Pituitary Gland

15.3.1 Introduction

Widely regarded as a “master gland”, the pituitary gland originates from the ectoderm and functions to secrete hormones that are regulated by hypothalamic stimuli.

15.3.2 AnteriorPituitary

The anterior lobe comprises two-thirds of the pituitary gland and consists of neuroendocrine cells responsible for the syn­thesis of major tropic hormones.

Fig. 15.9 Classification of cell types present in the anterior pituitary gland. [Chromophils are the active neuroendocrine cells present in the anterior pituitary. Further, they are categorised into acidophils and basophils based on their affinity for a particular type of stain]

Table 15.5 Different cell types in anterior pituitary, their distribution, hormones, and target organs

15.3.2.1 Cellular Types and Their Hormones

Based on the ability to take up general histological stains, cells in adenohypophysis are classified broadly into two categories, namely the chromophils and chromophobes (Fig.

15.3.2.2 Growth Hormone (GH)

Also referred to as Somatotropin, derived from the Greek words “Soma” meaning body and “tropikos” refer to turn or change. It is implicated in both pre-natal and post-natal animal growth that varies according to each physiological states such as pre-pubertal phase, pubertal phase, post- pubertal, and senescence. Regulated by genetics, it plays a prime role in attributing the phenotypic characteristics to different species in the animal kingdom.

15.3.2.2.1 Chemical Structure and Mechanism of Action

GH is a single-chain protein hormone synthesised and secreted by the somatotropes as a prohormone with 217 amino acids, while the mature hormone consists of 191 amino acids with two intramolecular di-sulphide bridges (Molecular weight: 22 KDa). They bind to spe­cific membrane-bound growth hormone receptors (GHRs) which belong to the family of tyrosine kinase-associated receptors. The activation of GHRs initiates signal trans­duction mechanism primarily by JAK-STAT pathway with a subsequent effect on cellular genetic machinery. Further­more, it also activates other signalling pathways such as Ras/MAPK and PI3K. Together, they regulate cell cycle, proliferation, gene expression, growth, and differentiation in various organs.

15.3.2.2.2 Biological Effects

Mainly considered as a hormone that regulates the body metabolism to suit different physiological states. However, it affect several organs including liver, bones, skeletal mus­cle, adipose tissue, and gonads (Fig. 15.10).

Fig.

feedback inhibition on the secretion of both GHRH and GH. [GHRH growth hormone-releasing hormone; GHIH growth hormone inhibiting hormone; GH growth hormone; IGF-1 insulin-like growth factor 1; (+) stimulate; (-) inhibit; (↑) increase; (#) decrease]

15.3.2.2.2.1 Effects of GH on Liver

Stimulating the hepatocytes to produce somatomedins (via JAK-STAT pathway) remains the most crucial target effect of GH. Somatomedins or insulin-like growth factors (IGFs) are regarded as the vital extra-hepatic mediators of GH actions. Somatomedin-A (IGF-2) and Somatomedin-C (IGF-1) are the two types of somatomedins implicated in pre-natal and post­natal growth, respectively. They mediate the effects of meta­bolic and functional changes that are observed in target organs. Moreover, GH stimulates hepatic glucose production by increasing the rate of gluconeogenesis and glycogenolysis. The production of transcription factors that belong to sterol regulatory element binding proteins (SREBs) stimulate the synthesis of lipid, sterols and their oxidation. Along with their increased synthesis, it also leads to the increased secretion of tri-glycerides. Furthermore, the regenerative capacity of liver is believed to be dependent on GH.

15.3.2.2.2.2 Effects of GH on Carbohydrate Metabolism Growth hormone stimulates the production of glucose from liver with a concurrent decrease in its utilisation by skeletal muscle and adipose tissues. The decreased peripheral utilisation of glucose is attributed to the attenuation of insulin effects such as increased glucose uptake, utilisation and decreased gluconeogenesis, producing GH-induced insulin resistance.

15.3.2.2.2.3 Effects of GH on Protein Metabolism

Growth hormone stimulates the rate of transcription, transla­tion with a concomitant rise in the uptake of amino acids. Moreover, reduced cellular dependence on gluconeogenesis for meeting energy demands is also prominent with GH stimulation. Overall, the above listed cellular processes favour the protein anabolism and supress the amino acid catabolism resulting in the accumulation of proteins in vari­ous cells especially the skeletal muscles.

15.3.2.2.2.4 Effects of GH on Fat Metabolism

The GH stimulation of hepatocytes and adipocytes leads to increased circulatory levels of free-fatty acids (FFA), TG, and cholesterol. This helps the target cells to utilise fats to meet their energy requirements while sparing the carbohydrates and amino acids.

15.3.2.2.2.5 Effects of GH on Skeletal Muscle

Growth hormones stimulate the protein accumulation, subse­quently used for synthesising myofibrils and collagen leading to hypertrophy of skeletal muscles. The GH-IGF1 axis dependent skeletal muscle growth and development plays a crucial role in post-natal growth of animals.

