CHAPTER 2

Hypothalamus and Pituitary Gland

Joseph N. Fisher, M.D.

Monday, January 13, 2003

(9:00 a.m.-9:50 a.m.)

Objectives:

1. Briefly outline physiologic principles and concepts of normal function.

2. Understand how diseases and/or pathological lesions of the hypothalamus and pituitary

produce abnormalities in hormone secretion from the hypothalamus, pituitary and target

organs and their resulting systemic effects according to the following scheme:

(a) Hypopituitarism:

(i) pathologic causes

(ii) mechanism(s) causing decreased pituitary cell function

(iii) biochemical and clinical consequences of hypofunction

(b) Hyperpituitarism:

(i) pathologic causes

(ii) mechanism(s) for pituitary cell hypersecretion

(iii) biochemical and clinical consequences of hyperfunction

3. Briefly outline clinical tests to localize and diagnose hypo- and hyperfunction, i.e., applied pathophysiology.

HYPOTHALAMUS AND PITUITARY

Normal hypothalamus and pituitary

This will have been covered in detail in the Anatomy Course.

A. Anatomy

1. Hypothalamus: optic chiasm

median eminence

pituitary stalk (infundibulum)

mammillary bodies

posterior perforated substance

lateral wall, third ventricle

2. Pituitary gland: normal adult weight: 600 mg

dimensions: 12 mm transverse

9 mm sagittal

6 mm vertical

adenohypophysis - anterior lobe

neurohypophysis - posterior lobe

intermediate lobe: vestigial remnants in man

blood supply: left and right

superior and inferior hypophyseal

arteries from the internal carotids

B. Histology

1. Adenohypophysis:

(a) Old classification: light microscopy

acidophil - GH, PRL

basophil - ACTH, ß-endorphin, TSH, LH, FSH

chromophobe - no known hormone; now known to make ACTH, PRL

(b) New classification: Immunohistochemistry (peroxidase) and

electron microscopy

GH cells (somatotrophs) - 50%

PRL cells (lactotrophs) - 20%

ACTH cells (corticotrophs) - 20%

TSH cells (thyrotrophs) - 5%

FSH,LH cells (gonadotrophs) - 5%

(c) Cytogenesis: Mammosomatotrophs

2. Neurohypophysis

C. Pathology

Classification Hypothalamus (including stalk) Pituitary

congenital hamartomas(gangliocytoma) craniopharyngioma

hypoplasia/aplasia

anencephaly (i.e., nl pituitary, (i.e., no pituitary,

no hypothalamus) normal hypothalamus)

traumatic head injuries post-surgery or

irradiation

inflammatory sarcoidosis sarcoidosis

tuberculosis tuberculosis

post-meningitic autoimmune hypophysitis

infiltrative Hand-Schuller-Christian Hand-Schuller-Christian

disease disease

amyloidosis

- hemochromatosis

- mucopolysaccharidosis

neoplastic germinoma GH-secreting adenoma

astrocytoma prolactin-secreting adenoma meningioma ACTH-secreting adenoma metastases TSH-secreting adenoma null-cell adenoma

-

vascular - infarction--partial or total

idiopathic hypophysiotropic hormone isolated ACTH deficiency

deficiency (single or multiple)

D. Physiology

1. Hypothalamic and anterior pituitary hormones

Adrenohypophysiotropic neurones: Synthesize and secrete peptides or bioamine hormones directly into fenestrated capillaries specialized to receive hormone granules at azonal-capillary terminations in the median eminence (tuber cinereum). The hormones are transported down the pituitary stalk (2 mm thick) via a network of fine vessels called the hypophyseal portal venous system, which terminates in capillaries surrounding the anterior pituitary cells.

Hormones produced in the anterior pituitary and the hypothalamic hormones that regulate their secretion. Studies utilizing immunoeutralisation indicate that VIP and PHI interact to release prolactin during sucking and stress. In man, an analogous peptide, PHM, appears to serve the same purpose. CRH interacts with ADH in a synergistic way in the stress-ACTH release.

Adapted from Besser & Cudworth, Clin. Endocrinolol. J. D. Lippincott, Philadelphia, 1987.

