ENDOCRINE SYSTEM
E. Adrenal Glands 1. Embryology
a. The adrenal glands develop from two differ
ent origins: the cortex, arising from the mesoderm, and the medulla, arising from the neuroectoderm and is found above the much smaller kidney by 8 weeks of gestation. Differentiation of the
adrenal medulla occurs late in development. The zona reticularis is not developed until the end of the third year of life and is not fully developed until around 15 years of age. The mesoderm is involved in the development of the gonads (Miller & Flück, 2014).
b. Fetal cortisol is necessary as a fetus prepares for extrauterine transition. An increase in fetal cortisol occurs in the last 10 weeks of gestation and prepares several systems that are critical for survival. As delivery approaches, cortisone, the active form that would be detrimental in early fetal development, is converted by the liver and lung tissues to cortisol (Dattani & Gevers, 2016).
Cortisol progressively decreases during the first 2 months of life.
c. Early in the fetus’s development, there is no epinephrine. Norepinephrine is the dominant cat
echolamine at birth (Miller & Flück, 2014).
2. Location. The adrenal glands are small glands that lie atop the kidneys. Each gland has two distinct parts, the cortex, constituting 80% of the gland, and the medulla, constituting 20% of the gland (Babler et al., 2013).
3. Anatomic Structure. The adrenal gland is sur
rounded by a fibrous capsule. The adrenal cor
tex has three histologically different zones: zona glomerulosa, the outermost layer, which constitutes 15% of the cortex; zona fasciculate, the middle layer, which constitutes 75% of the cortex; and the zona reticularis, the innermost layer, constituting 10% of the cortex. The adrenal medulla has sympathetic and parasympathetic innervation but the adre
nal cortex does not. The adrenal circulation unlike other organs does not run in parallel. Arterial blood supplied by smaller arteries and flows toward the medulla, so medullary chromaffin cells see high steroid concentration in their circulation. The more conventional veins drain into the left renal vein and the vena cava (Miller & Flück, 2014).
4. Cell Types (Miller & Flück, 2014)
a. The adrenal cortex is responsible for the secre
tion of corticosteroids, which are synthesized from cholesterol. These hormones are released from three separate zones in the adrenal cortex. The three zones each secrete unique hormones and from the outside to inside they are often remem
bered by saying salt, sugar, and sex.
i. The zona glomerulosa is responsible for the secretion of mineralocorticoid and aldosterone.
ii. The zona fasciculata is responsible for secreting glucocorticoids, mainly cortisol and a small amount of androgen secretion.
iii. The zona reticularis is responsible for secreting androgen, estrogen, and small amounts of glucocorticoid.
b. The chromaffin cells are the major cells of the adrenal medulla and they store the catecholamines epinephrine and norepinephrine as secretory granules. They are synthesized from phenylala
nine with innervation from the parasympathetic and sympathetic nervous systems. In times of stress, exocytosis occurs after depolarization from
acetylcholine, and enhanced amounts of hor
mones are released (Brashers et al., 2014).
5. Aldosterone (Figure 6.9)
a. Biosynthesis. Aldosterone is the most potent mineralcorticoid and it is imperative for life functions due to its sodiumretaining proper
ties. It is a steroid compound synthesized from cholesterol absorbed from the blood. Synthesis begins in the zona fasciculata and reticularis with final conversion to active form in the zona glomerulosa (Brashers et al., 2014).
b. Regulation. It occurs primarily by angioten
sin II via the renin–angiotensin system, but it is
Stimulates posterior pituitary gland
Increased ADH secretion
Fight-or-Flight Reaction (increased heart rate, blood pressure, and glucose concentration)
Aldosterone Effects:
• Increased sodium and water reabsorption (sodium and water retention)
Stimulates sympathetic centers and adrenal medulla
Stimulates limbic lobe and other part of
cerebral cortex Stimulates
hypothalamus
Releases increased amounts of CRH
Stimulates anterior pituitary
gland to secrete increased amounts
of ACTH
Stimulates Adrenal Cortex:
• Marked increase of glucocorticoids (cortisol) secretion
• Moderate increase of mineralocorticoids (aldosterone) secretion
Cortisol Effects:
• Increased catabolism of tissue proteins, gluconeogenesis, producing hyperglycemia
• Decreased lymphocytes and immune responses
• Decreased eosinophils and allergic responses
Stress
Caused by real or perceived negative physiological, emotional, or cognitive stimuli
Increased catecholamines levels
(norepinephrine and epinephrine) in blood
Antidiuresis (decreased urine and water
retention)
Increased Blood Volume
Neuropeptide Y:
Vasoconstriction;
platelets aggregation;
vascular smooth muscle hypertrophy
FIGURE 6.9 Cortisol and aldosterone effects during stress.
ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; CRH, corticotropin- releasing hormone.
DEVELOPMENTAL ANATOMY AND PHYSIOLOGY ■ 501
also activated for release by volume depletion, decreased renal perfusion, ACTH and sodium levels, and hyperkalemia. A small increase in serum potassium will triple aldosterone release.
