Hypothalamic–Pituitary Complex (Neuroendocrine System)

ENDOCRINE SYSTEM

A. Hypothalamic–Pituitary Complex (Neuroendocrine System)

1. Embryology

a. The hypothalamus arises from the diencepha­

lon after a proliferation of neuroblasts. The fibers of the supraoptic tract are present by 12 weeks ges­

tation with maturation of the neurons by 30 weeks (Schoenwolf, Bleyl, Brauer, & Francis­West, 2015).

i. Antidiuretic hormone (ADH) and oxy­

tocin production begin at about 12 weeks gestation.

b. The pituitary gland has a double embryonic origin, which contributes to the differentiation of the anterior and posterior lobes. Pituitary devel­

opment begins around 4 weeks of gestation

(Schoenwolf et al., 2015). Pituitary hormone secretion begins by 8 to 10 weeks gestation (Dattani & Gevers, 2016).

c. Anterior pituitary is recognizable by 3 to 4 weeks gestation and appears fully functional by 17 weeks. It originates from Rathke’s pouch, which is ectodermal tissue from the oropharynx that migrates to join the posterior pituitary. By week 5 of gestation, a connection between Rathke’s pouch and the infundibulum is present (Dattani & Gevers, 2016).

i. Secretory granules are found by 10 to 12 weeks gestation and production of ACTH occurs by 8 weeks gestation, somatotropin by 10 or 11 weeks gestation, follicle­ stimulating hormone (FSH) and luteinizing hormone (LH) by 11 weeks gestation, prolactin by 12 weeks gestation, and TSH by 15 weeks’gestation (Dattani &

Gevers, 2016).

Central nervous system

Hypothalamus Input

Hypothalamus

Anterior pituitary Tropic hormones

Releasing hormones

TSH

T3 +T4

TRH

Target organ

Hormone

Physiologic effect Anterior pituitary

Short feedback loop

Short feedback loop

Thyroid or

Ultra- short feedback loop

Long feedback loop

– – –

– –

– – +

+ + +

FIGURE 6.1 Feedback loops.

TRH, thyrotropin-releasing; TSH, thyroid-stimulating hormone; T₃, triiodothyronine; T₄, thyroxine.

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d. Posterior pituitary originates from the neuro­

ectoderm of the diencephalon (hypothalamus).

It develops during week 5 or 6 of gestation (Schoenwolf et al., 2015).

i. The fetal posterior pituitary is capable of maintaining fetal osmolality and blood volume. In the fetus and newborn, increased levels of ADH are found secondary to hypoxia and stress. Serum levels of ADH in the newborn correlate with the length of labor. Data indicate that ADH secretion is

fully mature in the newborn; however, renal responsiveness may be decreased.

2. Role of the Hypothalamus. The hypothalamus functions as a center to integrate incoming stimuli from the CNS and the peripheral nervous system (PNS). It translates neurotransmitter hormonal sig­

nals into appropriate endocrine responses (Hall, 2016). Secretion of pituitary hormones is controlled through either hormonal or nervous system signals from the hypothalamus that terminate in the pos­

terior pituitary (Hall, 2016). The stimulating and Lactation

Decreases

Effector

Sensor-integrator Ca⁺⁺

Ca⁺⁺

Blood vessels

Blood vessels

PTH

Cell of parathyroid

Osteoclast Bone

Detected by Parathyroid

glands

Set point Increases via Ca⁺⁺

release into blood

Blood Ca⁺⁺

concentration Variable Correction

signal via parathyroid hormone (PTH)

release

Controlled variable

FIGURE 6.2 Negative feedback loops and their target cells.

inhibiting hormones from the hypothalamus are carried to the anterior lobe of the pituitary gland via the hypothalamic–hypophyseal portal vessels (Figure  6.3). The posterior pituitary is controlled by the hypothalamus via nerve fibers that termi­

nate in the posterior pituitary. The hypothalamus synthesizes ADH and transports it to the posterior pituitary.