Neurohypophysiotropic neurons: These are magnocellular (large, long) synthesizing antidiuretic hormone (ADH) and oxytocin, respectively, which are stored in and secreted from the posterior pituitary directly into systemic blood.

The hypothalamic-pituitary-target organ axis and feedback regulation

Negative feedback: An increase in the level of target gland hormone suppresses the secretion of its corresponding pituitary trophic hormone, or the appropriate hypothalamic releasing hormone, e.g., androgens inhibit LH/FSH and GnRH.

Positive feedback: An increase in the level of the target gland hormone produces an increased secretion of the corresponding trophic or releasing hormone, e.g., estrogens stimulate LH at the menstrual mid-cycle LH surge.

Long-loop feedback: Target gland hormone regulates secretion at hypothalamic and/or pituitary level.

Short-loop feedback: Pituitary gland hormone modulates one or more hypothalamic-releasing hormones; e.g., prolactin stimulates dopamine and inhibits GnRH release from hypophysiotropic neurones.

Ultrashort-loop feedback: A hypothalamic hormone influences the secretion of its own hormone secreting neurone (autoaxonal inhibition) or an adjacent neurone (para-axonal inhibition).

Neurosecretion

1. Pulsatility: Hypothalamic, pituitary and target gland hormones are usually not

secreted at a constant rate but in pulsatile fashions, e.g., CRH, ACTH and cortisol,

GnRH, LH and FSH and ß-estradiol release. This occurs over short periods, e.g., every 20 minutes, and allows for the fine modulations of hormone secretion.

2. Diurnal rhythms (also known as circadian rhythm): A time-dependent

variation in circulating hormone levels over a 24-hour period, e.g., ACTH, TSH and prolactin. ACTH levels peak at 6-8 a.m. and gradually decrease during the day to reach nadir (trough) at midnight.

3. Sleep-related hormone secretion: Growth hormone is secreted during the day in

slow pulsatile bursts. About 1-2 hours after the onset of sleep, corresponding to

rapid eye movement (REM) stage 3, and stage 4 on the EEG, a large surge of GH occurs.

These nocturnal, sleep related bursts account for nearly 70% of GH secretion, and tend to be greater in children and decrease with age. Prolactin secretion also increases after sleep but is not correlated to the EEG, and has a broader peak, with peak levels usually occurring between about 4 and 7 AM.

E. Pathophysiology

1. Hypopituitarism

(a) Definition: Partial or complete loss of secretion of one (monotropic

hypopituitarism) or more (polytropic hypopituitarism) pituitary

hormones with clinical manifestations of pituitary failure.

Monotropic hypopituitarism - isolated GH deficiency;

isolated LH/FSH deficiency; isolated ACTH deficiency(rare):

isolated TSH deficiency (rare).

Polytropic hypopituitarism - GH, PRL, LH/FSH, TSH, and ACTH

deficiency in various combinations.

Panhypopituitarism - anterior and posterior pituitary failure.

Fifty percent destruction of pituitary tissue causes no clinical consequences; 65-75% moderate effects, and 90% severe

hypopituitarism. Compressive lesions, e.g., expanding

pituitary tumors often, but not always, result in the sequence

of gonadotropic and GH failure, followed by PRL, TSH and,

finally, ACTH deficiencies

.

(b) Causes:

1. pituitary lesions, which lead to primary hypopituitarism.

2. hypothalamic lesions, which lead to secondary hypopituitarism

(c) Mechanisms:

1. Tumors: Hypothalamic tumors destroy the hypophysiotropic neuronal nuclei, resulting in absent hormone release into the portal vessels or from the neurohypophysis, and, in turn, loss of stimulation or inhibition of pituitary hormone release. Pituitary tumors infiltrate the normal pituitary cell mass, destroying or compressing the healthy cells. Any tumor, depending on its growth potential and invasiveness, can enlarge to fill the pituitary fossa, erode the walls, and spread outside the fossa: (1) downwards into the sphenoid sinus; (2) laterally into the cavernous sinus (producing III, IV or VI cranial nerve paralysis); or (3) superiorly through the diaphragma sellae, producing optic chiasmatic compression, with a bitemporal visual field defect (bitemporal hemianopsia) or pituitary stalk compression with additional hypothalamic hormone deficiency. Stalk distortion by a pituitary tumor can modify the blood supply to residual normal pituitary cells, reducing delivery of hypophysiotropic hormones. This, for example, can produce hyper- prolactinemia due to interruption of dopamine delivery to normal, intact lactotrophs adjacent to a nonfunctioning adenoma.

