3. Hypothalamic – Pituitary System

Content:

1. Regulatory axis hypothalamus-pituitary
2. Adenohypophyseal hormones
3. Hypothalamus and neurohypophysis

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Regulatory axis hypothalamus-pituitary

Definition of the system

Thanks to its impact on most of the other endocrine tissues and organs, the hypothalamo-hypophyseal system represents the most important component of the endocrine system. Apart from these so-called glandotropic functions (affecting other glands of endocrine secretion), it also has the capacity to regulate non-endocrine tissues as well, functions termed as aglandotropic.

Hypothalamus is a part of diencephalon („interbrain”) and, as its name already suggests, it is situated in the region of brain under the thalamus (and 3rd cerebral ventricle). This is the place where forebrain, midbrain and hindbrain meet one another. Hypothalamus is made of several nuclei with diverse functions (controlling, for example, thermoregulation, intake of food, functions of the autonomic nervous system or our experience of emotions). Thanks to an unique link between the hypothalamus and hypophysis, the axis represents a structure connecting nervous and endocrine system with an ability to convert humoral signals from the body periphery into efferent nerve impulses and conversely, to convert the afferent nerve impulses to humoral signals.

1) Anterior pituitary (adenohypophysis)

Together with a small part between the anterior and posterior lobes (the so-called pars intermedia) they represent a part of the gland formed from the ectodermal lining of the primitive oral cavity. The cells of anterior pituitary, under the control of hypothalamus, actively participate in the synthesis and secretion of the hypophyseal hormones.

2) Posterior pituitary (neurohypophysis)

Formed as a protrusion of interbrain’s neuroectoderm, the posterior pituitary is made mostly of axonal endings originating in the hypothalamic nuclei. Through these axons, the hormones produced by hypothalamus (the process known as neurosecretion) are delivered via plasmatic transport directly into the neurohypophysis. The axonal endings store the hormones in vesicles before secreting them into the bloodstream.

Hypothalamic regulation of adenohypophysis

For hypothalamus to effectively regulate the adenohypophyseal function, there has evolved a special vascular system between both parts of the brain – a hypophyseal portal system. As other portal systems in the human body, it is made of two consecutive, serially connected capillary networks. The first, primary, capillary plexus arises from arteria hypophysialis anterior (a branch of a. carotis int.) and can be found in infundibular region (on its ventral side and extending into eminetia mediana). Capillaries of this part of the portal system take up the hypothalamic hormones regulating the activity of anterior pituitary. In the region of eminentia mediana (belonging to the few areas of the brain not protected by the hematoencephalic barrier), the blood vessels connect together to form hypophyseal portal veins, carrying the blood through the infundibulum to the adenohypophysis. There the vessels branch out in order to form the other, secondary, capillary plexus.

The described system carries the hypothalamic hormones directly into the adenohypophysis, so they are not diluted in the systemic circulation and reach the secondary capillary plexus in high enough concentrations.

1) Liberins – also known as releasing hormones or releasing factors (RH / RF)

The effect of liberins on the secretion of hormones in the anterior lobe of pituitary is generally stimulatory – liberins promote their synthesis and release. It is interesting, that most of the liberins act (to a different extent) on more than one kind of a hormone.

a) Thyrotropin releasing hormone (TRH)

TRH is a tripeptide produced in the cells of paraventricular nucleus of hypothalamus. Its main task is to stimulate the secretion of TSH in the adenohypophysis, but at the same time it has similar effect on the secretion of prolactin. The regulation of its production is via a negative feedbackincrease in the concentration of thyroid hormones inhibits its synthesis. Furthermore, somatostatin also exerts some inhibitory effect on its production.

b) Gonadotropin releasing hormonealso known as gonadoliberin (GnRH; luteinizing hormone-releasing hormone LHRH)

This 10 amino-acid-long hormone, produced in the medial part of area preoptica, stimulates the production of adenohypophyseal LH and FSH. Its secretion occurs in pulses with variable frequency (pulses usually occur every 60 to 90 minutes and last about 1 minute). An important fact is that only secretion in pulses has a stimulatory effect. When the level of GnRH stays constantly high, the secretion of LH decreases until it completely disappears. Some forms of hormone therapy make use of this effect, for example to stop the spontaneous ovulation in women undergoing artificial fertilization.

