NEUROENDOCRINE SYSTEM

Embryologic origin of the hypophysis ( 18-2 )

The adenohypophysis and neurohypophysis have different embryologic origins. The adenohypophysis derives from an evagination, called Rathke's pouch , of the ectodermal lining of the future oral cavity, extending upward toward the developing neurohypophysis.

As Rathke's pouch is developing, an infundibular downgrowth from the floor of the diencephalon becomes tightly apposed to the pouch and becomes the neurohypophysis. The stem connected to Rathke's pouch disappears, but the connecting stem of the neurohypophysis remains as the core of the infundibular stem, or stalk.

Rathke's pouch develops into three different regions:

• 1.

  Cells of the anterior surface of the pouch give rise to the pars distalis, the bulk of the gland.

• 2.

  Cells of the posterior surface invade the infundibular process.

• 3.

  Superior extensions of the pouch surround the infundibular stem, forming the pars tuberalis.

Hypothalamohypophyseal portal circulation ( 18-3 )

The hypothalamus and the hypophysis form an integrated neuroendocrine network of blood vessels known as the hypothalamohypophyseal system . Its main function is a hormonal exchange required for a rapid communication between the hypothalamus and the hypophysis. The hormonal exchange is facilitated by the fenestrated structure of the capillaries in the hypothalamohypophyseal system.

The hypothalamohypophyseal system consists of two components:

• 1.

  The hypothalamic adenohypophyseal system , connecting the hypothalamus to the adenohypophysis.

• 2.

  The hypothalamic neurohypophyseal system , linking the hypothalamus to the posterior hypophysis.

The hypothalamus , corresponding to the floor of the diencephalon and forming part of the walls of the third ventricle, consists of at least twelve clusters of neurons, called nuclei , some of which secrete hormones.

The neurosecretory cells of the hypothalamus exert positive and negative effects on the hypophysis through neuropeptides (called releasing and inhibitory hormones or factors) , have a very short response time to neurotransmitters (fractions of a second) and send axons into the neurohypophysis. In contrast, the effects of hormones derived from the epithelial cells of the adenohypophysis have a longer response time (minutes or hours) and can persist for as long as a day or even a month.

A pair of superior hypophyseal arteries , derived from the internal carotid arteries, enter the median eminence and upper part of the infundibular stem and form the first sinusoidal capillary plexus (primary capillary plexus) . The primary capillary plexus receives the products of the neurosecretory cells grouped in the hypothalamic hypophysiotropic nuclei of the hypothalamus.

Capillaries arising from the primary capillary plexus project down the infundibulum and pars tuberalis to form the portal veins . Capillaries arising from the portal veins form a secondary capillary plexus that supplies the adenohypophysis and receives secretions from endocrine cells of the adenohypophysis.

Note that the majority of arterial branches penetrate the hypophysis to break up into capillaries for rapid hormone exchange. There is no direct arterial blood supply to the adenohypophysis .

The hypothalamohypophyseal portal system enables:

• 1.

  The transport of hypothalamic releasing and inhibitory neuropeptides from the primary capillary plexus to the hormone-producing epithelial cells of the adenohypophysis.

• 2.

  The secretion of hormones from the adenohypophysis into the secondary capillary plexus and to the general circulation.

• 3.

  The functional integration of the hypothalamus with the adenohypophysis, provided by the portal veins .

A third capillary plexus , derived from the inferior hypophyseal artery, supplies the neurohypophysis. This third capillary plexus collects secretions from neurosecretory cells present in the hypothalamus. The secretory products (vasopressin, also called antidiuretic hormone, and oxytocin) are transported along the axons into the neurohypophysis.

Histology of the pars distalis (anterior lobe) ( 18-4 and 18-5 )

The pars distalis is formed by three components:

• 1.

  Cords of epithelial cells .

• 2.

  Minimal supporting connective tissue stroma .

• 3.

  Fenestrated capillaries (or sinusoids) , which are parts of the secondary capillary plexus.

There is no blood-brain barrier in the adenohypophysis.

The epithelial cells are arranged in cords surrounding fenestrated capillaries carrying blood from the hypothalamus. Secretory hormones diffuse into a network of capillaries, which drain into the hypophyseal veins and from there into the dural venous sinuses.

