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 in the testes to stimulate the aromatization of estrogens from androgens and the production of androgen-binding protein, with binding affinity to testosterone.

In the female, LH stimulates steroidogenesis in the ovarian follicle and corpus luteum. In the male, LH controls the rate of testosterone synthesis by Leydig cells in the testis. The function of FSH and LH in the male is analyzed in Chapter 20, Spermatogenesis.

The release of FSH and GnRH is inhibited by (1) inhibin, a heterodimer protein formed by α- and β-peptide chains, secreted by the male and female target cells (Sertoli cells and granulosa cells and cells of the anterior hypophysis), and (2) estradiol.

The release of FSH in both females and males is enhanced by a homodimer protein, called activin, secreted by Sertoli cells and granulosa cells. It consists of two β chains. Little is known about what controls αβ (inhibin) and ββ (activin) dimerization.

We will discuss in Chapter 20, Spermatogenesis, and Chapter 22, Follicle Development and Menstrual Cycle, the functions of FSH and LH in spermatogenesis, Leydig cell function, folliculogenesis, and luteogenesis.

Clinical significance: Infertility

The secretion of FSH and LH can decrease when there is a deficient secretion of GnRH, caused by anorexia or a tumor of the hypophysis, which can destroy the gonadotrophs, thereby decreasing FSH and LH secretion.

A decrease in fertility and reproductive functions can be observed in females and males. Females can have menstrual disorders. Small testes and infertility can be seen in males (a condition known as hypogonadotropic hypogonadism) when GnRH secretion is deficient.

Castration (ovariectomy in the female and orchidectomy in the male) causes a significant increase in the synthesis of FSH and LH as a result of a loss of feedback inhibition. Hyperfunctional gonadotropic cells are large and vacuolated and are called castration cells.

Thyroid-stimulating hormone (thyrotropin)

Thyrotropic cells represent about 5% of the total population of the anterior hypophysis.

TSH is the regulatory hormone of thyroid function (Figure 18-9) and growth. The mechanism of action of TSH on thyroid cell function is discussed in the thyroid gland section of Chapter 19, Endocrine System. Thyrotropin-releasing hormone (TRH), a 3-amino-acid-peptide produced in the hypothalamus, stimulates the synthesis and release of TSH from basophils. TRH also stimulates the release of prolactin. The release of TSH is inhibited by increased concentrations of the thyroid hormones triiodothyronine (T₃) and thyroxine (T₄).

Figure 18-9 Thyroid-stimulating hormone (TSH)

Clinical significance: Hypothyroidism

A deficiency in the secretion of TSH (observed in rare cases of congenital hypoplasia of the hypophysis) produces hypothyroidism, characterized by reduced cell metabolism and temperature and basal metabolic rate and mental lethargy. Hypothyroidism is also observed in the autoimmune disorder Hashimoto’s disease. Hypothyroidism can also result from a disease of the thyroid gland or a deficiency in dietary iodine. We will discuss hyperthyroidism in the thyroid gland section of Chapter 19, Endocrine System when we describe Graves’ disease.

Adrenocorticotropic hormone

ACTH, or corticotropin, is a single-chain protein, 39 amino acids in length (4.5 kd), with a short circulating time (7 to 12 minutes). Its primary action is to stimulate growth and steroid synthesis in the zonae fasciculata and reticularis of the adrenal cortex. The zona glomerulosa of the adrenal cortex is under the control of angiotensin II (see the adrenal gland section of Chapter 19, Endocrine System). The effects of ACTH on the adrenal cortex are mediated by cyclic adenosine monophosphate (cAMP). ACTH also acts beyond the adrenal gland by increasing skin pigmentation and lipolysis.

ACTH derives from a large glycosylated precursor of 31 kd called pro-opiomelanocortin (POMC), processed in the anterior hypophysis. The products of POMC are the following (Figure 18-10):

1. An N-terminal peptide of unknown function, ACTH, and β-lipotrophic hormone (β-LPH). These three POMC derivatives are secreted by the anterior hypophysis.

2. The cleavage products of β-LPH, γ-LPH, and β-endorphin are released into circulation. β-LPH and γ-lipotrophic hormone (γ-LPH) have lipolytic action, but their precise role in fat mobilization in humans is unknown.

3. γ-LPH contains the amino acid sequence of β-melanocyte–stimulating hormone (β-MSH; not secreted in humans). β-Endorphin contains the sequences of met-enkephalin (met-enk). There is no evidence that β-endorphin is cleaved in the hypophysis to form met-enk.

4. ACTH is cleaved to α-melanocyte-stimulating hormone (α-MSH) and corticotropin-like intermediate peptide (CLIP). α -MSH and CLIP hormones, found in species with a hypophysis with a prominent pars intermedia, cause dispersion of melanin granules in melanophores and darkening of the skin of many fish, amphibians, and reptiles.

Figure 18-10 Processing of pro-opiomelanocortin (POMC)

The release of ACTH is controlled by the following (Figure 18-11):

1. A stimulatory effect determined by corticotropin-releasing hormone (CRH) from the hypothalamus. CRH co-localizes with antidiuretic hormone (ADH; see later section, Neurohypophysis) in the paraventricular nuclei. Both ADH and angiotensin II potentiate the effect of CRH on the release of ACTH.