Interestingly, the neurons synthesizing GnRH develop during the embryonic age in the area of a future nose cavity. They have to migrate (along the tract of the olfactory nerve) through the brain to a region of future hypothalamus. A genetic defect of this migration (an X-linked mutation) called a Kallmann syndrome causes the absence of GnRH-producing cells in the hypothalamus. As a consequence of low level of sex hormones, the gonads are underdeveloped (the condition termed hypogonadotropic hypogonadism) and, in the case of Kallmann syndrome, associated with impaired sense of smell.

c) Corticotropin, also known as corticoliberin (CRH)

Again a protein hormone made of 41 amino acids, produced by the paraventricular nucleus. It enhances the synthesis of proopiomelanocortin (POMC) and all of its derived hormones (ACTH, MSH, β-endorphin etc.).

d) Growth hormone releasing hormone, better known as somatoliberin (GRH)

GRH is synthesized in the nucleus arcuatus and is a representative of peptide hormones with the length of 44 amino acids. Its main function is to stimulate the production of growth hormone (somatotropinSTH). Through negative feedback, it also influences the synthesis of IGF-1 (insulin-like growth factor, mediating most of the STH’s effects).

2) Statins – also known as inhibitory hormones or inhibitory factors (IH / IF)

Statins decrease the production of hypophyseal hormones.

a) Somatostatin (growth hormone inhibitory hormone GIH)

Somatostatin is a hormone formed in the neurons of paraventricular nucleus of hypothalamus in the form of a preproprotein. This precursor molecule can be split into one of two forms: shorter, 14 amino-acid long molecule that constitutes most of the produced hormone (up to 90 %) or longer, 28 amino-acid hormone (around 10 % of the produced GIH). Both forms are active and their main role is to reduce the release of STH. To a lesser extent they also participate in the inhibition of TSH secretion.

b) Prolactin inhibitory hormone (PIH, dopamine)

PIH is synthesized, like GRH, in the nucleus arcuatus and is an inhibitor of prolactin and TSH production. Apart from an inhibitory effect of GRH, it is believed that the secretion of prolactin is suppressed by another neuropeptide called GAP (gonadotropin-releasing hormone associated peptide).

We must not forget the importance of dopamine as a neurotransmitter, especially in the „reward pathways” system.

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Adenohypophyseal hormones

Anterior pituitary (adenohypophysis), with its enormous influence over the endocrine and non-endocrine tissues and organs, represents a crucial part of the hormonal system. It secretes both, hormones with a direct influence on tissues (STH and prolactin) and glandotropic hormones as well (ACTH, TSH, FSH and LH). It therefore controls the activity of several endocrine glands and the failure in its secretory function can result in their malfunction, even when the glands themselves are not affected by any pathological process.

All adenohypophyseal hormones are made of amino acids and they vary in the length of the chain and its modifications:

1) Short peptide hormones: ACTH, α-MSH or β-endorphin

2) Protein hormones made of long chain of amino acids: STH and prolactin

3) Protein hormones with modified amino-acid chain – glycoproteins: TSH, LH and FSH

Glycoprotein hormones have a very characteristic structure, made of two subunits linked by non-covalent bonds. A-subunit has the same amino-acid arrangement in all hormones; they differ only in the composition of saccharide residues. On the contrary, β-subunit is structurally unique in every particular hormone and thus brings about its specific effect. Receptors, however, always recognize the complex of both subunits. That is why they are both necessary for a proper function of a hormone.

Chromophilic cells can further be divided according to the type of stain they take on. They can either stain with acidic stain (eosin) – the so-called acidophilic cells or with basic stain (hematoxylin) – the so-called basophilic cells.