There are three distinct types of endocrine cell in the adenohypophysis:

• 1.

  Acidophils (cells that stain with an acidic dye), which are prevalent at the sides of the gland.

• 2.

  Basophils (cells that stain with a basic dye and are periodic acid–Schiff [PAS]-positive), which are predominant in the middle of the gland.

• 3.

  Chromophobes (cells lacking cytoplasmic staining).

Acidophils secrete two major peptide hormones: growth hormone and prolactin .

Basophils secrete glycoprotein hormones: the gonadotropin follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) , or corticotropin. Chromophobes include cells that have depleted their hormone content and lost the staining affinity typical of acidophils and basophils.

The precise identification of the endocrine cells of the adenohypophysis is by immunohistochemistry , which demonstrates their hormone content using specific antibodies.

Hormones secreted by acidophils: Growth hormone and prolactin

Acidophils secrete growth hormone , also called somatotropin . These acidophilic cells, called somatotrophs , represent a large proportion (40% to 50%) of the cell population of the adenohypophysis. Prolactin-secreting cells, or lactotrophs , represent 15% to 20% of the cell population of the adenohypophysis.

Growth hormone ( 18-6 )

Growth hormone is a peptide of 191 amino acids in length (22 kd). It has the following characteristics:

• 1.

  Growth hormone has structural homology similar to prolactin and human placental lactogen. There is some overlap in the activity of these three hormones.

• 2.

  It is released into the blood circulation in the form of pulses throughout a 24-hour sleep-wake period, with peak secretion occurring during the first two hours of sleep .

• 3.

  Despite its name, growth hormone does not directly induce growth; rather, it acts by stimulating in hepatocytes the production of insulin-like growth factor-1 (IGF-1), also known as somatomedin C . The cell receptor for IGF-1 is similar to that for insulin (formed by dimers of two glycoproteins with integral cytoplasmic protein tyrosine kinase domains).

• 4.

  The release of growth hormone is regulated by two neuropeptides.

A stimulatory effect is determined by growth hormone–releasing hormone (GHRH), a peptide of 44 amino acids. An inhibitory effect is produced by somatostatin (a peptide of 14 amino acids) and by elevated blood glucose levels . Both GHRH and somatostatin derive from the hypothalamus. Somatostatin is also produced in the islet of Langerhans (pancreas).

IGF-1 (7.5 kd) stimulates the overall growth of bone and soft tissues. In children, IGF-1 stimulates the growth of long bones at the epiphyseal plates. Clinicians measure IGF-1 in blood to determine growth hormone function. A drop in IGF-1 serum levels stimulates the release of growth hormone .

IGF target cells secrete several IGF-binding proteins and proteases . The latter can regulate the delivery and action of IGF on target cells by reducing available IGF-binding proteins.

Prolactin ( 18-7 )

Prolactin is a 199-amino-acid single-chain protein (22 kd). Prolactin, growth hormone and human placental lactogen share some amino acid homology and overlapping activity,

The predominant action of prolactin is to stimulate the initiation and maintenance of lactation . Lactation involves the following:

• 1.

  Mammogenesis , the growth and development of the mammary gland, is stimulated primarily by estrogen and progesterone in coordination with prolactin and human placental lactogen.

• 2.

  Lactogenesis , the initiation of lactation, is triggered by prolactin acting on the developed mammary gland by the actions of estrogens and progesterone. Lactation is inhibited during pregnancy by high levels of estrogen and progesterone, which decline at delivery. Either estradiol or prolactin antagonists are used clinically to stop lactation.

• 3.

  Galactopoiesis , the maintenance of milk production, requires both prolactin and oxytocin.

The effects of prolactin, placental lactogen and steroids on the development of the lactating mammary gland are discussed in Chapter 23 , Fertilization, Placentation and Lactation.

Unlike other hormones of the adenohypophysis, the secretion of prolactin is regulated primarily by inhibition rather than by stimulation .

The main inhibitor is dopamine . Dopamine secretion is stimulated by prolactin to inhibit its own secretion.

A stimulatory effect on prolactin release is exerted by prolactin-releasing hormone (PRH) and thyrotropin-releasing hormone (TRH).

Prolactin is released from acidophils in a pulsatile fashion, coinciding with and following each period of suckling. Intermittent surges of prolactin stimulate milk synthesis .