Highlights of the hypothalamohypophysial system

The hypothalamus and the hypophysis (also known as the pituitary gland) form an integrated neuroendocrine network known as the hypothalamohypophysial system.

The hypothalamohypophysial system consists of two components: (1) the hypothalamic adenohypophysial system, connecting the hypothalamus to the anterior hypophysis; and (2) the hypothalamic neurohypophysial 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 clusters of neurons, called nuclei, some of which secrete hormones. These neuroendocrine cells are located behind the blood-brain barrier, but their secretory products are released outside the blood-brain barrier.

The neuroendocrine cells of the hypothalamus exert positive and negative effects on the pituitary gland through peptides called releasing and inhibitory hormones or factors, have a very short response time (fractions of a second) to neurotransmitters, and send axons into the neurohypophysis.

Axon terminals of the neuroendocrine cells in the neurohypophysis have abundant storage granules containing peptide hormones bound to a carrier protein, called neurophysin. Both hormones and carrier proteins are released by exocytosis into adjacent fenestrated capillaries under the control of neural stimuli.

The anterior hypophysis is highly vascularized. It has a fenestrated capillary plexus (called the primary plexus) in the lower hypothalamus, or pituitary stalk. The primary plexus is connected to a secondary plexus in the anterior lobe of the hypophysis by portal veins, forming the hypothalamohypophysial portal circulation.

Hormones from the anterior hypophysis are produced by epithelial cells, stored in granules—without a carrier protein—and released in a cyclic, rhythmic, or pulsatile manner into the secondary capillary plexus by endocrine stimuli.

The effects of hormones derived from the epithelial cells of the anterior hypophysis have a longer response time (minutes or hours) and can persist for as long as a day or even a month.

Embryologic origin of the hypophysis

The anterior hypophysis and neurohypophysis have different embryologic origins (Figure 18-2). The anterior hypophysis derives from an evagination (pouch of Rathke) of the ectodermal lining of the future oral cavity extending upward toward the developing neurohypophysis. The neurohypophysis develops from an infundibular downgrowth from the floor of the diencephalon. The connecting stem attached to the pouch of Rathke disappears. However, the connecting stem of the neurohypophysis remains as the core of the infundibular stem, or stalk.

Figure 18-2 Development of the hypophysis

The pouch of Rathke 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; and (3) superior extensions of the pouch surround the infundibular stem, forming the pars tuberalis.

Blood supply of the hypophysis: Hypothalamohypophysial portal circulation

The superior hypophysial artery (derived from the internal carotid arteries) (Figure 18-3) enters the median eminence and upper part of the infundibular stem and forms the first sinusoidal capillary plexus (primary capillary plexus), which receives the secretion of the neuroendocrine cells grouped in the hypothalamic hypophysiotropic nuclei of the hypothalamus.

Figure 18-3 Blood supply to the hypophysis

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 anterior hypophysis and receives secretions from endocrine cells of the anterior hypophysis. There is no direct arterial blood supply to the anterior hypophysis.

The hypothalamohypophysial portal system enables (1) the transport of hypothalamic releasing and inhibitory hormones from the primary capillary plexus to the hormone-producing epithelial cells of the anterior hypophysis; (2) the secretion of hormones from the anterior hypophysis into the secondary capillary plexus and to the general circulation; and (3) the functional integration of the hypothalamus with the anterior hypophysis, provided by the portal veins.

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

Histology of the pars distalis (anterior lobe)

The pars distalis is formed by three components: (1) cords of epithelial cells (Figure 18-4); (2) minimal supporting connective tissue stroma; and (3) fenestrated capillaries (or sinusoids) (Figure 18-5), which are parts of the secondary capillary plexus.

Figure 18-4 Identification of basophil, acidophil, and chromophobe cells in the anterior hypophysis

Figure 18-5 Vascular relationships and fine structure of the anterior hypophysis

There is no blood-brain barrier in the anterior hypophysis.

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 hypophysial veins and from there into the venous sinuses.

There are three distinct types of endocrine cell in the anterior hypophysis (see Figure 18-4): (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; and (3) chromophobes (cells lacking cytoplasmic staining).

Acidophils secrete two major peptide hormones: growth hormone and prolactin. Basophils secrete glycoprotein hormones: the gonadotropin folliclestimulating 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 anterior hypophysis is by immunohistochemistry, which demonstrates their hormone content using specific antibodies (see Figure 18-4).

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 anterior hypophysis. Prolactin-secreting cells, or lactotrophs, represent 15% to 20% of the cell population of the anterior hypophysis.

Growth hormone

Growth hormone is a peptide of 191 amino acids in length (22 kd). It has the following characteristics (Figure 18-6): (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.

Figure 18-6 Growth hormone

A stimulatory effect is caused 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.

Clinical significance: Gigantism (in children) and acromegaly (in adults)

Excessive secretion of growth hormone can occur in the presence of a benign tumor called an adenoma.

When the growth hormone-secreting tumor occurs during childhood and puberty at a time when the epiphyseal plates are still active, gigantism (Greek gigas, giant; extremely tall stature) is observed. If excessive growth hormone secretion occurs in the adult, when the epiphyseal plates are inactive, acromegaly (Greek akron, end or extremity; megas, large) develops. In acromegaly, the hands, feet, jaw, and soft tissues become enlarged. Long bones do not grow in length, but cartilage (nose, ears) and membranous bones (mandible and calvarium) continue to grow, leading to gross deformities.

A growth hormone–secreting adenoma does not show the typical pulsatile secretory pattern of the hormone. A decrease in the secretion of growth hormone in children results in short stature (dwarfism).

Prolactin

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 post partum (Figure 18-7). 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.

Figure 18-7 Prolactin

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 anterior hypophysis, 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.

Clinical significance: Hyperprolactinemia

Prolactin-secreting tumors alter the hypothalamohypophysial-gonadal axis, leading to gonadotropin deficiency. Hypersécrétion of prolactin in women can be associated with infertility, caused by the lack of ovulation and oligomenorrhea or amenorrhea (dysfunctional uterine bleeding).

A decrease in fertility and libido is found in males. These antifertility effects are found in both genders and are usually reversible. Galactorrhea (nonpuerperal milk secretion) is a common problem in hyperprolactinemia and can also occur in males.

Hormones secreted by basophils: Gonadotropins, TSH, and ACTH

Gonadotropins (FSH and LH) and TSH have common features: (1) they are glycoproteins (hence the PAS-positive staining of basophils), and (2) they consist of two chains. The α chain is a glycoprotein common to FSH, LH, and TSH, but the β chain is specific for each hormone. Therefore, the β chain confers specificity to the hormone.

Gonadotropins: Follicle-stimulating hormone and luteinizing hormone

Gonadotrophs (gonadotropin-secreting cells) (Figure 18-8) secrete both FSH and LH. Gonadotrophs constitute about 10% of the total cell population of the anterior hypophysis.

Figure 18-8 Gonadotropins (FSH and LH)

The release of gonadotropins is stimulated by gonadotropin-releasing hormone (GnRH; also called luteinizing hormone-releasing hormone [LHRH]), a decapeptide produced in the arcuate nucleus of the hypothalamus. GnRH is secreted in pulses at 60- to 90-minute intervals into the portal vasculature. A single basophil can synthesize and release both FSH and LH in a pulsatile fashion.

In the female, FSH stimulates the development of the ovarian follicles by a process called folliculogenesis. In the male, FSH acts on Sertoli cells