3. Anatomic Location (Figure 6.4). The hypothalamus is anterior and below the thalamus. It forms the floor and the walls of the third ventricle. The pitu­

itary gland (also called the hypophysis) is located in the sella turcica below the optic chiasm, on the supe­

rior surface of the sphenoid bone, and covered by dura. The pituitary gland is connected to the hypo­

thalamus by the pituitary stalk or infundibulum. The pituitary gland can be accessed surgically through the back of the nose. The pituitary gland has two distinct lobes that produce different hormones (Figure 6.4).

a. Anterior pituitary (adenohypophysis) consti­

tutes 75% of the weight of the pituitary gland (Brashers et al., 2014). Hypothalamic­releasing hormones control hormone secretion. The ante­

rior pituitary secretes growth hormone, ACTH, TSH, prolactin, FSH, and LH.

b. Posterior pituitary (neurohypophysis) hor­

mones are controlled by nerve fibers in the hypo­

thalamus called the hypothalamohypophysia tract (which contains approximately 100,000 nerve fibers). The posterior pituitary secretes ADH and oxytocin. These hormones are synthesized in the hypothalamus, transported via nerve tracts in the pituitary stalk, and stored in the posterior pituitary (Robinson & Verbalis, 2016).

c. Pituitary stalk serves as a communication and connection between the brain and the pitu­

itary gland. The stalk contains axons and neu­

ronal cells that originate in the hypothalamus (Brashers et al., 2014).

4. Cell Types of the Hypothalamus, Neurohypophysis, and Adenohypophysis

a. The supraoptic and paraventricular nuclei orig­

inate in the hypothalamus. Thirst receptors and osmoreceptors are located in the hypothalamus close to the supraoptic nucleus. ADH is formed primarily in the supraoptic nucleus, but small amounts of ADH are produced in the paraven­

tricular nucleus. Oxytocin is formed primarily in the paraventricular nucleus (Hall, 2016).

b. The posterior pituitary is composed of pituicytes. Pituicytes do not secrete hormones but rather provide support structures for the nerve fibers that come from the hypothalamus (Hall, 2016). These nerve­like endings contain secretory granules that lie on the surface of the capillaries where they release ADH and oxytocin.

c. The anterior pituitary consists of six different types of secretory cells (Brashers et al., 2014).

i. Somatotrophs secrete growth hormone (GH) and play a key role in metabolic pro­

cesses for growth.

ii. Lactotrophs secrete prolactin and proliferate during pregnancy secondary to elevated estrogen levels to aid in milk production.

iii. Corticotrophs secrete ACTH, which stimulates steroid production in the adrenals, beta­lipotropin and beta­endorphins in adi­

pose cells for release of fatty acids, regula­

tion of body temperature, and analgesia in brain receptors.

iv. Gonadotrophs secrete LH and FSH, which are necessary for ovulation, follicle maturation, and spermatogenesis.

Hypothalamus Optic chiasm

Artery

Anterior pituitary

Vein Posterior pituitarySinuses

Hypothalamic- hypophysial portal vessels Primary capillary plexus

Median eminence Mammillary body

FIGURE 6.3 Hypothalamic hypophyseal portal system.

Source: From Hall, J. E. (2016). Guyton and Hall textbook of medical physiology (13th ed.). Philadelphia, PA: Elsevier.

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v. Thyrotrophs secrete TSH, which stim­

ulates thyroid hormone production, iodide uptake, and hyperplasia of thymocytes.

vi. Melanotrophs secrete melanocyte­

stimulating hormone (MSH), which pro­

motes secretion of melanin.

5. Hypothalamic Hormones

a. Growth hormone-releasing hormone (GHRH) stimulates release of GH.

b. Thyrotropin-releasing hormone (TRH) stimu­

lates release of TSH.

c. Corticotropin-releasing hormone (CRH) stimu­

lates release of ACTH and beta­endorphin.

d. Gonadotropin-releasing hormone (GnRH) stim­

ulates release of LH and FSH.

e. Somatostatin inhibits release of GH, renin, and parathyroid hormone (PTH) and decreases secretion of TSH, glucagon, and insulin.

f. Dopamine (prolactin inhibitory hormone) inhib­

its synthesis and secretion of prolactin.

g. Prolactin-releasing factor (PRF) stimulates the secretion of prolactin.

h. Substance P inhibits synthesis and secretion of ACTH and stimulates secretion of GH, FSH, LH, and prolactin.

i. These hormones are transported to the anterior pituitary by the hypophyseal portal vessels. The releasing/inhibitory hormones regulate the stimulation and secretion of the anterior pituitary hormones (Brashers et al., 2014; Hall, 2016).