2. An inhibitory effect caused by high levels of cortisol in blood either by preventing the release of CRH or by blocking the release of ACTH by basophil corticotropic cells (ACTH-secreting cells).

Figure 18-11 Adrenocorticotropic hormone (ACTH)

ACTH is secreted in a circadian manner (morning peaks followed by a slow decline afterward).

Clinical significance: Cushing’s disease

An ACTH-secreting adenoma of the hypophysis causes Cushing’s disease. This disease is characterized by an increase in the production of cortisol by the zona fasciculata of the adrenal cortex (see the adrenal gland section in Chapter 19, Endocrine System), obesity, osteoporosis, and muscle wasting. A reduction in the secretion of ACTH results in diminished secretion of cortisol and in hypoglycemia.

A loss of ACTH decreases adrenal androgen secretion. In females, androgen deficiency causes loss of pubic and axillary hair. This effect is not observed in males because it is compensated for by the testicular secretion of androgens.

NEUROHYPOPHYSIS

The neurohypophysis consists of three histologic components (Figures 18-12 and 18-13): (1) Pituicytes, resembling astrocytes, provide support to the axons. (2) Unmyelinated axons, derived from neuroendocrine cells (called magnicellular neurons because their cell bodies are large) of the supraoptic and paraventricular nuclei, make up the infundibulum and form the hypothalamohypophysial tract. Axons, with bulging intermittent segments and terminals (called Herring bodies) containing secretory products (the neurophysin-hormone complex), are found in the pars nervosa (neural lobe). Neurophysin is secreted with the hormone and does not have an apparent biologic action other than serving as a hormone carrier during axonal transport. (3) Fenestrated capillaries are derived from the inferior hypophysial artery.

Figure 18-12 Neurohypophysis

Figure 18-13 Structure and function of the neuroendocrine cell

Pituicytes are astrocyte-like glial cells with abundant glial fibrillary acidic proteins, an intermediate filament protein, and a few lipid droplets in their cytoplasm. The cytoplasmic processes of pituicytes (Figure 18-14) (1) surround the axons derived from the neuroendocrine cells, (2) extend between the axon terminals and the basal lamina surrounding fenestrated capillaries, and (3) retract to enable the release into the blood of secretory granules stored in the axon terminals (see Figure 18-14).

Figure 18-14 Axon endings and pituicytes around fenestrated capillaries

Axons in the neurohypophysis derive from the supraoptic nuclei and the paraventricular nuclei.

Some neurons of the paraventricular nuclei are small and their axons project to the median eminence rather than to the pars nervosa. These neurons, called parvicellular neurons (Latin parvus, small), secrete ADH and oxytocin entering the hypophysial portal blood at the median eminence. Large neurons of the supraoptic and paraventricular nuclei, called magnicellular neurons (Latin magnus, large), give rise to axons forming the hypothalamic hypophysial tract. The terminals of these neurons are located in the pars nervosa. Both the supraoptic and paraventricular nuclei contain neurons synthesizing ADH and oxytocin. However, neurons of the supraoptic nuclei produce primarily ADH and the paraventricular nuclei synthesize primarily oxytocin.

In addition to these two nuclei, the hypothalamus has additional nuclei, the hypothalamic hypophysiotropic nuclei, with neurons producing releasing and inhibitory hormones to be discharged at the fenestrated capillaries of the primary plexus (see earlier, Blood supply of the hypophysis).

Although the neuroendocrine cells of the supraoptic and paraventricular nuclei are located behind the blood-brain barrier, their products are transported to nerve terminals and released outside the blood-brain barrier into fenestrated capillaries.

Clinical significance: Diabetes insipidus

Oxytocin participates in the contraction of smooth muscle, in particular the uterus during labor, and myoepithelial cells lining the secretory acini and lactiferous ducts of the mammary gland to facilitate milk ejection (or letdown of milk) during lactation (Figure 18-15).

Figure 18-15 Antidiuretic hormone and oxytocin

Antidiuretic hormone regulates water excretion in the kidneys and is also a potent vasoconstrictor at high doses (see Figure 18-15). This is the basis for its alternative name, vasopressin (arginine vasopressin [AVP]). An increase in osmotic pressure in circulating blood or reduced blood volume triggers the release of ADH. Retention of water reduces plasma osmolality, which acts on hypothalamic osmoreceptors to suppress the secretion of ADH.

ADH and oxytocin are transported down the axons and stored in nerve terminals within secretory granules, packaged together with a carrier protein, neurophysin. A common precursor gives rise to ADH, oxytocin, and the carrier neurophysin. ADH is bound to neurophysin II and oxytocin to neurophysin I. The released hormones circulate in blood in an unbound form and have a half-life of 5 minutes.

Neurogenic diabetes insipidus occurs when the secretion of ADH is reduced or absent. Polyuria is a common clinical finding. Patients with diabetes insipidus can excrete up to 20 L of urine in 24 hours. Neurogenic diabetes insipidus is caused by a head injury, an invasive tumor damaging the hypothalamic hypophysial system, or autoimmune destruction of vasopressin-secreting neurons.

Nephrogenic diabetes insipidus occurs in certain chronic renal diseases that are nonresponsive to vasopressin or as a result of genetic defects in renal receptors for vasopressin.