Hypothalamus and Pituitary Gland

Adrenal Glands

The Thyroid Gland

Reproduction

Gastrointestinal Hormones

References

Fig. 2-1 Anatomy of the hypothalamus and hypophysis, showing the hypothalamo-hypophysial portal system to the adenohypophysis and the neural pathways to the neurohypophysis.

Posterior Pituitary

The neurohypophysis secretes two nonapeptides, vasopressin and oxytocin, each of which contains a carboxy-terminal amide and a disulfide loop between residues one and six. However, the two peptides are actually synthesized in the peptidergic neurons of the supraoptic and paraventricular nuclei of the hypothalamus. The sequence of these peptides is encoded within a larger protein that also contains the sequences of other biologically active peptides; such a molecule is known as a polyprotein. The polyprotein precursor for the neurohypophysial hormones is cleaved into three pieces; the nonapeptide is the amino terminus, a neurophysin occupies the central region, and a 40-amino-acid glycoprotein forms the carboxy terminus. The neurophysin is a 10-kDa protein that binds the peptide hormone and protects it from rapid degradation. Larger proteins can form enough internal bonds to create a stable, tight globular structure with no exposed amino or carboxy termini. Such a structure is relatively resistant to proteolysis. The neurohypophysial hormones overcome the handicap of their small size by binding to a larger carrier protein. Further protection is afforded by the primary structure of the hormones themselves: each has its amino acids and carboxy termini blocked, as previously noted. The third product of the polyprotein, the carboxy-terminal glycoprotein, has no known function but may be involved in the processing of the precursor. After synthesis and cleavage of the polyprotein, the hormone and its neurophysin are packaged into vesicles, travel down the axons through the infundibulum, and are stored in the nerve endings in the posterior pituitary until they are released.

Vasopressin (VP), or antidiuretic hormone (ADH), is involved in water conservation. The most important stimulus for its secretion is an elevated blood osmolarity. Secretion can also be elicited by a 10% to 25% decrease in blood volume or by stress and nausea. The major effects of this hormone include the stimulation of water resorption in the kidneys and glycogenolysis in the liver. The former would obviously dilute the blood concentration and the latter may be part of the fight-or-flight response to stress (see the section on Adrenal Glands). ADH may also cause vasoconstriction, but this effect requires pharmacological concentrations of the hormone. Clinically, ADH deficiency results in diabetes insipidus, which is the inability to concentrate urine. As a result, patients can excrete as much as 15 liters of urine daily and must consume equal amounts of liquids to prevent dehydration.

The other peptide hormone is oxytocin, which stimulates smooth muscle contraction; it functions in both parturition and suckling. Uterine contractions at the time of parturition stimulate oxytocin release through a positive feedback loop that is broken when the fetus is finally expelled. Suckling triggers another neural reflex leading to oxytocin secretion, which stimulates the contraction of the myoepithelial cells around the alveoli and ducts of the mammary gland. This contraction forces milk toward the nipple, resulting in the milk “letdown,” and facilitates suckling. This is another example of positive feedback; the loop is interrupted when the infant is sated and stops nursing. Maternal deficiency of oxytocin does not impair delivery, but it is likely that fetal oxytocin crosses into the maternal circulation.

Hypothalamus

The hypothalamus also controls the anterior pituitary, although there are no neural pathways connecting the two structures. Instead, the control is exerted by hormones, which are carried from the hypothalamus to the adenohypophysis through a special circulatory system, the hypothalamo-hypophyseal portal system (Fig. 2-1). The superior hypophyseal artery supplies both the pituitary stalk and the median eminence; the latter forms part of the floor of the third ventricle. The primary capillary plexus is drained by the hypophyseal portal vessel, which opens into a second capillary bed in the anterior pituitary. The neurons in the hypothalamic-hypophysiotropic nuclei send their axons to the median eminence, where they secrete releasing and inhibiting factors into the primary plexus. These factors are then delivered directly to the anterior pituitary, where they regulate the secretion of hormones synthesized in the adenohypophysis.

The structures for many of these factors are known (Table 2-1). Most are small peptides that are synthesized as a larger precursor. In the case of the thyrotropin-releasing hormone (TRH), the precursor contains five copies of the sequence, Gln-His-Pro-Gly, flanked by pairs of basic amino acids. Couplets of basic residues indicate cleavage sites, a carboxy-terminal glycine is a signal for amidation, and the amino-terminal glutamine forms an intra-amino acid peptide bond between the α-amino group and the γ-carboxy group to produce pyroglutamic acid (pGlu). Amino-terminal pGlu’s and amidated carboxy termini protect the free ends of these peptides from degradation by exopeptidases. This is important for the releasing and inhibiting factors because their small size precludes any significant secondary or tertiary structure into which loose ends could be tucked. In the case of the gonadotropin-releasing hormone (GnRH) precursor, two factors may be produced: the GnRH forms the amino terminus, whereas a GnRH-associated peptide forms the carboxy terminus. This latter peptide has prolactin (PRL)-inhibiting activity, but its physiological significance has not been determined. The pituitary adenylate cyclase-activating polypeptide (PACAP) is unique in its wide distribution and broad specificity. This peptide is a member of the vasoactive intestinal peptide family (see section on Adipokines) and can stimulate the release of several pituitary hormones from the adenohypophysis, as well as epinephrine from the adrenal medulla and insulin from the pancreas.

Several releasing factors have similar activity; for example, either TRH or the prolactin-releasing peptide (PrRP) stimulates PRL secretion, and either ghrelin or the growth hormone-releasing factor (GHRF) triggers the release of growth hormone (GH). Other factors have multiple activities: GnRH releases both luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and PACAP stimulates the secretion of LH, PRL, GH, and the adrenocorticotropic hormone (ACTH). In some cases, the pattern of secretion provides signaling specificity; for example, rapid pulses (>1/h) of GnRH favor LH release.

Anterior Pituitary

The cells of the anterior pituitary can be histologically classified by the stains they take up. The chromophobes do not stain at all; at least one group, the...