Hypothalamus Third ventricle

Nasal cavity Pituitary diaphragm

Optic chiasm Thalamus Pineal gland Hypothalamus Optic chiasm Infundibulum Brainstem Pituitary (hypophysis)

Mamillary body Infundibulum Neurohypophysis Pars intermedia Pars Anterior Sella turcica (of sphenoid bone)

Adenohypophysis

FIGURE 6.4 Location and structure of pituitary gland and hypothalamic–pituitary–

adrenal complex.

6. Anterior Pituitary Hormones (Figures 6.5 and 6.6) a. Growth hormone

i. Biosynthesis. GH is a polypeptide hor­

mone secreted by the somatotroph cells.

ii. Regulation. The strongest stimulus for release is GHRH, but it can also be stimu­

lated by apomorphine, levodopa, and nor­

epinephrine (Kaiser & Ho, 2016). Endorphins will also cause a release during times of severe stress or exercise (Kaiser & Ho,

2016). GHRH is transported to the anterior pituitary via the hypothalamic–hypophyseal portal vessels. Starvation, hypoglycemia, stress, exercise, and low fatty acid levels can stimulate GH release.

iii. The inhibition of GH release occurs secondary to somatostatin, hyperglycemia, exogenous GH, obesity, and corticoste­

roids. Somatostatin is secreted by cells in the periventricular region (located above the optic chiasm) in the hypothalamus and

Kidney tubules Uterus smooth muscle

Oxytocin (OT)

Prolactin (PRL)

Skin

Melanocyte- stimulating hormone (MSH) Gonadotropic

hormones (FSH and LH)

Testis Testos-

terone

Estrogen Proges-

terone Thyroid gland

Thyroxine

Thyroid- stimulating hormone (TSH) Adrenocortico- tropic hormone (ACTH)

Adenohypophysis Neurophypophysis

Hypothalamic nerve cell

Bone Muscle Growth

hormone (GH)

Adrenal cortex Cortisol aldosterone

Antidiuretic hormone (ADH)

Mammary glands Mammary glands

Ovary

FIGURE 6.5 Pituitary hormones and their target organs.

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in the delta cells of the pancreas (Hall, 2016).

The peptide Gherlin, which is synthesized in gastric mucosa and in the hypothalamus, evokes the release of GH secretion, which induces food intake and is being widely studied in gastric bypass patients (Kaiser

& Ho, 2016).

iv. Secretion. GH is released in a pulsa­

tile fashion with increased levels occurring during slow wave deep sleep (70% of daily secretion) and during adolescence (Kaiser &

Ho, 2016).

v. Effects. GH is an anabolic hormone that facilitates linear growth in all tissues of the body with mediation from insulin­like growth factor 1 (IGF­1). GH increases the mobilization of fatty acids from adipose tis­

sue and enhances their conversion to acetyl coenzyme A to be utilized for energy, which spares protein usage. GH offers protection against hypoglycemia as it decreases car­

bohydrate utilization and increases blood glucose levels (Kaiser & Ho, 2016). GH stim­

ulates bone, cartilage, and tissue growth with the stimulation of osteoclast and osteo­

blasts which increase bone mass (Brashers et al., 2014).

vi. Abnormalities of GH secretion. In growth hormone deficiency (GHD), the ante­

rior pituitary fails to produce enough GH;

consequently, stature is less than genetic determination would indicate. Most GHD is idiopathic, however, it is important to rule out intracranial tumor. An excessive level of GH produces gigantism, usually caused by  pituitary adenoma. Acromegaly is due to  excessive GH secretion after the epiph­

yses of the long bones have closed, which results in excessive growth of the jaw, hands, and feet.

vii. Role in critical illness. Catabolic states induced by acute illness, including surgery, burns, multiple organ dysfunction, and trauma, produce a state of GH resistance as well as decreased production and action of IGF­1 (Kaiser & Ho, 2016). Surgeries or disease states that affect the hypothalamic–

pituitary system will also cause a state of low GH production. There is widespread interest in the use of GH in elevating sport performance and treating osteoporosis and malnutrition states.

