ductless) glands directly into the blood stream as against the products of exocrine glands that are secreted in the ducts. In this perspective, endocrine effect should be differentiated from paracrine (effect around the area of secretion) and autocrine effects (on the secretory cell). This differentiation is however semantic as a given substance can act in an endocrine, paracrine, and autocrine fashion at the same time. Thus, testosterone can act on facial skin (endocrine effect), Wolffian structure (paracrine effect), and on its producer Leydig cells (autocrine effect). The concept of hormone has now been expanded to include nonconventional substances, such as glucagon-like peptide 1 (GLP1) that is produced by the intestine and increases beta cell insulin secretion. Similarly, chemicals, such as leptin, C terminal natriuretic peptide, and ghrelin that act distant from their source of production, qualify to be classified as hormones.
WHAT IS AN ENDOCRINE ORGAN?
An endocrine organ comprises a group of hormone-producing cells. Conventionally, the term endocrine gland has been reserved to classical glands, such as pituitary, adrenal, thyroid, pancreas, gonads, and parathyroid glands. The concept of endocrine organs has also evolved with increasing understanding. Thus, duodenum that produces GLP1 in response to ingestion of food causing insulin release from pancreas represents an endocrine organ. Using this concept, it is easy to conceptualize previously inert organs, such as adipose tissue (leptin), stomach (ghrelin), bone (osteocalcin), skin (vitamin D), and kidney (renin) as endocrine organs.
WHAT ARE THE ROLE OF HORMONES?
Hormones affect every phase of life. They are key regulators of growth and pubertal development, reproduction, fluid, salt, glucose, and calcium homeostasis. Importantly they link metabolism with nutritional and environmental status. Hormone systems act in concert to achieve the homeostasis.
WHAT MAKES PEDIATRIC ENDOCRINOLOGY UNIQUE?
The complexities of hormone physiology are accentuated by dramatic changes in children and adolescents. This has significant implications on pathophysiology, assessment, and treatment. Physiological variations for an age become pathological for the other. Thus, luteinizing hormone (LH) level of 0.1 mU/L is low for an infant, normal for a child, and low for a 15-year-old boy. Understanding of interplay between physiology and pathology is essential.4
HOW HAS EVOLUTION PROGRAMMED THE ENDOCRINE SYSTEM?
Evolution has a major role in guiding the metabolic pathway and hormone action. During most of evolution, humans have faced scarcity of food, warmth, water, salt, and calcium. The endocrine system has evolved to conserve these with limiting regulation of overexposure (Fig. 1.1). Thus, while there are four hormones to increase glucose [growth hormone (GH), epinephrine, glucagon, and cortisol], only one hormone counters hyperglycemia (insulin). Same is true for sodium [major role of sodium conserving renin–angiotensin–aldosterone system (RAAS) and minor role of salt losing atrial natriuretic peptide (ANP)], calcium [predominant role of hypercalcemic parathyroid hormone (PTH) and calcitriol and minor role of hypocalcemic calcitonin], and fluid [key role of fluid-conserving arginine vasopressin (AVP) and minor role of fluid losing ANP]. Unfortunately, all the gains of biological evolution over thousands of years have been overridden by rapid industrial evolution that has turned the tables from deficiency to excess. When faced with excess water, salt, glucose, and calcium, humans are predisposed to develop hypertension, diabetes, and hypercalcemia due to weak defense mechanisms. This forms the basis of most modern noncommunicable diseases.
HOW DO HORMONES INTERACT WITH EACH OTHER?
Synergy and antagonism of hormones is essential for homeostasis. Hormones demonstrate pleiotropy (one hormone acting on multiple systems) and redundancy (many hormones with same action). They also interact with each other to stimulate or inhibit actions. This is exemplified by the combined effect of GH, thyroxine (T4), and estrogen on growth plate. Sodium and fluid homeostasis is maintained by collective actions of vasopressin, aldosterone, and ANP. PTH and calcitriol act in concert to increase calcium levels by increasing intestinal absorption, renal reabsorption, and skeletal resorption. This redundancy prevents development of deficiency with isolated defect in one hormone system. Moreover, same process is regulated by different hormone systems over age-groups. Thus, linear growth is controlled by insulin-like growth factor (IGF)1 in the fetal period, T4 in infancy, GH in childhood, and sex steroids in puberty. This forms the basis of age-specific differences in etiology of growth failure. Hypothalamic–pituitary axis controls most endocrine glands. Hypothalamic hormones control secretion of their counterpart pituitary hormones [thyrotropin-releasing hormone (TRH)–thyroid-stimulating hormone (TSH), corticotropin-releasing hormone (CRH)–adrenocorticotropic hormone (ACTH), gonadotropin-releasing hormone (GnRH)–LH/follicle-stimulating hormone (FSH), GH-releasing hormone (GHRH)–GH, and Dopamine–Prolactin].
Fig. 1.1: Evolutionary basis of modern diseases. Evolutionary trends have resulted in better adaptive mechanisms for deficiency of glucose, sodium, calcium, and fluid than excess. Excess intake of water, salt, glucose, and calcium predisposes to develop hypertension, diabetes, and hypercalcemia.Source: Bajpai A, Dave C. Hormone physiology. In: Basics of endocrinology. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(GH: growth hormone; EPI: epinephrine; PTH: parathyroid hormone; ANP: atrial natriuretic peptide)
There is however significant cross talks with major clinical implications (Fig. 1.2). TRH increases prolactin causing hyperprolactinemia in untreated primary hypothyroidism. Prolactin inhibits gonadotropin production causing hypogonadism. Regulation of fluid and osmolality status by AVP, RAAS system, and natriuretic peptide is an example of hormone cross talk. Hypovolemia and hyperosmolality triggers AVP and RAAS axis while inhibiting ANP production causing sodium and fluid retention. In hypervolemic states, ANP inhibits both AVP and aldosterone production increasing volume and sodium loss.
HOW IS HORMONE ACTION MEDIATED?
Hormone action is a concerted process involving development of the endocrine gland, synthesis of hormones, their release, transport, activation, action on receptor, formation of second messenger, inactivation, and feedback regulation (Fig. 1.3). These processes are tightly regulated to ensure homeostasis. Abnormality in any of these processes results in pathology.