Acidophilic cells synthesize simple proteins and include:

1) Somatrotropic cells producing growth hormone

2) Mammotropic cells producing prolactin

Basophilic cells synthesize glycoproteins and involve:

1) Corticotropic cells producing ACTH

2) Thyrotropic cells producing TSH

3) Gonadotropic cells producing FSH and LH

The following table sums up the main hormones produced in anterior pituitary and their basic characteristics.

Hormone

Structure

Cells

Target tissues

Main effect

Growth Hormone (GH, STH)

Polypeptide

Acidophilic, somatotropic

Growth plates, liver, adipose tissue

Growth of bones in length, diabetogenic effect, increase in lean body mass

Prolactin (PRL)

Polypeptide

Acidophilic, lactotropic

Mammary gland

Lactotropic – production of milk

Follitropin (FSH)

Glycoprotein

Basophilic, gonadotropic

Gonads

Follicle maturation, spermatogenesis

Lutropin (LH)

Glycoprotein

Basophilic, gonadotropic

Gonads

Ovulation, synthesis of testosterone

Thyrotropin (TSH)

Glycoprotein

Basophilic, thyrotropic

Thyroid gland

Synthesis and release of thyroid hormones

Adrenocorticotropic hormone (ACTH)

Polypeptide

Basophilic, corticotropic

Adrenal glands

Synthesis of glucocorticoids and mineralocorticoids

Somatotropin (STH; GH – growth hormone)

Chemical structure and metabolism

Somatotropin is a polypeptide hormone synthesized by somatotropic cells of anterior pituitary. It is encoded on the long arm of chromosome 17, which is occupied by several genes coding for various related proteins.

1) Most of GH found in blood (approximately 75 %) is the so-called „normalvariant (coded by hGH-N gene), also labeled as 22k STH due to it molecular mass of 22 000.

2) To a lesser extent a product of another genehGH-V, the so-called „variableform, can be found in bloodstream. It is produced mostly in the placenta during pregnancy. Both normal and variable forms are 191 amino acids long and they slightly differ in their sequence.

3) Alternative splicing of mRNA for hGH-V results in a molecule of STH that is shorter and thus lighter with molecular mass is 20 000 – it is therefore termed 20k STH. The biological activity of 20k STH do not differ from 22k STH and it makes up approximately 10 % of somatotropin in the blood.

Somatotropin exhibits a significant interspecies variability in its effect despite the high degree of similarity (homology) in the molecular structure. In practice, STH from other animal species (with the exception of higher primates) will not work in humans. That is the reason why, for the treatment of STH deficiency, we use genetically engineered recombinant hormone.

Approximately half of the STH molecules found in the blood are bound to a special transport protein called GHBP (GH binding protein). GHBP is an extracellular domain of GHR (GH receptor – see further in this chapter) that is most probably made by its cleavage. Binding to a transport protein increases the biological half time of somatotropin, which is quite short for unbound molecules (around 6-20 minutes). Quick breakdown takes place in liver.

The secretion of STH is pulsatile with interval within the range of several hours. The most intense pulse takes place several hours after falling asleep and overall, the amount of STH released during the sleep represents around 70 % of its daily production. The hormone is mainly secreted during 3rd and 4th phase of non-REM sleep.

Mechanism of action and target tissues

The effect of growth hormone on its target tissues takes place in two ways:

1) Directly – through its own receptor (GHR)

GHR belongs to a group of transmembrane receptors that include receptors for prolactin and for many cytokine molecules. It is associated with an intracellular tyrosine-kinase called JAK2. When the GH binds to its receptor, it causes its homodimerization followed by a phosphorylation and activation of JAK2 kinase. This kinase then further mediates the intracellular signaling pathway (via the so-called STAT transcription factors).

2) Indirectly – through an effect of IGFs (insulin-like growth factors)

IGF receptors are transmembrane as well and their structure resembles that of insulin receptor (they share the same receptor family; both receptors are approximately 60% homological in their structure): two extracellular alpha and two transmembrane beta subunits having intracellular domains with tyrosine-kinase activity.