Parasellar tumors (e.g., meningioma) can directly compress the median eminence or stalk or invade the hypothalamus or pituitary.

Metastatic (secondary) tumor (e.g., lung, breast) may lodge in the vascular median eminence and destroy this segment, producing anterior hypopituitarism and diabetes insipidus or form a metastatic deposit in the pituitary itself without producing any clinical effects, because of adequate pituitary reserve.

2. Vascular infarction:

Intra- or postpartum pituitary necrosis (Sheehan's syndrome)

is due to severe blood loss occurring before,during or after

delivery,producing clinical shock (hypotension). The pituitary

gland normally enlarges in pregnancy due to hyperplasia of

lactotrophs and, to a lesser extent, other cell types. This increase in cell mass renders the cells vulnerable to ischemia and necrosis at the time of delivery. In nonpregnant women or in men, shock rarely causes pituitary infarction.

Pituitary apoplexy (intrapituitary hemorrhage): Hemorrhage into a pituitary tumor may occur spontaneously, because the tumor compresses vessel walls and redistributes blood flow, leading to hypoxic injury, damage to capillary integrity and extravasation of blood from the capillaries into the tumor. The tumor and/or normal tissue may be completely destroyed, resulting in autocure and/or hypopituitarism, but the degree of damage varies and the tumor can regrow. The bleeding may extend superiorly into the subarachnoid space, causing a subarachnoid hemorrhage.

3. Inflammatory lesions: Sarcoidosis, tuberculosis and post-meningitic fibrosis cause destruction of the median eminence. Encephalitis can occasionally destroy hypothalamic nuclei.

4. Infiltration: Amyloidosis and hemochromotosis directly damage pituitary cells.

5. Head or post-surgical trauma: Direct or indirect injuries may damage the median eminence or the stalk. Removal of too much normal pituitary tissue at the time of transsphenoidal or transcranial pituitary adenomectomy can cause pituitary cell deficiency.

6. "Idiopathic" hypopituitarism: A condition characterized by multiple pituitary hormone deficiencies presenting clinically in children before puberty. Previously, the cause of the hypopituitarism was unknown. Currently better radiological and endocrine techniques have shown this condition results from selective deficiencies in the secretion of hypothalamic hormones. The pathological and functional processes leading to the deficiencies at the hypothalamic level are unknown.

7. Autoimmune hypophysitis: A chronic inflammatory disease in which pituitary cell destruction results from an inflammatory infiltrate of lymphoid cells. Circulating antibodies to pituitary cell components have been investigated, but are rarely found.

By utilizing the information in Figure 2, the exact site of hormone deficiency could theoretically be predicted from a simultaneous measurement of peripheral blood levels of the appropriate hypothalamic hormone, its corresponding pituitary hormone and, in turn, the target gland hormone. In practice, it has not been possible to measure the hypothalamic hormones reliably, and the location of the lesson is inferred from hormone levels (see Table 1) and radiological techniques.

TABLE I

HYPOPITUITARISM

Deficient Clinical Clinical

Hormone Effects Consequences Manifestations

TSH low T₄, low T₃ Hypothyroidism Weight gain, no energy, cold

intolerance, sluggishness,

low or normal dry cool skin, delayed

range TSH relaxation of reflexes

ACTH low cortisol Hypoadrenalism Hypotension, anorexia, weight

low androgens loss, aches and pains, loss

of axillary hair in women

LH/FSH low testosterone Hypogonadism Impotence (men), infertility

low estradiol/ Amenorrhea (women),

progesterone infertility

(female)

GH low somatomedin-C Short stature (children)

(IgF₁) Growth failure Insulin sensitivity (adults)

? Premature aging

PRL low PRL Failed lactation Alactia

(adult)

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Tests of hypothalamic-pituitary function:

(a) Clinical examination