Development of an Endocrine Gland
Endocrine embryology provides insight into pathophysiology and assessment. Most endocrine glands are of dual origin with a neural and mesodermal component. This results in differential effect and regulation of pituitary (anterior and posterior), adrenal (cortex and medulla), and thyroid (follicular and parafollicular) glands. Thus, while anterior pituitary is regulated by the hypothalamic–hypophyseal portal system sensitive to radiotherapy, posterior pituitary is radioresistant as it represents extension of neurons from hypothalamus. Adrenal cortex produces steroid hormones, while medulla synthesizes catecholamines. Thyroid gland is unique in the sense that C cells develop from downward extension of pharyngeal pouches but get evenly distributed in whole thyroid gland. Gonadal development involves combination of steroidogenic cells from the urogenital ridge and germ cells from the hind gut. Neuronal migration plays an important role in the development of GnRH neurons that migrate from the olfactory placode. Defective migration of these neurons results in the development of Kallmann syndrome associated with anosmia and hypogonadotropic hypogonadism. Defective migration of embryonic cells results in localization of cells in ectopic areas producing adrenal rest tumors in uncontrolled congenital adrenal hyperplasia (CAH) and germ cell tumor (brain, mediastinum, and liver).
Fig. 1.2: Hypothalamic pituitary cross talk. Hypothalamic hormones control secretion of their counterpart pituitary hormones (TRH–TSH, CRH–ACTH, GnRH–LH/FSH, GHRH–GH, and Dopamine–Prolactin). A number of cross talks are operative besides the direct regulatory and feedback effects. TRH increases prolactin which in turn inhibits gonadotropin production. Cortisol inhibits GH, TSH, and AVP release, while AVP increases cortisol production by stimulating CRH release.Source: Adapted with permission from Bajpai A, Dave C. Hormone physiology. In: Basics of endocrinology; 2018. MedEClasses. <https://learning.growsociety.in> [accessed 25 October 2018].
(ACTH: adrenocorticotropic hormone; AVP: arginine vasopressin; CRH: corticotropin-releasing hormone; FSH: follicle-stimulating hormone; GH: growth hormone; GHRH: growth hormone–releasing hormone; GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone; TRH: thyrotropin-releasing hormone; TSH: thyroid-stimulating hormone; IGF1: insulin-like growth factor 1).
Fig. 1.3: GHRH–GH–IGF1 axis. GH secretion is regulated by stimulatory effects of GHRH and inhibitory effects of somatostatin. Environmental factors (adiposity) and other hormones (thyroxine, estradiol, and insulin) also regulated GH production. GH transports in the blood bound to GH-binding protein and acts on GH receptor at liver to produce IGF1. IGF1 is bound to IGF-binding protein and acts on Type 1 IGF receptor to induce chondrocyte growth.Source: Bajpai A, Agarwal N. Growth physiology & assessment physiology. In: Growth disorders. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(GH: growth hormone; GHRH: growth hormone–releasing hormone; IGF1: insulin-like growth factor 1; GHBP: growth hormone binding protein; IGFBP: insulin growth factor binding protein)
Codevelopment of organs with endocrine glands explains the multisystem involvement of embryological disorders, such as DiGeorge syndrome, where defective III and IV branchial arch development results in hypoparathyroidism, cardiac defect, and thymic defects (Table 1.1).
Hormone Synthesis
Hormone synthesis is an intricate process involving multiple steps. Low molecular weight hormones (epinephrine, cortisol, and aldosterone) are synthesized rapidly in response to signal and not stored as a precursor. Large peptide hormones (GH, PTH, prolactin, insulin, and glucagon) on the other hand require multiple steps for synthesis and are stored in secretory granules (Fig. 1.4).
Their blood levels are regulated at the level of release. Compounds produced during hormone cleavage may play an important role. Neurophysin II, a byproduct of AVP synthesis, for example is critical for folding of AVP molecule, and its deficiency causes autosomal dominant central diabetes insipidus. Substrate deficiency may also result in low hormone levels (adrenocortical deficiency in Smith-Lemli-Opitz syndrome and hypothyroidism in iodine deficiency).
Hormone Structure
Hormone structure has important implications on synthesis, transport, action, and metabolism. From a structural point of view, hormones can be classified as steroids, peptides, and amines (Table 1.2).
Fig. 1.4: The process of insulin synthesis. Insulin is synthesized as large preprohormone. It is cleaved into proinsulin which is stored in secretory granules. After the signal in beta cells, it is cleaved into insulin and C-peptide via proconvertase and released into circulation.Source: Bajpai A, Agarwal N. Diabetes mellitus. In: Glucose disorders. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
Peptide hormones: These are key regulators of growth (GH), adrenal (ACTH), thyroid (TSH), fluid (AVP), gonadal (LH, FSH), calcium (PTH), and glucose (insulin, glucagon) metabolism. Because of hydrophilic nature, they transport freely in the circulation without a transport protein. This results in their short half-life making their direct assessment difficult. This problem can be obviated by pooled sample (LH, FSH, and prolactin), stimulation test (GH), or surrogate markers of hormonal production (C peptide for insulin and copeptin for AVP). Given their lipophobic nature, they do not enter the cells and act on the membrane receptors with immediate onset of action. Peptide hormones are usually metabolized and excreted in the urine.
Steroid hormones: These play an important role in the regulation of pubertal development (sex steroids), glucose (cortisol), calcium (calcitriol), and salt homeostasis (aldosterone). They are smaller than peptide hormones and can be produced rapidly. Lipophilic nature makes their storage difficult as they readily cross the cell membrane. They need to be bound to transport proteins to travel to different parts of the body. Steroid hormones cross the plasma membrane and act on intracellular receptor. This results in a lag period in their action. Local activation [testosterone to estradiol by aromatase, testosterone to dihydrotestosterone (DHT) by 5-alpha reductase-2] and inactivation [cortisol to cortisone by 11β-hydroxysteroid dehydrogenase II (11BHSDII)] play an important role in tissue specificity of steroid hormone action. These hormones are metabolized in the liver and excreted in the urine. Urinary metabolite assessment is an integral part of assessment of steroid hormones.
Amine hormones: These hormones are small in size comprising 3–10 amino acids. They are synthesized rapidly and are involved in immediate regulation of blood pressure (epinephrine), thermogenesis (T4), and fluid homeostasis (AVP). They have short half-life and rapid turnover with synthesis at the time of need. Their actions are mediated by cell surface or nuclear receptors.
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Hormone Release
Hormone release provides an important step for regulation of peptide hormones. Insulin release is triggered by the closure of adenosine triphosphate (ATP)–sensitive potassium channel in nutrient replete state [increased ATP to adenosine diphosphate ratio] as indicated by increased glucose, amino acids, and lipid levels (Fig. 1.5). It is further calibrated by nutrient signals from the intestine (incretin) and nervous system (vagus and sympathetic signals). This allows release of insulin even before increase in blood glucose levels and cessation of secretion before the advent of hypoglycemia allowing tight regulation of glucose levels. Same mechanisms are involved in regulation of calcium (PTH) and osmolality (AVP). Excessive release of preformed hormones causes transient hormone excess (syndrome of inappropriate antidiuretic hormone secretion with AVP neuron damage and thyrotoxicosis due to thyroiditis).