The effects of growth hormone
1) Growth stimulation

a) It stimulates chondrogenesis and sulphate deposition to cartilage in young individuals with unclosed growth plates – the bones grow in length

b) It has effect on organ growth as well

2) Metabolic changes

a) It activates protein anabolism with positive nitrogen balance, transport of amino acids to the cells, increase in mRNA transcription and translation and increase in the collagen synthesis

b) It causes an electrolyte retention (Na+, phosphates, K+, Mg2+ and Ca2+), necessary for growing tissues

c) It has diabetogenic effect promoting the increase in glucose release from the liver (through gluconeogenesis, the amount of glycogen rather increases) and decrease in peripheral glucose utilization. The effect can even result in hyperglycaemia

d) It decreases the amount of adipose tissue in the body (increasing the so-called lean body mass) via activation of lipolysis. The fatty acids and glycerol are released into the bloodstream and serve as an energy source. The process can result in ketogenic effect (when the ketone bodies are synthesized from surplus of FFA). The amount of plasmatic cholesterol decreases

3) Prolactin-like effects

Thanks to its structural similarity with prolactin, the STH exerts an effect on lactotropic receptor and can stimulate lactogenesis.

Regulation

The regulation of growth hormone secretion occurs via a negative feedback – an increase in the level of IGF-1 inhibits the secretion of STH and stimulates the secretion of somatostatin. Hormones regulating the synthesis of STH involve:

1) Episodically produced GRH stimulating the synthesis and release of STH in anterior pituitary

2) Somatostatin (SIH), produced in pulses, with an inhibitory effect on STH production

Apart from these hypothalamic products, there are other stimuli regulating the level of STH in human body. The production increases after stressful stimuli (due to its metabolic effects, STH is considered to be a stress hormone), for example a lack of food, excessive physical activity or hypoglycemia. An increase in the plasmatic level of some of the amino acids, glucagon or α-adrenergic agonists also causes a rise in STH production. Decrease, on the other hand, might be caused by an increase in glycaemia, β-adrenergic agonists and indirectly by rise in free fatty acids or cortisol in blood.

Disorders

Surplus of growth hormone in children (who still have unclosed growth plates) results in an excessive growth of body and extreme height – the condition is called gigantism. In adults, the epiphyseal parts of the bones no longer have the ability to grow, but an observable enlargement of body extremitiesacral parts such as lower jaw, brow ridges, hands, feet or nose – occurs. The resulting change in body proportions is called acromegaly.

A shortage of somatotropin in childhood causes small staturedwarfism. The reason may lie in inadequate production of STH or insensitivity of its receptors.

Prolactin (PRL)

Chemical structure and metabolism

Prolactin is 199 amino-acids long polypeptide hormone structurally similar to growth hormone (showing 35% homology in amino acid sequence) and hCS (also known as human placental lactogen). It is produced by acidophilic population of adenohypophyseal cells, called lactotrophs. During the pregnancy these cells increase in size and number to meet the organism’s requirements for the hormone in the period of lactation.

Mechanism of action and target tissues

Prolactin acts through its transmembrane receptor, which belongs to the same receptor family as STH receptor and cytokines’ receptors. The transduction cascade is similar for all members of the family and it includes, for example, transduction via JAK-STAT signal pathway.

The best known effect of prolactin is its stimulation of breast milk production. However, prolactin has many other, not so well known, roles in the bodies of vertebrates (including humans) mostly related to the function of immune system and metabolism. These effects place him on the borderline between the hormones and cytokines.

The main effect of prolactin is lactotropic – the induction and maintenance of breast milk production. Mammary glands of pregnant women, under the influence of sex hormones, are already differentiated and ready to respond to physiological levels of prolactin with an increased milk secretion (especially the synthesis of milk proteinscasein and lactalbumin). The prolactin itself encourages the growth of the gland and enlargement of its alveoli and milk ducts.

Another effect of prolactin is an inhibition of GnRH secretion and thus, indirectly, of gonadotropins as well (see hyperprolactinemia).

Regulation

The main regulatory step of prolactin synthesis is its inhibition by prolactin inhibiting hormone (PIH; dopamine) tonically secreted by hypothalamus.