b. Adrenocorticotropic hormone

i. Biosynthesis. ACTH is a polypeptide hormone secreted by corticotroph cells.

ii. Regulation. The stimulation for the release of ACTH is CRH, which is secreted by the hypothalamus. Pain, stress (cyto­

kines and catecholamines), trauma, hypoxia, low cortisol levels, and vasopressin admin­

istration also stimulate release of ACTH (Kaiser & Ho, 2016).

iii. Inhibition to release of ACTH occurs primarily through negative feedback loops in response to an integrated neuroendo­

crine process to control the stress response.

The response will in turn decrease the for­

mation of CRF, vasopressin, and dopamine.

Exogenous steroids decrease ACTH secre­

tion and can lead to adrenal insufficiency (AI; Kaiser & Ho, 2016).

iv. Secretion. ACTH has a 24­hour circa­

dian pattern with ultradian pulsality that is controlled peripherally by corticosteroids (Kaiser & Ho, 2016). However, this circa­

dian rhythm is not established in newborns.

Highest levels occur in the early morn­

ing and decrease throughout the day and reach the lowest point between 11 p.m. and 3 a.m. The rhythm is affected by the light/

dark cycle and is lost during times of stress.

ACTH has melanocyte­stimulating abilities, which determine the concentration of mela­

nin in the skin (Hall, 2016).

v. Effects. ACTH stimulates the secretion of the adrenocortical hormones (glucocorti­

coids, mineralocorticoids, and androgens to produce and secrete cortisol and aldosterone [refer to text on cortisol and aldosterone in

“Adrenal Glands”]).

vi. Abnormalities of ACTH secretion.

Long­term ACTH oversecretion stimulates hypertrophy, proliferation, and hyperfunc­

tion of the adrenal cortex (Hall, 2016).

Undersecretion of ACTH leads to AI.

vii. Role in critical illness. Relative AI is seen in critical illness, especially in sepsis. Hydrocortisone therapy is used for treatment. Treatment is reserved for children with catecholamine resistance (more than two vasoactive agents), sepsis, and those refractory to fluid resuscitation (Carcillo & Fields, 2002). Children on chronic

steroids require stress doses of steroids when undergoing surgery or they are critically ill (see “Critical Illness­Related Corticosteroid Insufficiency”).

c. Thyroid-stimulating hormone

i. Biosynthesis. TSH, also known as thyro- tropin, is a glycoprotein hormone secreted by the thyrotroph cells.

ii. Regulation. Stimulations for the release of TSH include TRH, exposure to severe cold, and decreased level of thyroid hor­

mone. Somatostatin and negative feedback from increased blood levels of thyroid hor­

mones inhibit TSH. Dopamine inhibits TSH secretion and other catecholamines raise lev­

els (Brashers et al., 2014).

iii. Effects. TSH stimulates the thyroid gland to release T₃ and T₄, increase glucose uptake and oxidation, stimulate iodide metabolism, and increase thyroid cell size and vascularity (Brashers et al., 2014).

iv. Abnormalities of TSH secretion.

Hypersecretion of TSH induces hyperthy­

roidism. Hyposecretion of TSH induces hypothyroidism.

v. Role in critical illness. Nonthyroidal illness syndrome, or sick euthyroid syndrome, is the most common thyroid abnormality in acute care. This abnormality occurs in patients with critical illness, postsurgery, or when fasting (not caused by pituitary dysfunction) and can be acute or chronic (von Saint Andre­von Arnim et al., 2013). The situ­

ation can be compounded when the child is receiving steroids, amiodarone, iodine dyes, propylthiouracil (PTU), or high­dose pro­

pranolol. T₃ levels are low, T₄ levels are normal or low, and TSH may be normal or reduced secondary to a decreased response to TRH.

It is unclear whether these changes reflect a protective response or a maladaptive pro­

cess, but studies have shown an association between sick euthyroid and severity of illness and clinical outcomes (von Saint Andre­von Arnim et al., 2013). There is debate regarding thyroid supplementation and most authors agree that supplementation is not necessary as a normal TSH reflects a euthyroid state.

