E N D O C R I N E S E R I E S #5

The Hypothalamus

Mary Set& RNC, MS, ARNP

THE HYPOTHALAMUS ARISES FROM THE VENTRAL PORTION input into the endocrine system and alters glandular functionof the diencephalon (Figure 1). Hypothalamic nucleiand supraoptic track fibers develop by 12 to 14 weeks of ges-tation, with maturation of the target organs of the endocrine

ABSTRACTsystem. Homeostatic blood levels

35 weeks. The hypothalamusdevelops simultaneously with butThe hypothalamus is an integral part of the neuroen-

independently of the pituitarydocrine system. The anatomy, embryologic development,sent back to the hypothalamus orthe target gland itself to inhibit

gland. Located in the forebrain,and normal function of the hypothalamus are describedhere. Pathophysiology of congenital abnormalities and

hormone synthesis when ade-in the reg ion o f the dien-cephalon, the hypothalamus lies

quate blood levels are reached.

addition, nursing implications of caring for such an infant hor-

are addressed. mones and the resulting actionsof the anterior pituitary hor-

floor and part of the lateral wall mones affect regulation of the&he 2).2

the neurosecretory cells, the hypothalamus controls therelease of hormones from the anterior pituitary gland.

~IYIOTHALAMIC-PITIJlTAIiYThe hypothalamus acts as a control center for the autonom-

\vithvarious lobes of the pituitary gland by two different types ofpathways. One is a vascular link with the anterior pituitary,

rior pituitary hormones. The posterior pituitary is an extension

Acting as the core of a negative feedback network, thehypothalamus secretes liormone~rele3singtither pitu-it3rv hormones. Because of the close interaction be0lreen thehypothalamus and the pituitary gland, the nervous system has

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thyroid, adrenal, and gonadal limction as wei as growth andsomatic development.3-s

The integration of the neurologic and endocrine systems isbidirectional. Not only does the nervous system affectendocrine function, but the endocrine system can regulatefunctions of the nervous system. The immune system affectsregulation of the neuroendocrine system as well. For example,cytokines, substances produced by the immune system, havebeen shown to act on the hypothalamus to stimulate ordepress hormone-releasing hormones. Cytokines includeinterleukins, tumor necrosis factor, and interferons.Interleukin-1 produced by macrophages act on the hypotha-larn~~s to stimulate secretion of corticotropin-releasing lior-monc (CRH), which ultimately results in the release ofcortisol from the adrenal cortex. In addition, many immuno-logically reactive cells actually secrete hormones such asadrenocorticotropic hormone (ACTH), previously thoughtto originate only in the pituitary gland. The interrelationships

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FIGURE 1 n External view of the brain.

(A) View of the brain at the end of the fifth week. (B) Similar view at seven weeks. (C) Median section of this brain, showing the medial surface of theforebrain and midbrain. (D) Similar section at eight weeks. (E) Transverse section of the diencephalon, showing the epithalamus dorsally, the thalamuslaterally, and the hypothalamus ventrally.

Midbrain

Cerebral hemisphere

A\ \ / \

Forebrain Optic cup Olfactory bulb Optic nerve

Epithalamus

Sulcus limitans

Mamillary body Level of section Elnfundibulum

Optic chiasmaEpendymal roof

Epithalamus

Thalamus

Hypothalamic sulcus

Hypothalamus

From: Moore KL, and Persaud TVN. 1998. The Developing Human: C/inico//y Oriented Embryology, 6th ed. Philadelphia: WB Saunders, 471. Reprinted bypermission.

FIGURE 2 n The hypothalamic reqion of the brain. FIGURE 3 = Hypothalamic releasing factors and actions of anteriorpituitary hormones.