The amount of synthesized prolactin increases during the pregnancy until it reaches its maximum in the time before birth, followed by a decrease, until the concentration returns to the levels seen in non-pregnant women. Breastfeeding causes sharp increase in the prolactin secretion, however, this at first, prompt response weakens over time.

The secretion itself is stimulated by a mechanical irritation of nipple, not necessarily occurring only in the course of breastfeeding. Besides breastfeeding, the production of prolactin increases during physical activity, stress, sexual intercourse and rise was observed while sleeping as well.

Lactotrophs are under stimulatory effect of several hormones – namely estrogens, TRH and TSH.

Disorders

Increased secretion of prolactin leads to a state of hyperprolactinemia inducing galactorrhea even in non-pregnant women. Due to its inhibitory effect on gonadotropins it causes a cessation of ovulation (state of anovulation) and menstrual cycle (amenorrhea), eventually resulting in woman’s infertility. This phenomenon can physiologically be seen during the period after birth (if the woman is breastfeeding), pathologically in tumors of adenohypophysis secreting prolactin or in infundibular injuries. The latter case occurs due to a failure in passage of PIH from hypothalamus, which happens through infundibulum. Hypothyroidism is another condition that may cause hyperprolactinemia, as it leads to high levels of TRH and TSH.

Hyperprolactinemia in men reduces the production of testosterone, a state associated with hypogonadism, oligospermia, drop in libido (and even impotence) and growth of breasts (gynecomastia).

Follicle-stimulating hormone (FSH; Follitropin) and Luteinizing hormone (LH; Lutropin)

Chemical structure and metabolism

Together with TSH, FSH and LH belong to a family of adenohypophyseal glycoprotein hormones consisting of two subunits (see subchapter hypothalamic regulation of adenohypophysis). Synthesis occurs in basophilic gonadotropic cells.

Saccharide residues bound to protein parts of hormone subunits (e.g. mannose, galactose, N-acetylgalactosamine, N-acetylglucosamine) slow down its degradation and extend its biological half time. In case of LH and FSH it reaches values around 60 and 170 minutes, respectively.

Mechanism of action

Both gonadotropin receptors are metabotropic, coupled with a stimulatory G-protein. Hormone binding initiates the well-known transduction cascade: the stimulatory α-subunit activates adenylate cyclase, which starts to produce cAMP leading to an activation of cAMP-dependent protein kinase A (PKA). Able to phosphorylate other molecules, the PKA either stimulates or inhibits (depending on the phosphorylated substrate) other components of the pathway.

Action of FSH

FSH, being the tropic hormone of both Sertoli and granulosa cells, is important for gametogenesis in both sexes.

In women FSH activates the growth of follicles and induces the synthesis of aromatase in the granulosa cells (in order for them to produce estrogens). The follicle with the highest number of FSH receptors (which is therefore the most stimulated one) develops to form a mature Graafian follicle. After reaching its first concentration peak (around 13th day of the cycle), the FSH stimulates the 1st meiotic division. FSH is therefore inevitable for proper development and maturation of follicles.

FSH helps to maintain males’ gametogenic function (spermatogenesis). It stimulates the formation of androgen-binding protein (ABP) in Sertoli cells. ABS is able to bind testosterone and ensures that its local concentration in the area of seminiferous tubules is high enough for the production of sperms – the usual concentration of testosterone in blood does not have significant stimulatory effect on spermatogenesis.

Action of LH

Luteinizing hormone is essential in the phase of the final maturation of follicle and induction of ovulation. It is the steep rise in LH concentration immediately before the ovulation that is responsible for its induction. After the pre-ovulatory maximum, the concentration drops during the luteal phase. If conception and implantation of embryo does not take place, the yellow body gradually degrades and as the amount of sex hormone it produces decreases, the menstrual phase begins. Otherwise, embryonic trophoblast synthesizes hCG that takes over the functions of LH.

In males the lutropin acts as tropic hormone of Leydig cells, stimulating their production of testosterone.