Thyroid testing should be repeated once the illness has resolved as hypothyroidism and sick euthyroid can be difficult to distinguish;

however, true hypothyroid patients will have low T₄ and increased TSH, whereas an

elevation in reverse T₃ level is indicative of sick euthyroid state (von Saint Andre­von Arnim et al., 2013). In premature infants, hypothyroxinemia of prematurity can also result in abnormal thyroid function studies, but this is typically transient.

d. Follicle-stimulating hormone

i. Biosynthesis. FSH is a glycoprotein hor­

mone that is secreted by the gonadotroph cells.

ii. Regulation. The stimulus for FSH release is GnRH secreted by the hypothalamus. FSH secretion is inhibited through negative feed­

back secondary to increased levels of estrogen secreted by the ovaries and increased levels of inhibin secreted by the testes.

iii. Effects. In males, FSH stimulates tes­

ticular growth; following puberty, FSH pro­

motes spermatogenesis. In females, FSH stimulates the growth of the ovarian follicles and the secretion of estrogen.

iv. Role in critical illness is unknown.

e. Luteinizing hormone

i. Biosynthesis. LH is a glycoprotein hor­

mone that is secreted by the gonadotroph cells.

ii. Regulation. The stimulus for release of LH is GnRH secreted by the hypothalamus.

Inhibition for the release of LH is negative feedback secondary to increased levels of estrogen, progesterone, and testosterone.

iii. Effects. In males, LH stimulates the pro­

duction of testosterone from the Leydig cells and maturation of spermatozoa. In females, LH stimulates estrogen and progesterone production. LH is responsible for ovulation and maintenance of the corpus luteum.

iv. Role in critical illness is unknown.

f. Prolactin

i. Biosynthesis. Prolactin is a polypeptide hormone that is secreted by the lactotroph cells.

ii. Regulation. The stimulus for the release of prolactin is oxytocin, which is secreted by the posterior pituitary, TRH, and prolactin­

releasing hormone (PRH) from the hypothal­

amus (Brashers et al., 2014). Immune­derived cytokines and stress also stimulate prolactin release. Inhibition of the release of prolac­

tin is dopamine, which is secreted by the hypothalamus.

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iii. Effects. Prolactin stimulates lactation and during pregnancy increases the growth of the ductal system in the breast and the produc­

tion of breast milk. It maintains the corpus luteum and progesterone production during pregnancy. Prolactin stimulates immune func­

tion by supporting the growth and survival of lymphocytes (Brashers et al., 2014).

iv. Role in critical illness. Exogenous dopa­

mine blocks prolactin production and may be associated with clinically significant effects on the immune system. Prolactin acts as a second messenger in the IL­2 and B­cell activation and differentiation and on several types of lymphocytes that can directly affect the immune system (Clayton & McCance, 2014). These relationships are under investi­

gation for possible immune therapy.

7. Posterior Pituitary Hormones (Figure 6.5) a. ADH, or arginine vasopressin (AVP)

i. Biosynthesis. ADH is a polypeptide. The prohormone is carried in vesicles through

the axons to the posterior pituitary. Final synthesis of the prohormone to ADH occurs in the vesicles during axonal transport.

ii. Regulation. Osmoreceptors in the ante­

rior hypothalamus are in close proximity to the supraoptic nucleus. When serum osmolality increases, the cells in this area begin to shrink, stimulating the release of ADH. Nonosmotic regulation occurs with pain, nausea, medi­

cations, cardiac failure, and any volume loss (von Saint Andre­von Arnim et al., 2013).

iii. The most potent stimulus for ADH release is arise in serum osmolality. Osmotic changes as small as 1% stimulate the release of ADH with normal set point of 280 mOsm/kg (Brashers et al., 2014; Robinson & Verbalis, 2016). These small changes in osmolality also stimulate the thirst mechanism, a pro­

tective mechanism to maintain water bal­

ance and prevent dehydration. A decrease in circulating blood volume perceived by the baroreceptors in the carotid sinus of the aortic arch also stimulates ADH release

Thyroid gland Thyrotropin

Growth hormone

Adrenal cortex

Promotes secretion of insulin

ACTH

Increases blood glucose

level Pancreas

Ovary Mammary

gland

Prolactin Luteinizing

Corticotropin

Follicle stimulating

Anterior pituitary gland

FIGURE 6.6 Metabolic functions of anterior pituitary hormones.