Mature central nervous system

.hypothalamus(dfencephalon)

Midbrain(mesencephalon)

(myelencephalon)

from: Kandel ER, Schwartz JH, and Jesse1 TM. 1991. Principles of NeuralScience, 3rd ed. New York: Elsevier, 299. Reprinted by permission.

between the immune, neurologic, and endocrine systemsaffect cellular communication in such an integrated way thatthese systems together are referred to as the neuro-endocrine-immune system.2>3

H O R M O N E S E C R E T I O NAppropriate levels of endocrine hormones are maintained

by negative feedback. Hypothalamic hormones control theinhibition or release of hormones from the anterior pituitaryvia the hypothalamic-pituitary axis (Figure 3). A hypothalam-ic releasing hormone stimulates the adenohypophysis (anteri-or pituitary) to produce a specific hormone. The hormonereleased by the anterior pituitary then stimulates a specificendocrine gland to produce another hormone, which in turnacts on a specific target organ. The specific hormone isreleased until the physiologic level is achieved. A critical orhomeostatic blood level determines when the hypothalamusstops secreting releasing hormones. Pituitary hormones affectthe fimction of target tissues by altering cellular chemistry,adjusting cell membrane permeability, or acting on a cell as awhole.5

Hypothalamic hormones include growth hormone-releas-ing hormone (GHKH), somatostatin (SST), CRH, thy-rotropin-releasing hormone (TRH), gonadotropin-releasinghormone (GnRH), and prolactin-inhibiting hormone (PIH).

Growth hormone-re!easinH horvnone stimulates the anteriorpituitary to release growth hormone. The major target tissuesof growth hormone are the liver and adipose tissues. Growthhormone has powerful effects on growth and metabolism,including linear growth; stimulation of bone and cartilagegrowth; stimulation of insulin-like growth factor (IGF- 1 );

Hypothalamus

GHRH Somotostatin* CRH TRH GnRH PH

TSH FSH Proloctin?I 1 JA 1

Body Adrenal Thyroid Ovaries Testes Ovaries Mammarygrowth cortex gland

I I

gland

1 1glucocorticoids Thyroxine Estrogen Progesterone

mineralocorticoidssex hormones

* Indicates action of somatostatin.Adapted from: Meyers FH, Jawetz E, and Goldfien A. 1972. Review of

Medical Pharmacology, 3rd ed. Los Altos, California: Lange, 390.

increased DNA, RNA, and protein synthesis; elevation ofblood glucose levels; promotion of positive nitrogen balance;and increased fat mobilization. Somatostatin inhibits the ante-rior pituitary release of growth hormone (GH), thyroid-stim-ulating hormone (TSH),insulin, glucagon, gastrin, andprolactin.3,4

Corticotropin-releasing hornzone stimulates the anteriorpituitary to secrete ACTH. Adrenocorticotropic hormonecontrols the function of the adrenal cortex and stimulatesrelease of glucocorticoids, mineralocorticoids, and some weakandrogcns.

Tbyrotvopivt-releasing horvnone stimulates the anterior pitu-itary to release TSH and prolactin. The major target tissue ofTSH is the thyroid gland, whereas the mammary gland is thetarget tissue of prolactin.

Gonadotropin-releasing hormone stimulates the anteriorpituitary to release follicle-stimulating hormone (FSH) andluteinizing hormone (LH), which target the ovaries and thetestes, controlling reproductive function.

Prolactin-inhibitintj hormone inhibits the release of pro-Iactin from the anterior pituitary. Unlike the secretion ofother pituitary hormones,the secretion of prolactin isincreased in the absence of hypothalamic influences.

Dopamine, the most important PIH, suppresses all aspects ofprolactin synthesis and secretions.6

The hypothalamus also secretes the prohormones that areresponsible for the stimulation of antidiuretic hormone(ADH, arginine) and oxytocin from the posterior pituitary.Antidiuretic hormone is important in the regulation of plasmaosmolaliqr; it increases the permeability of the distal tubuleand collecting duct of the renal nephron, resulting in reab-sorption ofwater and reduction in plasma osmolality and con-centration ~furinc.~~

Both the anterior and posterior hypothalamus controlthermoregulation in response to skin receptors. The anteriorhypothalamus is temperature sensitive and controls heat lossmechanisms. The posterior hypothalamus is the site of thesetpoint, or threshold temperature; heat production and lossare regulated to maintain the core temperature within a rangedetermined by the setpoint. The posterior hypothalamus isthe central controller of responses to cold and heat stimuli,receiving input from central and peripheral receptors. Withcold stress, the thcrmorcgulatory center acts to conserve heator increase heat production. Thermoregulation is more diffi-cult in the neonate because of the thinner layer of subcuta-neous fat and larger surface-to-volume ratio, especially inpreterm infants.118 The threshold for heat productiondepends more on skin temperatures in the neonate than inadults. As a result, cold responses are related more to skintemperature than to core temperature changes.,9

PATHOPHYSIOLOGYThe etiology of hypothalamic dysfunction in preterm and

term infants includes congenital abnormalities, intraventricu-lar hemorrhage, bacterial meningitis, tumors, trauma, andkernicterus. Symptoms and signs of hypothalamic dysfunctioninclude sexual abnormalities (hypogonadism in neonates),diabetes insipidus (DI), somnolence, thermodysregulation,and sphincter disturbance.