Regulation

Regulation of FSH and LH synthesis is rather complex and is associated with other hormones involved in the ovarian and menstrual cycles.

1) FSH is under the regulatory influence of hypothalamic GnRH. At the end of each cycle, after the degradation of yellow body, the concentration of estrogens and progesterone decreases. Thus their inhibitory effect on the FSH synthesis diminishes and the level of FSH rises again (and starts to stimulate the follicular growth). LH stays relatively low during this period – loss of inhibition from estrogens and progesterone would lead to a mild increase in its concentration, but the increasing level of estrogens synthesized in growing follicles (via a negative feedback) decreases the LH level during the follicular phase.

2) The amount of LH and FSH prior to ovulation drops due to high concentration of estrogens (produced in Graafian follicle) and inhibin (a protein formed by the granulosa cells that inhibits the secretion of FSH in hypophysis). The peak of estrogens immediately before the ovulation causes a pulse of GnRH and gonadotropins. The subsequent rise of FSH induces the completion of the 1st meiotic division and (much steeper) rise of LH (occurring approximately on day 14) induces the ovulation, usually 10 hours after the rise.

3) After the ovulation, the corpus luteum is formed, producing mainly progesterone and, to a lesser extent, estrogens. They both decrease the secretion of GnRH thus indirectly inhibiting the secretion of LH and FSH as well. Their level continues to be low until the end of luteal phase, when the yellow body degrades.

In men, the regulation of FSH involves a simple negative feedback loop through inhibin secreted by Sertoli cells. Testosterone inhibits the synthesis of LH both directly (affecting adenohypophysis) and indirectly (affecting hypothalamic production of GnRH).

Thyroid stimulating hormone (TSH; thyrotropin)

Chemical structure and metabolism

Thyroid stimulating hormone represents yet another glycoprotein hormone consisting of two subunits (see previous parts). It is 211 amino acids long and formed in pulses by basophilic thyrotropic cells of anterior pituitary. Its biological half time is around 1 hour; the degradation occurs mainly in kidneys and partly in liver.

Mechanism of action and target tissues

TSH acts through a metabotropic transmembrane receptor coupled with Gs-protein, which is expressed by the follicular cells of the thyroid gland. Binding of TSH causes the α-subunit to activate the adenylate cyclase, followed by an increase in intracellular cAMP and PKA activation.

TSH is a tropic hormone of thyroid gland and plays a crucial role in the regulation of its function, particularly the synthesis of T3 and T4. TSH increases the activity of Na+/I-symporter leading to a higher iodide uptake from blood and their transport to follicular cells. Further, it stimulates the synthesis of thyroglobulin, iodine organification, iodothyronine condensation, endocytosis of colloid into the cytoplasm, cleavage of T3 and T4 from thyroglobulin and their release into the bloodstream.

In general, TSH activates the synthetic metabolic pathways of thyroid follicular cells and their increase in size and number.

Regulation

Regulatory hormone, in control of TSH secretion, is TRH that is produced in hypothalamus. TRH stimulates both the synthesis and the release of TSH. Apart from it, dopamine and somatostatin also influence the production of TSH, having an inhibitory effect.

Increased concentration of thyroid hormones (T3 and T4) causes the decrease in the plasma level of TSH both at the level of its production in pituitary and the production of TRH in hypothalamus.

Secretion of TSH is reduced by glucocorticoids and (via TRH) stressful stimuli as well. Thyroid hormones are involved in the long-term settings of metabolic activity and changes in the temperature have influence on their production. Low temperature activates the production of TSH in particularly in newborns; the effect is weaker in case of adults.

Disorders

Shortage of iodine in food causes T3 and T4 insufficiency and high TSH concentrations. Follicular cells are excessively stimulated (in order to uptake as much iodine from blood as possible) and grow, leading to a state of enlargement of the whole thyroid gland – a condition called goitre (struma). Goitre is defined as an enlargement of thyroid gland regardless of cause. In the case of iodine insufficiency, it may either be endemic (tied to areas rare in iodine – for example landlocked countries) or sporadic (caused by dietary iodine deficiency, which is however abundant in the particular area).