Hormone Transport
Hydrophilic peptide hormones are transported in blood stream without binding proteins. GH is however bound to extracellular domain of GH receptor, while IGF1 is bound to IGF-binding protein (IGFBP). Insulin inhibits the synthesis of IGFBP increasing free IGF1 level and growth. This explains increased growth in children with obesity. Steroid hormones are bound to transport protein [cortisol-binding globulin, sex hormone–binding globulin (SHBG), vitamin D–binding globulin]. Besides helping in transport of hormones, these proteins act as reservoirs stabilizing hormonal levels. This makes their direct assessment easier than peptide hormones. Abnormalities in transport proteins however have to be considered while assessing hormone levels. T4 is bound to transport proteins [T4-binding globulin (TBG), albumin, and transthyretin]. Since hormone action depends on free hormone concentration, fluctuations in transport protein do not alter hormone function. They may however cause diagnostic confusion with inappropriate diagnosis of deficiency with low protein levels (TBG, corticosteroid-binding globulin deficiency, nephrotic syndrome, chronic liver disease) or excess with increased levels (pregnancy, estrogen, oral contraceptives, Table 1.3). Free hormone assessment [free T4 (FT4), free testosterone, urinary free cortisol] is indicated in these states. Hormone requirement increases with increase in the level of its binding globulin (T4 and hydrocortisone during pregnancy). Inhibitors of hormone binding cause rapid increase in free hormones (increase in FT4 with intravenous heparin). Altering binding protein level is an important way of modulating hormone action (increased SHBG with estrogen decreases free testosterone levels in polycystic ovary syndrome).
Fig. 1.5: Process of insulin release. Insulin release from the beta cells is stimulated by the closure of ATP-sensitive potassium channels. This is regulated by the nutrients. Glucose is sensed by glucokinase enzyme to increase ATP-to-ADP ratio closing the channel. Other nutrients, such as amino acids and fatty acids, also increase ATP levels causing insulin release. Apart from nutrients, neural system acting via vagus and sympathetic pathway is an important regulator of insulin release. Insulin secretion is also regulated by the endocrine system (somatostatin inhibits release and stimulatory pathways, namely, the incretin, growth hormone, estradiol, and cortisol increase secretion).Source: Adapted with permission from Bajpai A, Agarwal N. Diabetes mellitus. In: Glucose disorders. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(ADP: adenosine diphosphate; ATP: adenosine triphosphate)
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Local Metabolism
Site-specific action of hormones is mediated by local metabolism and receptor distribution. Local metabolism involves activation [estradiol, triiodothyronine (T3), and DHT] and inactivation (cortisol) of hormones. Conversion of T4–T3 by monodeiodinase (MDI) 2 spares the brain from adverse effects of low thyroid levels during fetal period and illness. Aromatase converts testosterone to estradiol for action at the levels of adipocyte, growth plate, testis, bone, and brain in males to allow targeted effects. Importantly, these changes in local hormone concentrations are not picked up on blood levels. Local activation of testosterone to DHT is responsible for specific sites of androgen action. Inactivation of cortisol to cortisone by 11BHSDII protects mineralocorticoid receptor from the action of cortisol. Both aldosterone and cortisol have similar affinity to mineralocorticoid receptor. Cortisol levels are manyfold higher than aldosterone but do not act on mineralocorticoid receptor due to inactivation. 11BHSDII deficiency inhibits inactivation of cortisol, resulting in its action on the mineralocorticoid receptor causing apparent mineralocorticoid excess.
Hormone Action
Hormone action involves binding to receptor and production of second messenger. The site of receptor has a major implication on time course of actions. Peptide hormones cannot cross the cell membrane and act on membrane receptors, while steroid hormones cross the cell membrane and act on intracellular receptors, regulating transcription and protein synthesis. This explains different time course of action for peptide (rapid) and steroid hormones (slow).
Membrane Receptors
Membrane receptors possess extracellular and intracellular domain linked to second messenger system [cyclic adenosine monophosphate (cAMP), inositol triphosphate, calcium-calmodulin system] which trigger subsequent action. The major classes of extracellular receptors include G-protein-coupled, tyrosine kinase, and cytokine receptors (Fig. 1.6).
Fig. 1.6: Types of hormone receptors.
(GPCRs: G protein coupled receptors; TRH: thyrotropin releasing hormone; cAMP: cyclic adenosine monophosphate; AVP: arginine vasopressin; ACTH: adrenocorticotropic hormone; CRH: corticotropin releasing hormone; GHRH: growth hormone releasing hormone; HNF: hepatocyte nuclear factor)
G-protein-coupled receptors: G-protein-coupled receptors are the largest family of receptors utilized by most peptide hormones. They contain an N-terminal extracellular domain, seven transmembrane spanning alpha helices, and the C-terminal intracellular region (Fig. 1.7). Binding of hormone with its receptor promotes association with a heterotrimeric G-protein-stimulating dissociation of guanosine diphosphate from the α-subunit, allowing guanosine triphosphate to bind to the unoccupied site. Activating mutation of GNAS in McCune-Albright syndrome causes activation of GnRH (precocious puberty), ACTH (Cushing syndrome), GH (GH excess), and TSH (thyrotoxicosis) receptors. Inactivating mutation of GNAS gene causes resistance to PTH (pseudohypoparathyroidism), GHRH (growth failure), TSH (subclinical hypothyroidism), and LH (delayed puberty). G-protein-coupled receptors act through the cyclic AMP signal pathway and the phosphatidylinositol signal pathway. Some G-protein-coupled receptors, such as melanocortin-2 receptor (MC2R) for ACTH, utilize accessory proteins for action. Defective MC2R-associated protein results in ACTH-resistant familial glucocorticoid deficiency.
Type 1 cytokine receptors: Certain hormones, such as GH, prolactin, and leptin, mimic cytokine action and act on type 1 cytokine receptor. These receptors require homodimerization for activation (Fig. 1.8). Activated receptors stimulate Janus-associated kinase to phosphorylate tyrosine residues on the cytoplasmic region of the receptors. Signal transducers and activators of transcription (STATs) attaches to the phosphorylated receptor domains. The phosphorylated STATs subsequently dissociate from the receptors and translocate to the nucleus to control the activity of regulatory regions of target deoxyribonucleic acid.