Hypothalamic injury causes decreased secretion of mostpituitary hormones, but can cause hypersecretion of hor-IIIOIICS normally under inhibitory control by the hypothala-m u s . Impairment of inhibitory control can lead toinappropriate ADH secretion, resulting in the syndrome ofinappropriate secretion of antidiuretic hormone (SIADH).6Characteristic presenting signs of SIADH include weightgain, edema, and hyponatremia with low plasma osmolality.Urine output may be low, with high specific gravity and urinesodium levels. Any disorder or process that interferes withinput to the hyl-othalamus-sLlcl1 as pulmonary diseases, cen-tral ner\~ous system disorders, hvpothyroidislii, or drugs thataffect the central nervous sys;em-may cause SIADH.OTreatment often consists of tluid restriction, and diuretics ma!be used in sonic iiistmccs.5

Congenital MalformationHypothalamic dysf&iction from congenital malformations

of the brain or hypothalamus is a common cause of hypopitu-itarism. Infants with congenital GH deficiency often have anabnormal pituitary stalk and hypoplasia of the anterior pitu-itary. Holoprosencephaly, resulting from an abnormal midlinedevelopment of the embryonic forebrain, is typically associatedwith hypothalamic insufficiency. Facial dysmorphism of holo-prosencephaly ranges from cyclopia to hypertelorism, as well asabsence of the nasal septum, midline clefts of the palate or lip,and sometimes a central single incisor. GH deficiency andother pituitary hormone deficiencies may be present.

Congenital hypothyroidism occurs in 1 in 5,000 new-borns. It is generally classified as primary, secondary, or ter-tiary. Infants with congenital hypothyroidism, whetherattributable to primary, secondary, or tertiary failure, appearclinically normal at birth. Most are diagnosed in the firstthree months of life through newborn screening programsbecause of failure to thrive and grow and other problems.12Clinical signs and symptoms of congenital hypothyroidism ininfancy include umbilical hernia, dry skin, large tongue,hypotonia, inactivity, mottled skin, prolonged jaundice, lowbirth weight, poor feeding, transient hypothermia, and largefontanels.lJ3 Primary hypothyroidism is most often causedby developmental defects such as ectopic thyroid, thyroidhypoplasia, or agenesis.l4 Secondary and tertiary hypothy-roidism are due to failure of secretion of TSH and TRHfrom the pituitary and hypothalamus, respectively.15

Congenital hypothyroidism due to hypothalamic-pituitarydefects results in ineffective TSH stimulation of thyroid hor-mone secretion and can be caused by a variety of abnormali-ties in TSH synthesis and metabolism. These includeanomalous hypothalamic or pituitary development, isolatedor familial deficiencies in TRH or TSH secretion, or TSHdeficiency in association with other pituitary hormone defi-ciencies. Hypothalamic-pituitary hypothyroidism is rare. Thecombined prevalence of these abnormalities is approximately1 in 60,000 to 140,000 live births. Infants with primaryhypothyroidism have low serum T4 and high TSH concentra-tions in neonatal blood samples, and infants with hypothalan-ic-pituitary defects have low T4 and normal plasma TSHlevels. As a result, infants with TSH deficiency are not detect-ed by most screening programs, which report as positive onlythose infants with elevated plasma TSH levels. An infant witha low free T4 should be carefully examined for evidence ofhypothyroidism, and other tests of pituitary function shouldbe performed. A subnormal TSH response to TRH confirmsa diagnosis of pituitary TSH deficiency; a normal or pro-longed peak level of TSH atier TKH stimulation supports adiagnosis of hypothalamic TIU3 deficiency.,

Diabetes insipidus is a disease ofantidiuretic hormone deli-ciency. Central DI is most often caused by a destructive lesion;iffecting the Iieuroh~poph~selil system. Infants with central