Hormones formed from proopiomelanocortin (POMC)

Chemical structure and metabolism

Proopiomelanocortin is 241 amino acids long polypeptide produced by corticotropic cell of anterior pituitary. Its synthesis starts with a longer precursor molecule called pre-POMC. After the cleavage of the signal sequence POMC is formed. Further cleavage of POMC may result in 3 groups of peptides:

1) Adrenocorticotropic hormone (ACTH), which may be further cleaved into α-MSH (melanocyte-stimulating hormone) and CLIP (corticotrophin-like intermediate peptide)

2) β-LPH (lipotropin) that may be further transformed to β-MSH, β-endorphin and γ-LPH

3) N-terminal peptide, the parent molecule of γ-MSH

After the particular peptides are formed by cleavage of their parent molecules, further modifications may take place – for example ACTH is glycosylated or β-endorphin acetylated (resulting in decrease in its activity).

Adrenocorticotropic hormone (ACTH)

ACTH is 39 amino acids long linear polypeptide acting via a receptor coupled with Gs-protein (activating adenylate cyclase and cAMP production). Its secretion occurs in pulses, physiologically being most frequent in the morning (up to 75 % of daily production takes place between 4 and 10 am) and the least in the evening.

The regulatory pathway involves the hypothalamic CRH and, interestingly, even ADH, but only that portion which is secreted into the region of eminencia mediana. Glucocorticoids show a negative feedback effect and at the level of hypothalamus and hypophysis inhibit the synthesis of ACTH. Stress raises the concentration of ACTH almost exclusively via an increase in the production of CRH.

Other

B-lipotropin (β-LPH) represents the C-terminal part of POMC molecule. Its physiological role in human body seems to be negligible (activation of lipolysis, fatty acids mobilization) and it is usually quickly converted to other cleavage products (like β-endorphin).

Endorphins produced in hypophysis play role in the regulation of pain perception (they have the same receptors as opiates).

Melanocytes stimulating hormone (MSH) occurs in different forms (α, β and γ). In some animal species it induces the production of melanin granules (melanogenesis), however, they have questionable effect on pigmentation in humans.

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Hypothalamus and neurohypophysis

Neurosecretion

As it was already mention in the introduction to this chapter, the hormones of posterior pituitary (oxytocin and antidiuretic hormone) are not produced by cells of the gland itself. The site of their synthesis is hypothalamus and in fact they are neurohormones – meaning hormones produced by and released into the bloodstream from the nerve cells.

The synthesis takes place in the so-called magnocellular neurons (named due to their considerable size) of two hypothalamic nucleisupraoptic and paraventricular. Antidiuretic hormone is supposed to be produced mainly in nucleus supraopticus and oxytocin in nucleus paraventricularis, but both nuclei are capable of production of both hormones. After they are synthesized, granules with the hormones are transferred via axoplasmic anterograde transport (meaning in the direction from nucleus to the periphery) to the end of axon located in the neurohypophysis. The hormones are bound to specific transport proteins – the so-called neuorphysins that are produced together with them. Neurophysin I with oxytocin are synthesized in the form of a common precursor molecule (preprooxyphysin) and are subsequently split to form two separated molecules, which are then transported together. Formation of ADH happens analogically, the precursor molecule prepropresophysin is split to ADH and neurophysin II, the two to be transported together.

In case of secretory stimulus (nerve impulse) a spilling of granule content directly into the systemic circulation takes place. The reason for such arrangement is probably an effort to bypass the blood-brain barrier. The hormones are released together with their neurophysin transport molecules.

Vasopressin / antidiuretic hormone (ADH; arginine-vasopressin)

Chemical structure

ADH is short, 9 amino acids long peptide hormone. Except for a form found in most mammals called (due to a presence of arginine on 8th position of the amino-acid chain) arginine-vasopressin, there are other substituted forms of vasopressin. One example can be found in pigs, which have vasopressin with lysine substituted on 8th position (so-called lysine-vasopressin).