Fig. 1.7: Mechanism of action of G-protein-coupled receptor. Binding of hormone with G-protein-coupled receptor promotes association with a heterotrimeric G-protein-stimulating dissociation of GDP from the α-subunit, allowing GTP to bind to the unoccupied site.Source: Adapted with permission from Bajpai A, Dave C. Hormone physiology. In: Basics of endocrinology. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(GDP: Guanosine diphosphate; GTP: Guanosine triphosphate)
Tyrosine kinase receptors: These receptors are connected to tyrosine kinase. Binding of the hormone to the receptor transfers phosphate from ATP to tyrosine residues of the receptor stimulating second messengers (Fig. 1.9). Abnormalities of tyrosine kinase receptors are responsible for Rabson–Mendenhall syndrome (insulin), Kallmann syndrome [fibroblast growth factor (FGF) receptor (FGFR)1], and achondroplasia (FGFR3).
Intracellular Receptors
Steroids, vitamin D, and T4 traverse the cell membrane and act on intracellular receptors. The ligand–receptor complex binds to hormone response element stimulating transcription (Fig. 1.10). Steroids, such as estrogen and glucocorticoids, also act on cell membrane receptors with rapid response. T3 binds to nuclear receptors after transport in the cell by transmembrane transporter monocarboxylate transporter 8 (MCT8). MCT8 deficiency produces severe form of hypothyroidism in the wake of elevated T3, T4, and TSH levels.
Fig. 1.8: Mechanism of action of GH receptor a Type 1 cytokine receptor. GH binding to the receptor induces dimerization of the extracellular domain. This induces phosphorylation of Janus kinase leading to the activation of STAT pathway. This JAK–STAT pathway triggers second messenger systems to produce GH effect.Source: Bajpai A, Dave C. Hormone physiology. In: Basics of endocrinology. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(GH: growth hormone; JAK: Janus kinase; STAT: signal transducer and activator of transcription; MAPK: mitogen activated protein kinase).
Fig. 1.9: Mechanism of action of insulin receptor. Binding of insulin to the receptor transfers phosphate from ATP to tyrosine residues of the receptor stimulating second messengers.Source: Bajpai A, Dave C. Hormone physiology. In: Basics of endocrinology. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(ATP: adenosine triphosphate; MAP: mitogen activated protein).
Receptor Characteristics
Hormone–receptor binding has peculiar characteristic that determines hormone action. This includes binding of one receptor by many hormones (cross-reactivity), binding of one hormone to many receptors (pleiotropism), decrease in number with increased exposure (desensitization), and differential binding to ligands (relative affinity).
Cross-reactivity: Receptors express cross-reactivity to structurally similar hormones, resulting in hormonal overlap. This is most evident for peptide hormones [human chorionic gonadotropin (HCG) and LH; TSH and FSH]. Extremely elevated TSH levels in primary hypothyroidism act on the FSH receptor producing ovarian cysts and peripheral precocious puberty (Van Wyk–Grumbach syndrome). HCG acts on TSH receptor to induce gestational thyrotoxicosis. Partial cross-reactivity explains growth-accelerating effect of insulin acting on Type 1 IGF1 receptor and hypoglycemic effect of IGF1 acting on insulin receptor.
Pleiotropism: Many hormones bind to more than one receptor causing myriad effects. Estradiol binds to estrogen receptor alpha and beta besides the membrane receptor producing organ-specific effects. This allows development of targeted pharmacological agents working on a specific receptor type. Binding of hormones to alternate receptors (cortisol to mineralocorticoid receptor) can have dramatic impact in pathological states (apparent mineralocorticoid excess due to 11BHSDII deficiency).
Desensitization: Receptor density is influenced by ligand levels. Glucocorticoid receptors are diminished in children with long-standing Cushing syndrome. Correction of the disease produces features of cortisol deficiency despite normal cortisol levels due to reduced receptor number. Increased thyroid receptor expression reduces the adverse effects of severe hypothyroidism.
Fig. 1.10: Mechanism of action of thyroid receptor a nuclear receptor. Thyroid hormone crosses cell membrane with the help of MCT8 transporter and attaches to RXR. Thyroid hormone–RXR complex then goes to nucleus and attaches to hormone-binding domain of HRE inducing gene expression and to protein synthesis.Source: Bajpai A, Dave C. Hormone physiology. In: Basics of endocrinology. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(ATP: adenosine triphosphate; HRE: hormone response element; MCT8: monocarboxylate transporter 8; RXR: retinoid-X receptor; FT3: free triiodothyronine; FT4: free thyroxine)
Relative affinity: Differential affinity of ligands to a receptor determines its effect. Both DHT and testosterone bind to the same androgen receptor though the affinity is much higher for DHT. Reduced DHT production due to 5 alpha reductase deficiency presents with XY disorders of sex development (DSD) due to inefficient androgen effect. Increased testosterone production at puberty allows testosterone to act on androgen receptor causing virilization.
Pathophysiology
Abnormalities in receptor action are responsible for a number of endocrine disorders (Table 1.4). Activating disorders present with features of hormone excess in the wake of low levels, while high levels with clinical picture of hormonal deficiency suggests inactivating defects. GNAS1 disorders (deficiency in PHP I and excess in McCune-Albright syndrome) affect multiple hormones acting through G-protein-coupled receptors including PTH, LH, FSH, ACTH, GHRH, and TSH. Hormone receptors represent important therapeutic targets with agonists used for deficiency and antagonists for excess states.12
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Hormonal Regulation
Hormone levels are maintained within a narrow range by a complex interplay of regulators, hormone sensing, and feedback.
Regulator: Most hormones are regulated by stimulators and inhibitors. The predominant tone of regulation predicts the likely etiology of a disorder. Anterior pituitary hormones (GH, TSH, ACTH, LH, and FSH) are stimulated by hypothalamic peptides with the exception of prolactin that is inhibited by dopamine. Hypothalamic lesions therefore cause hypopituitarism with hyperprolactinemia. Prolactin levels are low in pituitary lesions making prolactin a discriminatory investigation in hypopituitarism. Regulatory agents represent a therapeutic option with the use of inhibitors in excess (somatostatin in hyperinsulinism) and stimulants in deficiency states (kisspeptin in hypogonadotropic hypogonadism).
Hormone sensing: Appropriate sensing of hormone effect by target organs or sensors is of paramount importance for hormonal regulation. Abnormal sensing of hormonal effect results in unregulated hormonal levels and pathology. Calcium levels are sensed by calcium-sensing receptors inhibiting PTH secretion and renal calcium reabsorption. Activating calcium-sensing receptor mutation causes hypocalcemia with hypercalciuria while hypercalcemia with hypocalciuria is observed with inactivating mutation. Glucokinase, beta cell glucose sensor, regulates insulin secretion. Inactivating glucokinase mutation inhibits insulin release causing diabetes mellitus, while activating mutation results in neonatal hypoglycemia.