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DI have dilute urine compared to plasma osmolality and lowto undetectable levels of plasma ADH. The symptoms resolveafter administration of ADH. Although transient DI mayfollow any injury to the neurohypophysis, permanent DIoccurs only when damage is high in the pituitary stalk.6

Other disorders associated with hypothalamic hypofunc-tion include hypothalamic dwarfism; Kallmanns syndrome,idiopathic hypogonadotropic hypogonadism, and fertileeunuch syndrome associated with G&H deficiency; and ter-tiary adrenal insufficiency. Diencephalic syndrome, a rare dis-order associated with GH hypersecretion, is almost always aresult of hypothalamic neoplasm.

CASE STUDYBaby girl (BG) C was delivered at 40 weeks gestational age

(by dates) to a 21.year-old mother whose pregnancy wasuncomplicated. Fetal tachycardia developed about an hourbefore delivery. After six hours of labor, the infant was deliv-ered vaginally with the assistance of low forceps. The infantwas dusky and required mask oxygen for approximately twominutes. Apgars were 7 at one minute and 9 at five minutes.Because the tachycardia continued at ten minutes of age andBGC was noted to be very pale, she was transferred to theNICU for fluid resuscitation for suspected hypovolemia.

A sepsis workup was performed and antibiotics started.Tachycardia continued over the next few hours (-200 bpm).Multiple fluid boluses were given with some improvement intachycardia and peripheral perfusion. The infants plateletcount was 73,000/mm3 initially, and a platelet transfusionwas given. Physical examination revealed prominent moldingof the head and a large cephalohematoma. Neurologic exami-nation was unremarkable at admission.

Within nine hours of birth, BGC was having frequent peri-ods of shallow respirations and apnea, resulting in desatura-tions and requiring almost constant stimulation. She wasintubated and placed on mechanical ventilation. Her hemat-ocrit level dropped precipitously (from 54 mg/dl to 27mg/dl) at about 14 hours of age, necessitating a packed redblood cell (PRBC) transfusion. Increased prothrombintime/partial prothrombin time (PT/lTT), decreased fibrino-gcn, and fibrin split products were also noted, consistent withdisseminated intravascular coagulation (DIC). Coagulationstudies improved after further platelet, fresh frozen plasma(FFP), and PRBC transfusions. BGC also required initiationofvasopressors for hypotension at 17% hours of age.

A cranial ultrasound done at 12 hours of age was normal.The infant bcgnn exhibiting seizure activity (arching, swim-ming motions, and tonic positioning), as well as prolongedclonus, at approximately 13 hours of age. She was gilzen aloading dose of phenobarbital and, subsequently, phenytointo control seizures. Her neurologic status changed dramati-tally; she had only occasional spontaneous movements, intet--mittent respiratory efforts, and minimal response to kyaiii.

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By 24 hours of age, BGCs pupils were fixed, dilated, andunresponsive to light, and the infant developed right-sidedexophthalmos. A follow-up cranial ultrasound on day 2 of liferevealed an area that was hyperechoic and was felt to be afocal parenchymal hemorrhage or periventricular leukomala-cia. A highly abnormal EEG on day 3 of life showed lowamplitude background and was compatible with a severebicortical dysfimction, carrying a poor clinical prognosis inlight of the infants clinical history. Concurrently, the infantsurine output increased and urine was very dilute. Serum sodi-um and serum osmolality were elevated (150 mg/dl and 3 15mg/dl respectively), and glucose levels were increased. Theinfant was diagnosed with diabetes insipidus and was treatedwith desmopressin (DDAVP). Synthroid was started at 25 pgonce daily in response to abnormally low TSH and freethyroxine levels (0.67 milliunits/ml and 0.63 ng/dl, respec-tively)

A computed tomography (CT) scan of the brain at one weekof age showed an extensive subdural, subarachnoid, and sub-galeal hemorrhage and hypoxic degeneration to the entire cere-bral area and brain stem. Magnetic resonance imaging alsoshowed extensive areas of hemorrhage within multiple compart-ments, suggestive of hypoxic/ischemic injury. The infant contin-ued in a comatose state with no hope of improvement.Life-sustaining treatments were discontinued after discussionand agreement with the parents.