This response is imperative for the prevention of the serious cardiotoxic effects brought about by hyperkalemia. Inhibition of aldosterone release occurs secondary to volume expansion, hypo
kalemia, and low angiotensin levels (Brashers et al., 2014; Hall, 2016).
c. Effects. Aldosterone is responsible for 90%
of mineralocorticoid activity (Hall, 2016). It acts on the distal tubule, collecting tubule, and col
lecting duct of the kidney to promote sodium reabsorption and potassium excretion. Along with renal reabsorption of sodium, there is a concurrent movement of water into the vascular bed. The net effect is an increase in extracellu
lar sodium, an increase in extracellular vol
ume, and a decrease in extracellular potassium.
Aldosterone promotes reabsorption of sodium and excretion of potassium by the sweat and salivary glands, which promotes hydrogen ion excretion by the kidney and sodium absorption by the intestines. If aldosterone is low or absent, bowel absorption of sodium and water will not occur and diarrhea will result (Brashers et al., 2014; Hall, 2016).
d. Role in critical illness. Aldosterone is key to maintenance of extracellular volume. Excess release can have lasting effects of more than 1 to 2 days with notable increase in arterial blood pressure. A subsequent natriuresis occurs, which increases the excretion of both water and sodium, and once it normalizes the pressure will return to the previous level (volume rise of 5%–15%
causes blood pressure rise of 15–25 mmHg;
Hall, 2016).
6. Cortisol (Figure 6.9)
a. Biosynthesis. Cortisol is a steroid compound derived mostly from cholesterol and is the main product excreted by the adrenal cortex (Miller &
Flück, 2014). It is the most potent of the glucocor
ticoids and has a halflife of 90 minutes (Brashers et al., 2014).
b. Regulation. The primary stimulus for secre
tion of cortisol is ACTH, but stress is another strong stimulus. Release of cortisol is inhibited by negative feedback to either the hypothalamus or the anterior pituitary secondary to increased cortisol levels, which produces a decrease in CRH release in the hypothalamus or decrease in ACTH release in the anterior pituitary (Brashers et al., 2014).
c. Secretion. Secretion is regulated by the hypo
thalamus and anterior pituitary. It is released immediately after stimulation from ACTH. It has a diurnal rhythm release with ACTH and peaks in the hours just before awakening. It circulates bound to albumin, the glycoprotein cortisol- binding globulin (CBG; also known as transcortin) or in the unbound active form (Brashers et al., 2014). Transcortin serves an important role in the negative feedback loop for cortisol and is ele
vated when estrogen levels are high (Clayton &
McCance, 2014).
d. Effects. Cortisol is responsible for 95% of glu
cocorticoid activity and is necessary in life for stress protection (Hall, 2016). Cortisol increases gluconeogenesis and glycogenolysis to provide a substrate for this stressful time, often leading to hyperglycemia. Protein synthesis decreases, and catabolism of protein increases. Cortisol promotes mobilization of fatty acids from the tis
sues. An antiinflammatory cascade occurs with its release that counteracts and modulates the body’s immune response and endothelial integ
rity. Cortisol is potentiated by nitric oxide and it also provides vascular tone to increase blood pressure and prevent capillary leak (Brashers et al., 2014; LevyShraga & PinhasHamiel, 2013).
e. Role in critical illness. Absolute AI is rare.
Relative AI, in which cortisol production is inad
equate to the level of stressful stimuli, can be seen in sepsis, trauma, or surgery (LevyShraga &
PinhasHamiel, 2013). Critical illness-related cor- ticosteroid insufficiency (CIRCI) will be discussed later in the chapter.
7. Abnormalities of Adrenal Cortical Function
a. AI results in insufficient glucocorticoid and mineralocorticoid release or production and will require the child to have lifelong administration of exogenous hormones. It presents in childhood primarily as congenital adrenal hyperplasia (CAH) or Addison’s disease. CAH is an auto
somal recessive congenital disorder and is the leading cause of AI in childhood (Webb & Krone, 2015). It usually presents in the newborn period with symptoms of shock, ambiguous genitalia, and the very diagnostic electrolyte abnormal
ities of hyponatremia and hyperkalemia. It has many variants that explain the specific present
ing symptoms and is now part of the newborn screen with a 17hydroxy progesterone level (White, 2016). Addison’s disease is a rare autoim
mune or infectious process in children. It results from an absent or damaged adrenal gland.
The deficiency produces initial weakness with
weight loss, hyperpigmentation, dehydration, electrolyte imbalances, and altered metabolism (Brashers et al., 2014). The presentation may progress and lead to adrenal crisis with hypo
tension and cardiovascular collapse. Children present in shock due to the acute depletion of adrenal cortical hormones. It is precipitated by vomiting, diarrhea, convulsions, coma, hypoten
sion, hyperpyrexia, tachycardia, and cyanosis.