ACTH, adrenocorticotropic hormone.

(Robinson  &  Verbalis, 2016). Infants, small children, patients who are comatose or dis­

oriented, or individuals who have abnormal thirst response are not able to meet these physiologic demands; therefore, they are dependent on others to ensure an adequate intake of water. Hemorrhage (10%–20%

circulating blood loss), hypotension, nau­

sea, hypercapnia, morphine, nicotine, and hypoxemia can activate the release of ADH (Hall, 2016; Robinson & Verbalis, 2016).

Catecholamines and angiotensin II can mod­

ulate the release of ADH, which is a power­

ful stimulus to ACTH and prolactin release.

iv. ADH release is inhibited by a serum osmolality below 275 mOsm/kg (Robinson

& Verbalis, 2016). The baroreceptors in the carotid sinus and the volume receptors in the left atrium send signals to the brain­

stem via the vagus and glossopharyngeal nerves. The stimulus is then carried to the hypothalamus. This pathway is primarily inhibitory; however, a fall in pressure or volume decreases the amount of inhibition, facilitating the release of ADH. Vincristine, cyclophosphamide, alcohol, and gluco­

corticoids inhibit ADH release (Brashers et al., 2014). Atrial natriuretic factor (ANF) inhibits ADH release and its effects on the kidney.

v. Effects. Three receptors mediated by binding to G proteins are responsive to ADH: V₁, V₂, and V₃. V₁ receptors are located in the liver, adrenals, brain, and smooth muscle. When stimulated, they produce smooth­muscle contraction, which leads to powerful vasoconstriction. V₂ receptors are located in renal tubular cells, primarily in the collecting tubule and the ascending loop of Henle causing increased permeabil­

ity leading to increased water reabsorption, increased circulating blood volume leading to an antidiuresis. V₃ receptors have a con­

centrated location in the anterior pituitary as cortotroph cells but are also found in kidney, thymus, heart, lung, spleen, uterus, and breast tissue. These receptors stimu­

late the activity of phospholipase C, which raises intracellular calcium levels and aids in the release of ACTH (Brashers et al., 2014;

Molina, 2013). ADH enhances sodium chlo­

ride (NaCl) transport out of the ascending limb of the loop of Henle. This serves to max­

imize the interstitial osmotic gradient in the

renal medulla, facilitating water reabsorp­

tion and urine concentration (Figure 6.7).

vi. Abnormalities of ADH. Deficiency results in diabetes insipidus (DI). Excess ADH results in SIADH (Yee et al., 2010).

vii. Role in critical illness. Vasopressin is administered to patients who have refractory hypotension with vasodila­

tory shock states or after cardiac bypass to increase  systemic vascular resistance (Brashers et  al., 2014). Vasopressin is also administered  to patients with acute or chronic ADH deficiency secondary to sur­

gery. The following disorders are asso­

ciated with ADH: SIADH, cerebral salt wasting (CSW), and DI and are discussed later in this chapter.

b. Oxytocin

i. Biosynthesis. Oxytocin is a polypep­

tide that is almost identical to ADH except for the placement of two of the amino acids in the peptide chain. Like ADH, the pro­

hormone for oxytocin is carried in vesicles through axons from the hypothalamus to the posterior pituitary, where the final

VP secretion Renal water reabsorption

Hyperosmolality Hypotension Hypovolemia Nausea

Hypoglycemia Pain

Thirst Drinking

Osmosensor Bar

osensor

FIGURE 6.7 Regulation of vasopressin, secretion, and serum osmolality.

VP, vasopressin.

Source: From Majzoub, J. A., Muglia, L. J., & Srivatsa, A. (2014).

Disorders of the posterior pituitary. In M. Sperling (Ed.), Pediatric endocrinology (4th ed., pp. 405–443). Philadelphia, PA: Elsevier.