ADH is metabolized mainly in liver, but the elimination takes place through urine as well.

Mechanism of action and target tissues

The main effect of vasopressin is to increase the permeability of renal collecting ducts. What follows is a rise in the reabsorption of water and urine concentration and decrease in the urine volume. The volume of intravascular fluid increases and (because the reabsorbed water does not contain ions) its osmotic pressure decreases. The effect is mediated by special receptors termed V2, which are Gs-metabotropic receptors causing the aquaporin channels AQ2 (waiting in presynthesized vesicles in the cytoplasm) to be built in the basolateral membrane of the cells forming the lining of collecting ducts. These cells are normally not very permeable for water.

ADH also acts as a vasoconstrictor and leads to blood redistribution and centralization, especially form the dermal, muscular and splanchnic circulation. The action is mediated via V1A Gq-protein coupled receptors. Transduction cascade causes the release of endothelial Ca2+ ions that lead to vasoconstriction. These receptors are also responsible for the release of von Willebrand factor, an important constituent of coagulation system, from endothelial cells.

V1B receptors (having the same transduction mechanism as V1A) mediate the stress response in brain and increase the release of ACTH in adenohypophysis.

Regulation and disorders

Nerve impulses that lead to ADH secretion are activated by a variety of stimuli. Among the most important are changes in osmolarity and volume of extracellular fluid.

The osmolarity of blood plasma is detected by receptors in anterior hypothalamus. The region contains specialized cells, which change their volume depending on the osmotic content of the blood (decrease causes water to enter the cells and enlarge and vice versa). Receptors are very sensitive especially to increase in osmolarity – a change as small as 1 % leads to ADH secretion.

The volume of extracellular fluid (ECF) is monitored by baroreceptors of cardiovascular system. These involve low-pressure receptors in heart atria and large veins and high-pressure receptors in sinus caroticus and arcus aortae. Decrease in the volume of ECF acts as a stimulatory impulse for ADH secretion and vice versa.

ADH belongs to a group of stress hormones – its role in these situations is to maintain the intravascular volume. Therefor the secretion rises due to physical and emotional stress (for example during pain or exercise). On the contrary, alcohol inhibits the ADH secretion.

Other condition, occurring mainly in people with brain lesions, is characterized by the other extreme – an excessive ADH production with retaining of water in the body. Syndrome of inappropriate antidiuretic hormone secretion (SIADH), as the condition is called, causes a dilution of blood constituents (for example hyponatremia). Furthermore, as the volume of ECF increases, the secretion of aldosterone is inhibited and more salts are lost.

Oxytocin

Chemical structure

Oxytocin shows a structural similarity to ADH. Similar to ADH, it is made of 9 amino acids and differs from it only in two of them. This resemblance causes a partial overlapping of effects of both hormones. Oxytocin is metabolized in liver.

Mechanism of action and target tissues and regulation

Oxytocin has a Gq-coupled receptor that is mostly expressed by the myoepithelial cells of the mammary gland, brain and (during pregnancy) myometrium and endometrium.

Close to the end of pregnancy the oxytocin has an uterokinetic effect – it causes contraction of smooth muscle cells of the uterus. The sensitivity of myometrium to oxytocin is inhibited by progesterone and it rises with increasing concentration of estrogens, which occurs during pregnancy. The most important stimulus that causes a massive oxytocin release during childbirth is a mechanical irritation of the genital tract by the descent of fetus. A positive feedback loop occurs afterwards, further increasing the release of oxytocin until the fetus and placenta are both expelled from the woman’s body. Oxytocin is artificially used to initiate the delivery or to assist a prolonged labor.

Other place of oxytocin action is the mammary gland, where it stimulates the contraction of myoepithelial cells of the lactiferous ducts. These contractions enable the ejection of milk to the surface of nipple. The action is reflexive and initiated by the touch receptors in the skin around the nipple (for example during the sucking). The reflex is also triggered off by an irritation of genitals or stronger emotions.

Subchapter Authors: Josef Fontana, Petra Lavríková and Patrik Maďa

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