Hormonal feedback: Feedback regulation is critical part of hormonal regulation. Excess hormone effect is sensed by the body triggering negative feedback to bring its level back in the normal range. Most feedback processes inhibit the trophic hormone (negative feedback); positive feedback is characteristic of proliferative phase of menstrual cycle where elevated estradiol levels further enhance LH levels triggering ovulation. Feedback mechanism emphasizes the need for interpretation of hormonal levels in the context of its effect. TSH levels should therefore be undetectable with high FT4; detectable TSH in this setting suggests thyroid hormone resistance or TSH-secreting adenoma. Similarly, normal PTH in the presence of hypocalcemia, ACTH with low cortisol, and LH with low testosterone suggest deficiency, while detectable insulin during hypoglycemia indicates excess.
Hormonal Metabolism
Hormone metabolism plays an important role in the termination of its action. Impaired metabolism can cause hormonal disorders. The 24 hydroxylase inactivates 25 hydroxyvitamin D (25OHD) into 24,25-dihydroxyvitamin D. The 24 hydroxylase deficiency causes increased 25OHD levels and hypercalcemia, while increased expression due to enzyme inducers (phenytoin, phenobarbitone) causes vitamin D deficiency. Increased metabolism can unmask covert deficiency of the hormone. Hypothyroidism reduces glucocorticoid metabolism preventing adrenal insufficiency in children with compromised glucocorticoid13 reserve. Initiation of thyroid treatment in this setting without glucocorticoid supplementation precipitates adrenal insufficiency by increasing cortisol metabolism. This highlights the need for correction of glucocorticoid deficiency before starting T4 or GH therapy in multiple pituitary hormone deficiency. P450 enzyme inducers (phenytoin, rifampicin, and carbamazepine) may also precipitate adrenal insufficiency as observed after the initiation of antitubercular treatment in children with disseminated tuberculosis and adrenal involvement. Extra-adrenal isoforms of adrenal enzymes alter presentation of CAH variants. The 3 beta hydroxysteroid dehydrogenase (3BHSD) deficiency impairs conversion of delta 5 to delta 4 compounds effectively blocking all androgen production. This is expected to cause androgen deficiency and XY DSD. Girls with the disorder however also have atypical genitalia due to extra-adrenal 3BHSD activity.
HOW DO HORMONES CHANGE OVER LIFE SPAN?
Dynamic changes differentiate pediatric from adult endocrinology. A child undergoes tremendous endocrine changes in the fetal, neonatal, childhood, and adolescent periods. This has significant implications on hormonal assessment (age-specific reference levels), manifestations (physiology vs pathology), and management.
Fetal Period
Fetal period lays the foundation of sustaining an independent postnatal life. This is characterized by close interaction of mother, placenta, and fetus.
Fetal endocrinology: Fetal period is an anabolic state with rapid growth and accumulation of glycogen, fat, and calcium. The anabolic state is maintained by increased insulin and low glucagon, T4, and cortisol levels. The fetus depends on mother for regulation of temperature, glucose, calcium, and electrolytes and can therefore survive even without functional pituitary, thyroid, and adrenal glands.
Hypothalamic–pituitary axis: The hypothalamic–pituitary axis usually matures by 18–20 weeks for most endocrine organs. The axis is however quiescent with the exception of hypothalamic–pituitary–testicular axis. Fetal growth is independent of GH and thyroid hormones and is regulated by environment and IGF1.
Thyroid: Fetus lives in a relatively hypothyroid state to avoid catabolic effect of thyroid hormones. This is achieved by shifting thyroid metabolism from activation (MDI 1) to inactivation (MDI 3). The limited amount of thyroid available is used by the brain by increased local conversion by MDI 2 (Fig. 1.11). This allows athyreotic fetuses to have normal brain development with small amount of maternally transferred T4.
Fig. 1.11: Transition of thyroid hormone metabolism from fetal to neonatal period. Fetus lives in a relatively hypothyroid state to avoid catabolic effect of thyroid hormones. This is achieved by shifting thyroid metabolism from activation (MDI 1) to inactivation (MDI 3). The limited amount of thyroid available is used by the brain by increased local conversion by MDI 2. Thyroid physiology witnesses a dramatic shift at birth with increased MDI 1 and decreased MDI 3 activity. This postnatal thyroid surge has major implication on neonatal thyroid assessment.Source: Bajpai A, Dave C. Thyroid physiology & assessment. In: Thyroid disorders. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(MDI: monodeiodinase)
This also explains transient hypothyroxinemia observed in premature infants. This represents a physiological variation and does not need treatment.
Parathyroid: Calcium is actively transferred from the mother to fetus by placental transporters. Around 80% of this happens in the third trimester. Preterm infants are, therefore, at a higher risk of hypocalcemia. Transfer of calcium from mother to fetus is regulated by parathyroid hormone-related protein (PTHrP), secreted from the placenta to produce a maternal–fetal gradient of 1.4:1. Fetus has an independent calcium regulatory mechanism with an intact PTH axis.
Glucose metabolism: The fetus is entirely dependent on mother for provision of glucose with a maternal–fetal gradient of 20 mg/dL (1.1 mmol/L). Sudden cessation of maternal glucose supply due to hypoglycemia has devastating impact on the fetus. This highlights the importance of avoiding maternal hypoglycemia in pregnancy. High glucose level in the fetus increases insulin levels while inhibiting glucagon (Fig. 1.12). This increased insulin-to-glucagon ratio in the fetal period is responsible for fetal growth and hepatic glycogen deposition. Maximum glycogen deposition occurs in the third trimester. Preterm neonates have limited glycogen store and are therefore at an increased risk of hypoglycemia.
Adrenal: The definitive zone of adrenals is quiescent in the fetal period, while the fetal zone acts like a factory to supply dehydroepiandrosterone sulfate (DHEAS) to the placenta. Cortisol is produced transiently between 8 weeks and 12 weeks to inhibit ACTH-induced increased DHEAS production and virilization of female fetus. Aldosterone production is minimal in the fetal period.
Gonads: Fetal testis is one of the most active endocrine organs producing copious amounts of anti-Müllerian hormone (AMH) (causing Müllerian regression), testosterone (producing virilization), and insulin-like factor 3 (inducing testicular descent). Leydig cell activity is controlled by placental HCG till 12 weeks of gestation and pituitary LH subsequently. This prevents the development of hypospadias in fetus with hypogonadotropic hypogonadism. Fetal hyperactivity predisposes testis to second hit damage in steroidogenic acute regulatory protein deficiency where accumulated cholesterol destroys Leydig cells causing testicular failure. Ovaries are quiescent during this period and preserved from the effect explaining later development of ovarian failure.