This case study illustrates abnormalities in hypothalamicfunction that can occur as a result of trauma to the brain and,specifically, the hypothalamus. Baby Girl C exhibited hypose-cretion of thyroid hormone, as well as ADH deficiency,resulting in central diabetes insipidus.

SUMMARYAlthough the hypothalamic-pituitary axis provides over-

sight for the endocrine system, regulation may be dysfunc-tional as a result of brain insult, disease, or geneticabnormality or in infants who are premature. Measurement ofkey hormones, such as thyroid hormone or cortisol, can giveinsight into possible deficiencies. If found, deficiencies of allmajor hormones can be replaced. Such treatment may be crit-ical in improving morbidity and avoiding unnecessary mortnl-ity in these infants.

Treatment or prevention of the etiologies responsible folinappropriate hormone secretion should be implemented assoon as hypothalamic disease is diagnosed. Early detectionand treatment in some cases \vill improve long-term out-comes. In other cases, supportive care of the infant and farnil)is the only option. (3)

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2. Toto KH. 1994. Endocrine nnd Metabolic Deranflements:Clinical Relevance in the Critically Ill. Flower Mound, Texas:Barbara Clark Mims Associates, 34.

3. Toto KH. 1994. Endocrine physiology: A comprehensive review.Critical Care Nursing Clinics of North America 6(4): 637-659.

4. Ramsey I. 1986. A Synopsis of Endocrinology and Metabolism, 3rded. Bristol, England: John Wright.

5. Gamblian V, et al. 1998. Assessment and management ofendocrine dysfimction. In Comprehensive Neonatal Nursing: APhysiologic Perspective, 2nd ed., Kenner C, Lott JW, andFlandcrmeyer AA, cds. Philadelphia: WB Saunders, 476495.

6. Reichlin S. 1992. Neuroendocrinology. In Williams Textbook ofEndocrinology, 8th ed., Wilson JD, and Foster DW, eds.Philadelphia: WB Saunders, 165-248.

7. Hedge GA, Colby HD, and Goodman RL. 1987. ClinicalEndocrine Physiology. Philadelphia: WB Saunders.

8. Guyton AC. 1992. Function of the Human Body, 5th ed.Philadelphia: WB Saunders, 404.

11. Reiter EO, and Rosenfeld. 1992. Normal and aberrant growth.

9. Mestyan J, et al. 1964. Surface temperature versus deep body

In Williams Textbook of Endocrinology, 8th ed., Wilson fD, and

temperature and the metabolic response to cold of hypothermic

Foster DW, eds. Philadelphia: WB Saunders, 1427-1508.

premature infants. Biology of the Neonate 1: 230.

10. Scheithauer BE, et al. 1997. Neurohypophysis and hypothala-mus. In Bloodworths Endocrine Pathology, 3rd ed., Lechago J,and Gould VE, eds. Baltimore: Lippincott Williams & Wilkins,25-83.

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12. Miculan J, et al. 1993. Congenital hypothyroidism: Diagnosisand management. Neonatal Network 12(6): 25-34.

13. Polk DH, and Fisher DA. 1996. Thyroid disorders. In IntensiveCare of the Fetus and Neonate, Spitzer AR, ed. St. Louis: Mosby-Year Book, 958-969.

14. Gamella TL, et al. Neonatology: Management, Procedures, On-Call Problems , Diseases, and Drzgs, 4th ed. Stamford,Connecticut: Appleton & Lange, 546-549.

15. Moshang T, and Thornton P.S. 1994. Endocrine disorders. InNeonatology: Pathophysiology and Management of the Newborn,4th ed., Avery GB, Fletcher MA, and MacDonald MG, eds.Philadelphia: Lippincott Williams & Wilkins, 774-791,

About the AuthorMary Settle is a neonatal nurse practitioner in the NICU at Scott &

White Memorial Hospital in Temple, Texas. Her undergraduate degree

For &rther information, please contact:

is from Lanston University, and she received her masters degree porn theUniversity of Maryland in 1998. Ms. Settle is a member of NANN.

Mary Settle, RNC, MS, ARNPScott & White Memorial HospitalNeonatal Intensive Care Unit2401 South 31st StreetTemple, TX 76508E-mail: msettle@mailcity.com

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