AI can also result from exogenous suppression of hormones with oral or intravenous (IV) ste
roids, as well as an abrupt withdrawal of ste
roids after chronic use (White, 2016). Children who suffer from severe sepsis, are premature or less than 6 months of age, and those who have had etomidate administration are at higher risk for adrenal sufficiency.
b. Hyperfunction of the adrenal cortex, or Cushing syndrome, is a rare disorder in children resulting in excess cortisol. Excess cortisol can be rarely caused by a pituitary adenoma but more common causes include administration of high dose of exogenous steroids or chronic use of steroids (Brashers et al., 2014). The very typical “Cushingoid” effects include weight gain, moon facies, truncal striae, atropy of skin or bruising, emotional lability, hyperglycemia, and high blood pressure (Brashers et al., 2014).
With longterm steroid excess, children will have problems with bone demineralization and stunted growth.
8. Epinephrine
a. Biosynthesis. Epinephrine is a catecholamine derived from the amino acid tyrosine, which is then converted to dopamine in the sympathetic nerve endings. Dopamine is converted to nor
epinephrine, which is converted to epinephrine in the adrenal medulla. Epinephrine secretion is 80% of the total catecholamine secreted by the adrenal medulla and at rest it is released at 0.2 mcg/kg/min (Hall, 2016).
b. Regulation. Neuroendocrine (stress, fear, illness) stimulation causes epinephrine and norepinephrine to be directly released into the blood. Any stimulus that produces a sympa
thetic response stimulates secretion of epineph
rine. The effects are rapid but only seen for seconds to minutes (Brashers et al., 2014). ACTH and glucocorticoids also stimulate release of epi
nephrine. Inhibition of epinephrine is through negative feedback loops; high levels of circulat
ing catecholamines will produce downregula
tion of sympathetic receptors.
c. Effects. Epinephrine stimulates the beta
adrenergic receptors in the end organs. The greatest effect is due to stimulation of the sym
pathetic beta1adrenergic receptors in the heart, resulting in increased cardiac contrac
tility, conduction velocity, and heart rate. The net result is an increase in cardiac output and blood pressure. In isolation, stimulation of the beta2 adrenergic receptors of the vascular bed promotes relaxation; however, during stress the vasoconstricting effects of norepinephrine coun
teract significant vasodilation. Other effects of stimulation of the beta2adrenergic receptors are intestinal, bladder and uterine relaxation, and bronchial dilation. Epinephrine increases metabolic activity to a much greater degree than norepinephrine. It increases glycogenolysis and glucose release, resulting in elevations of blood glucose to supply fuel substrates. Circulating epinephrine accounts for 10% of the sympathetic activity during the stress response (Hall, 2016).
d. Role in critical illness. Epinephrine is used for hypotension, cold shock, bradycardia, and asystole (Chameides, Samson, Schexnayder, &
Hazinski, 2011). Cold shock states are char
acterized by the presence of cold extremities, delayed capillary refill, and low cardiac output.
The actions of epinephrine are dose dependent.
At lower doses, epinephrine will have greater beta2 adrenergic effect and SVR may fall whereas at higher doses alphaadrenergic effects will be seen and SVR will rise (Davis et al., 2017).
9. Norepinephrine
a. Biosynthesis. Norepinephrine is synthesized from its precursor dopamine in the nerve end
ings of the sympathetic nervous system with only minor sources from the medulla.
b. Regulation is the same as for epinephrine.
c. Effects are secondary to stimulation of the alphaadrenergic receptors in the end organs.
The most significant effect during stress is peripheral vasoconstriction supporting blood pressure. Stimulation of the alphaadrenergic receptors also produces dilation of the iris, con
traction of the bladder and intestinal sphincters, and pilomotor contraction.
d. Role in critical illness. Norepinephrine is used in hypotensive, vasodilated, warm shock states (Chameides et al., 2011). Children with warm shock will have flash capillary refill;
warm, pink extremities; and bounding pulses.
Norepinephrine is used to reverse this low SVR
CLINICAL ASSESSMENT OF ENDOCRINE FUNCTION ■ 503
state, which is characterized by a wide pulse pressure (when the diastolic pressure is half of the systolic; Davis et al., 2017).
10. Hyperfunction of adrenal medulla is rare, and is most often caused by a catecholaminesecreting tumor called pheochromocytoma. This tumor arises when the chromaffin cells of the adrenal gland fail to involute and the excess production can cause lifethreatening hypertension, tachycardia, diapho
resis, tremors, and headaches (KlineTilford, 2016).
Diagnosis is made through measurements of meta
nephrine and catecholamine levels and urine vanil
lylmandelic acid (VMA). Hypertension control is imperative and is often initially done with alpha
and betablocker infusions with subsequent tumor resection. Care must be taken, however, to avoid using betablockers alone as unopposed alpha activ
ity could occur.
CLINICAL ASSESSMENT OF ENDOCRINE FUNCTION
Many endocrine disorders develop slowly over time and often go unrecognized by those (parents and care
givers) with daily contact with the child. Assessment through careful history, documentation of past medical conditions, growth patterns, developmental milestones, physical exam findings, and family history are critical to the accurate diagnosis of specific endocrine disorders.