Fetal endocrine programing: Uterine environment has a significant impact on fetal endocrine programing. This is demonstrated by transitional changes in glucose (hypoglycemia in infant of diabetes mother) and calcium levels (hypercalcemia with maternal hypocalcemia) and long-term metabolic effect of fetal undernutrition.
Maternal adaptation: Mothers supply glucose, calcium, and energy to the fetus. This is achieved by inducing maternal insulin resistance by human placental lactogen (HPL) (to increase glucose), bone resorption (by PTH-related peptide), and increased energy consumption.
Fig. 1.12: Regulation of fetal glucose metabolism and its postnatal impact. The fetus is entirely dependent on mother for provision of glucose. The continuous glucose supply of the fetus from mother suddenly stops at delivery predisposing the neonate to hypoglycemia. Increased epinephrine and glucagon levels along with reduction in insulin induce glycogenolysis to stem the rapid decline in glucose. This is followed by increased gluconeogenesis and ketogenesis. Despite these defense mechanisms, blood glucose falls dramatically in the first 24 hours causing transitory hypoglycemia in predisposed individuals. The transition is complete by 48 hours of life beyond which any hypoglycemia should be considered pathological.Souce: Adapted with permission from Bajpai A, Dave C. Neonatal hypoglycemia. In: Glucose disorders. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(HPL: human placental lactogen).
This highlights the need for increased caloric and calcium consumption of mother and the role of maternal malnutrition in exacerbating fetal undernutrition. Placental HCG acts on TSH receptor to induce a mild thyrotoxic state lowering TSH levels by 1 mU/L. Increased estradiol elevates binding globulin increasing T4 and cortisol requirement during pregnancy. Increased binding globulins also increase total thyroid hormone prompting a change in cutoff to one and a half time above the nonpregnant levels.
Placental endocrinology: Long considered to be a mechanical barrier between the mother and the fetus, placenta plays an active role in fetal–maternal endocrinology (Fig. 1.13).
Placental hormones: Placenta secretes HPL which increases fetal glucose supply by inducing maternal insulin resistance. Placental HCG sustains fetal Leydig cell function till 12 weeks of life, while PTHrP is the major determinant of fetal calcium transport. Placental vasopressinase metabolizes maternal AVP precipitating covert diabetes insipidus in carrier mothers with X-linked nephrogenic diabetes insipidus.
Placental barrier: Placenta acts as a mechanical barrier for large molecules like PTH, insulin, and TSH protecting the fetus from large fluctuation in maternal levels allowing independent fetal parathyroid, pancreas and thyroid development. On the other hand, placenta allows transfer of T4, T3, antithyroid drugs, glucose, and calcium. Transplacental passage of maternal T4 protects athyreotic fetuses from hypothyroidism-induced brain damage. Untreated maternal and fetal hypothyroidism therefore has significant effect on brain development. TSH receptor antibody (and not thyroid peroxidase) crosses the placenta causing transient hypothyroidism (blocking antibody) and thyrotoxicosis (stimulating antibody).
Placental sieve: Placental enzymes determine the transfer of steroids from fetus to mother and vice versa. Thus, 11BHSDII inactivates hydrocortisone and prednisolone with no effect on dexamethasone.
Fig. 1.13: The feto-maternal-placental endocrine unit. Placenta plays an important role in regulation of feto-maternal endocrine unit. It produces to induce maternal insulin resistance (human placental lactogen), calcium transport (PTH-related peptide), and testicular stimulation (human chorionic gonadotropin). Placental sieve prevents transfer of TSH, PTH, insulin, testosterone, estradiol, cortisol, and prednisolone while allowing TRH, dexamethasone, T4, and TSH-receptor antibody.Source: Bajpai A, Dave C. Hormone physiology. In: Basics of endocrinology. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(PTH: parathyroid hormone; TRH: thyrotropin-releasing hormone; TSH: thyroid-stimulating hormone)
Hydrocortisone and prednisolone are therefore the preferred glucocorticoid formulations for maternal treatment (autoimmune conditions, adrenal insufficiency), while dexamethasone should be used for fetal treatment (surfactant production, congenital heart block, and prenatal treatment for CAH). Placental 17β-hydroxysteroid dehydrogenase II protects the female fetus from maternal hyperandrogenism and male fetus from elevated maternal estradiol levels. Placental aromatase prevents maternal virilization.
Changes at Birth
Birth represents a watershed moment from an endocrine perspective and represents a shift from dependent phase to an independent survival. Immediate challenges include hypothermia and interrupted glucose and calcium supply. This triggers a shift from anabolic to catabolic state. Key mediator of this are hypothalamic hormones TRH and CRH and epinephrine.
Thermogenesis: The key defense against hypothermia in the immediate neonatal period is T4-induced nonshivering thermogenesis. Thyroid physiology witnesses a dramatic shift with increased MDI 1 and decreased MDI 3 activity (Fig. 1.11). This postnatal thyroid surge has major implication on neonatal thyroid assessment. TSH, T4, and T3 levels are significantly elevated in the first 3 days of life highlighting the need for neonatal screening for hypothyroidism after this period. TSH levels remain high up till 3 weeks of life suggesting the need for higher cutoff for assessment during this period.
Glucose metabolism: The continuous glucose supply of the fetus from mother suddenly stops at delivery predisposing the neonate to hypoglycemia. Increased epinephrine and glucagon levels along with reduction in insulin induce glycogenolysis to stem the rapid decline in glucose. This is followed by increased gluconeogenesis and ketogenesis. Despite these defense mechanisms, blood glucose falls dramatically in the first 24 hours causing transitory hypoglycemia in predisposed individuals. The transition is complete by 48 hours of life beyond which any hypoglycemia should be considered pathological.
Calcium metabolism: Decline in calcium levels triggers PTH release while inhibiting calcitonin production stabilizing calcium levels. Predisposed individuals (prematurity, birth asphyxia, and infant of diabetic mother) develop hypocalcemia in this transitory period. Calcitriol plays a minor role in the maintenance of neonatal calcium levels in the first 2 weeks of life. Infants born to vitamin D–deficient mothers and who are not supplemented with vitamin D, therefore, do not develop hypocalcemia before 2 weeks of life.
Growth hormone: Immediate postnatal period is characterized by increased GH levels due to lack of inhibition. This has limited effect due to relative insensitivity in this stage.
Adrenal: The most dramatic postnatal change occurs in the adrenal gland which shows rapid involution of the fetal zone and maturation of definitive zone. Adrenal glands produce a large amount of sulfated and structurally related steroids in the neonatal period confounding immunoassay results. This highlights the need for extraction and structure-based mass spectroscopy for the assessment of neonatal adrenal functions. Salt regulation in the first 2 weeks is independent of aldosterone explaining the lack of salt wasting in neonates with CAH during this period. This is followed by a phase of mineralocorticoid resistance mandating the need for high fludrocortisone requirement at this stage. Neonates with 11 hydroxylase deficiency with accumulation of weak mineralocorticoid deoxycorticosterone have transient salt wasting due to mineralocorticoid resistance at this state with subsequent development of hypertension.
Childhood
Childhood is a period of stable growth and endocrine parameters. Gonadotropins remain suppressed throughout childhood under hypothalamic inhibitory control (Fig. 1.14). This makes assessment of testicular function based on basal gonadotropin and testosterone levels difficult during childhood. AMH and inhibin B are better markers of testicular function at this age.
Pubertal Changes
Puberty is characterized by dramatic changes with achievement of 40% adult bone mass, 25% growth, and 100% reproductive potential. In addition to the obvious changes in gonadotropins and sex steroid levels, puberty witnesses changes in the GH–IGF1, insulin–glucose, PTH–calcitriol, and thyroid and adrenal axis.
Fig. 1.14: Hypothalamic–pituitary–gonadal axis across life span. The hypothalamic–pituitary axis is highly active in the fetal period and early infancy. It is subsequently quiescent in childhood to become active during puberty.Source: Bajpai A, Dave C. Pubertal physiology & assessment. In: Basics of endocrinology. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
Lack of understanding of these changes results in inadvertent labeling of physiology as pathology.
Growth hormone–IGF1 axis: GH secretion increases by twofold during puberty under the influence of sex steroids (Fig. 1.15). GH levels may be inappropriately low in children with delayed puberty only to become normal after puberty. This results in false diagnosis of GH deficiency (GHD) in the absence of sex steroid priming and highlights the need for sex hormone priming in individuals with growth failure, delayed puberty, and predicted adult height in the target height range. This indicates the need for increasing GH dose during puberty. IGF1 levels dramatically increase during puberty highlighting the need for age-specific cutoffs.
Body composition: Puberty is associated with changes in body composition with fat deposition in abdomen in boys and mammary and gluteal region in girls. Increased sex steroid hormones induce insulin resistance with increased likelihood of acanthosis, nonalcoholic fatty liver disease, and type 2 diabetes.
Calcium metabolism: Sex steroids are associated with increased calcium absorption in response to estrogen causing increased bone mineral density. There is a lag of 2–3 years between achievement of adult height and bone mass predisposing adolescents of that age to fracture.
HOW DO HORMONE SYSTEMS RESPOND TO NUTRITION?
Most hormonally regulated processes, such as growth, puberty, and bone mineralization, are energy intense requiring adequate nutrition (Table 1.5). The key link between nutrition and endocrine function is adipocyte hormone leptin.
Fig. 1.15: Growth hormone levels across life span. Growth hormone levels are low in the fetal period and rise significantly at birth due to lack of inhibition. Subsequently production rate remains stable across childhood with twofold increase at puberty. This is followed by gradual decrease after the completion of statural growth to adult levels.Source: Bajpai A, Agarwal N. Growth hormone therapy. In: Growth disorders. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
Overnutrition: Overnutrition stimulates the body to grow, enter puberty, and increase metabolic rate. This is associated with significant changes in hormone profile.
Growth: Growth is accelerated in obesity due to insulin action on type 1 IGF receptor and increased free IGF1 levels due to decreased IGFBP levels. Obesity is a GH-sensitive state with low GH and high IGF1 levels. This may result in false diagnosis of GHD in obesity. Lower GH cutoffs are recommended for obese adults; similar guidelines have not been developed for children. GH requirements of obese children with GHD tend to be lower due to increased GH sensitivity. Body surface area–based dosing is therefore desirable in this setting as weight-based dosing results in unwarranted high dose.
Thyroid: Obesity is associated with mildly increased TSH levels in the wake of normal T4 levels. This represents a futile effort to increase metabolism and is the effect and not the cause of obesity. Thyroid replacement is not needed in obese children with mildly elevated TSH levels (below 10 mU/L).
Adrenal: Obesity causes mild hypercortisolism resulting in misdiagnosis of Cushing syndrome. This has prompted lower cutoff for overnight dexamethasone suppression test (cortisol below 50 nmol/L, 1.8 µg/dL). Premature activation of adrenal androgen axis causes adrenarche discordant to gonadarche.
Puberty: Obese girls have early but disjuncted puberty with increased gap between thelarche and menarche. In obese boys, increased aromatase activity of adipose tissue enhances estrogen production delayed puberty. They have discordance between pubic hair growth and testicular enlargement.
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Bone mineralization: Obesity increases bone formation due to elevated IGF1 and estradiol levels.
Glucose metabolism: Obesity results in overspill of fat from the subcutaneous tissue and deposition in visceral tissue. This produces an insulin-resistant state predisposing to metabolic syndrome, nonalcoholic fatty liver disease, type 2 diabetes, and polycystic ovarian syndrome. The development of these complications is related to inherent capacity of an individual to store fat determined by size at birth. Low-birth-weight individuals therefore tend to develop metabolic complications at lower body mass index than those with high birth weight.
Undernutrition: Undernutrition represents a state of energy conservation with postponement of growth, puberty, and bone mineralization. This may be due to decreased intake, systemic illness, or eating disorders, such as anorexia nervosa.
Growth: Undernutrition is a GH-resistant state with low IGF1 levels despite high GH levels. This has implications in the assessment of GH–IGF1 axis. GH levels may be spuriously high resulting in missed diagnosis of GHD. IGF1 levels are unreliable and should not be assessed in undernourished children.
Thyroid: Undernutrition is associated with low T3 levels (due to increased MDI 3 action) in the setting of low TSH (due to increased cerebral MDI 2 action).
Adrenal: Stress response as part of undernutrition results in mildly elevated ACTH and cortisol levels.
Puberty: Undernutrition delays puberty due to decreased leptin levels. Delayed puberty in undernutrition is characterized by absent pubic hair development as against normal pubic hair development in hypogonadotropic hypogonadism.
Bone mineralization: Bone mineralization is reduced due to vitamin D deficiency and secondary hyperparathyroidism.
Glucose metabolism: Malnutrition modulates the development of diabetes resulting in severe hyperglycemia without ketosis (malnutrition-dependent diabetes mellitus).
HOW DO HORMONES ADAPT TO ILLNESS?
Hormones play an important role in combating acute illness and stress. Key response to stress is shift of metabolic pathway from catabolism to energy conservation.
Adrenal: The main regulator of stress response is cortisol and inability to mount stress response is the most frequent cause of adrenal crisis. This mandates the need for stress dosing in children with adrenocortical insufficiency.
Glucose metabolism: Counterregulatory hormone excess during stress predisposes to development of diabetic ketoacidosis in children with diabetes.
Thyroid: Acute illness increases MDI 3 levels decreasing T3 levels along with decreased TSH due to enhanced MDI 2 action. This constellation of low T3, normal/low T4, and low TSH is characteristic of nonthyroidal illness and should not be considered a marker of central hypothyroidism. TSH levels are further reduced by inhibitory effects of stress-induced hypercortisolism and vasopressors, such as dopamine used in treatment. Recovery from systemic illness is characterized by elevated TSH causing a diagnostic dilemma of primary hypothyroidism. Thyroid functions should not be assessed in hospitalized subjects unless mandatory to avoid diagnostic confusion. Thyroid hormone treatment should be started only in the presence of persistent and significant elevation of TSH.
Growth hormone: GH therapy worsens the outcome of patients admitted in intensive care unit. This emphasizes the need for discontinuing GH in hospitalized children.
WHAT ARE THE CAUSES OF HORMONAL DISORDERS?
In the perspective of physiology, hormonal disorders can occur at the level of gland formation, synthesis, release, activation, receptor binding, or metabolism (Fig. 1.16). In general, deficiency disorders are the acts of omission (defective gland development, hormone synthesis or secretion defect or receptor defect), while excess disorders represent the acts of commission (increased production, release, activation, and receptor action). This explains the preponderance of deficiency states. Pathophysiology can be predicted by the predominant tone of regulation. Thus, as pubertal onset is actively inhibited in the prepubertal age-group, precocious puberty is largely caused by decreased inhibitory signals. Similarly decreased stimulatory signals are the main cause of delayed puberty. The direction of development also determines the effect of physiology. In the absence of any active intervention, the default mode of development of a fetus is female gender. XY DSD is usually an act of omission, while XX DSD represents act of commission.
HOW IS HORMONE STATUS ASSESSED?
The options for endocrine assessment include measurement of the hormone, feedback regulator, surrogate markers of action, metabolites, and cosecreted compounds.19
Fig. 1.16: Template for disorders of the GH–IGF1 axis and their treatment. Inefficient action of the GH–IGF1 axis may be observed in the setting of hypothalamic–pituitary damage, or reduced function of GHRH, GH, GH receptor, IGF1 gene, or IGF1 receptor. Treatment options for deficiency include GH, GHRH (in hypothalamic cases), and IGF1 (in GH insensitivity). GH–IGF1 axis excess is observed with increased GH production due to tumor or somatotroph hyperplasia. Treatment options for GH excess include excision of the lesion, suppression of GH secretion with octreotide or GH-receptor blockage with pegvisomant.Source: Bajpai A, Agarwal N. Growth hormone therapy. In: Growth disorders. MedEClasses; 2018. <https://learning.growsociety.in> [accessed 25 October 2018].
(GH: growth hormone; GHRH: growth hormone–releasing hormone; IGF1: insulin-like growth factor 1)
Basal levels are indicated for hormones with long half-life and stable levels (25OHD, T3, T4, and TSH). Pooling the samples taken in triplicate reduces the variation for pulsatile hormones (cortisol, LH, FSH, testosterone, and prolactin). Assessment of trophic hormone provides information regarding diagnosis and therapy (TSH for hypothyroidism, gonadotropin for delayed puberty, and ACTH for adrenal insufficiency). Surrogate markers of hormone effect provide an estimate of hormone functions (serum calcium and phosphorus levels for PTH, ketone levels for insulin). Urinary metabolites provide composite information about hormone synthesis and metabolism. Dynamic tests are indicated when basal hormones are not discriminatory. Stimulation tests are performed in deficiency states (GHD, adrenal insufficiency, and delayed puberty), while suppression tests are indicated for excess (glucose suppression test, dexamethasone suppression test). Many peptide hormones have short half-life making their assessment challenging (insulin, AVP, ACTH, and CRH). Some of these are secreted with other compounds with long half-life in equimolar amount. Assessment of these cosecreted compounds provides an indirect estimate of hormone levels (C peptide for insulin, copeptin for AVP). The hormone levels are tightly regulated by feedback mechanism of the target effect. Increased hormone effect inhibits hormone production, while levels increase with lower effect. Thus, the level of a hormone should be interpreted in the light of target effect.
HOW ARE HORMONE DISORDERS MANAGED?
The most fascinating aspect of pediatric endocrinology is dramatic improvement with therapy. The choice of therapy is directed by the underlying disorder. Deficiency states can be treated with hormone replacement (insulin, GH, T4, and hydrocortisone), end products of hormone action (testosterone for hypogonadotropic hypogonadism, calcium and calcitriol for hypoparathyroidism, sodium chloride for pseudohypoaldosteronism), gene therapy [adrenoleukodystrophy (ALD)], secretagogues (GH secretagogues for hypothalamic GHD), or organ restoration (islet cell transplant for type 1 diabetes or hematopoietic stem cell transplant for ALD). Excess states can be treated with inhibitors of secretion (somatostatin receptor ligand for GH excess, hyperinsulinism, cabergoline20 for hyperprolactinemia), antagonist (glucagon for hyperinsulinism, antiandrogen for testotoxicosis), counteragents (glucose for hyperinsulinism), monoclonal antibody (anti-FGF23 antibody for hypophosphatemic rickets), gene silencers, gland ablation (radioactive iodine ablation), and surgical removal for tumors (parathyroid, pituitary, or adrenal tumors). The choice of therapy is guided by the cost, availability, and efficacy.
Pediatric endocrinology has often compared with mathematics given the logical path of assessment and management. The key formulas of pediatric endocrinology rest with physiology. A keen understanding of physiology is the cornerstone of successful assessment and management of pediatric endocrine disorders.
BIBLIOGRAPHY
- Bajpai A, Dave C. Physiology. In: Basics of endocrinology, 2018. <https://learning.growsociety.in/module/bone-and-calcium> [accessed 21 October 2018].
- Kronenberg HM, Melmed S, Larsen PR, et al. Principles of endocrinology. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, (Eds) Williams textbook of endocrinology, 4th edition Philadelphia: Elsevier; 2016, pp. 2–11.
- Kublaoui B, Levine MA. Receptor transduction pathways mediating hormone action. In: Sperling MA (Ed) Pediatric endocrinology, 4th edition Philadelphia: Saunders Elsevier; 2014. pp. 158–86.
- Sperling MA. Overview and principles of pediatric endocrinology. In: Sperling MA, (Ed) Pediatric endocrinology, 4th edition Philadelphia: Saunders Elsevier; 2014. pp. 158–86.