15.3.2.2.2.6 Effects of GH on Bones

The IGF-1 produced from liver or locally produced is a chief regulator of the longitudinal growth of bones in young animals. The GH-IGF1 axis stimulates the rate of chondrogenesis in growth plate leading to the formation of new cartilaginous tissue. This increased deposition of carti­laginous tissue between the shaft and epiphysis results in longitudinal bone growth. The osteoblasts that are stimulated by GH-IGF1 axis further help in the ossification of newly laid cartilage. The rate of GH stimulated chondrogenesis and consequent longitudinal bone growth is maximum at pubertal and peri-pubertal periods.

15.3.2.2.2.7 Effects of GH on Cardiovascular System

The GH-IGF1 dependent of amino acids uptake, specific gene transcription, deposition of proteins, and collagen results in the hypertrophy of cardiomyocytes. Along with hypertrophy, inhibition of apoptosis in cardiomyocytes contributes to an increase in cardiac mass. Furthermore, GH stimulates the expansion of vascular system by increased expression of angiogenic factors that result in the endothelial cell proliferation and tube formation. Hence, both increased cardiac mass and expansion of vascular system help in meeting the circulatory requirements for rapid growth and development of an animal.

15.3.2.2.2.8 Effects of GH on Gonads

The presence of a blood-testis barrier limits the access of GH to testicular cells. The positive regulation of GH on testicular growth, development, steroidogenesis, and gametogenesis is thought to be dependent on IGF-1,although the exact under­lying mechanisms are largely unknown. In addition, it plays an important role in the maintenance, development of ovarian follicles and promotes the initial steps of steroidogenesis in corpus luteum.

15.3.2.2.2.9 Effects of GH on Adipose Tissue

Growth hormone causes lipolysis by activating various clas­ses of lipases like hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), and monoacylglycerol lipase (MGL). The increased lipolysis is necessary to shift the cellular metabolism to lipids. The rise in oxidation of free- fatty acids (FFA) leads to an increased production of ketone bodies, which is termed as ketogenic effect of GH. GH-induced insulin resistance leads to a decrease in the insulin dependent glucose uptake by adipocytes. There­fore, the increased mobilisation of lipids with a concurrent inhibition of lipogenesis in the adipose tissue results in the depletion of fat reserves.

15.3.2.2.2.10 Regulation of Secretion

The hypothalamic hormones GHRH and GHIH regulate the pulsatile secretion of GH.

Know More...

• Gigantism: A pathological condition due to the excess secretion of GH in pre-pubertal life, characterised by abnormal longitudinal growth of long bones.

• Dwarfism: The abnormal stunting of longitudinal growth due to the deficiency of GH.

• Acromegaly: The pathological condition characterised by excess thickening of bones (bone deposition) due to hypersecretion of GH in post- pubertal life.

• Somatopause: The gradual decrease in the secre­tion of GH and IGFs due to ageing is referred to as somatopause.

15.3.2.3 Prolactin (PRL)

The lactation promoting effect of administering bovine pitui­tary gland extract in rabbits has led to an inception of the term “Prolactin”. Primarily known as a hormone for lactation, it regulates diverse functions in animals including their behavioural patterns.

15.3.2.3.1 Chemical Structure and Mechanism of Action

Prolactin is a single-chain polypeptide hormone with 199 amino acids and three intramolecular disulphide bonds, synthesised from a prohormone consisting of 229 amino acids after the removal of signal sequence (1-30 amino acids). Transmembrane prolactin receptors (PRLR) belong to the fam­ily of tyrosine kinase-associated receptors and initiate signal transduction up on binding to PRL. The classical JAK-STAT and Ras/Raf/MAPK pathways are considered as the chief signalling mechanisms that impart the biological effects. In addition, the activation of other kinases such as c-src and Fyn leads to the stimulation of intracellular mechanisms.

15.3.2.3.2 Biological Effects

Regulating development of mammary gland, maternal behaviour, initiation, and maintenance of lactation are the major biological effects of PRL. In addition, it acts as a luteotrophic factor in rodents and sheep. However, it is majorly concerned with regulating plumage and crop-milk secretion in birds.

15.3.2.3.2.1 Effects on MammaryGland Development and Lactation

Prolactin drives the Iobuloalveolar development during ges­tation and plays a considerable role in mammogenesis. It stimulates transcription and translation of casein gene associated with increase in amino acids uptake in alveolar cells. It triggers the synthesis of α-lactalbumin, a regulatory sub-unit for the lactose synthase system. The positive regula­tion α-lactalbumin activates the lactose synthase and triggers lactose synthesis. Therefore, PRL-dependent initiation of lactose and casein synthesis is responsible for lactogenesis and galactopoiesis.

15.3.2.3.2.2 Effects on Animal’s Behaviour

The increased levels of PRL during the peri-parturient period impart maternal behaviour including nest-building behaviour, nursing, and cleaning of young ones. After partu­rition, the rise in PRL levels leads to an inhibition on GnRH secreting neurons with a subsequent delay in the onset of oestrous cycle. The rise in oestrogen levels during oestrous cycle stimulates the release of PRL and thought to have a positive effect on sexual receptivity in female animals.

15.3.2.3.2.3 Effects of PRL in Birds

It stimulates the secretion of crop milk for nourishing young ones. In addition, it has an effect on plumage pattern, broodi­ness in hens.

15.3.2.3.2.4 Regulation of Secretion

The activation of dopaminergic neuroendocrine cells due to a rise in PRL levels serves as the basic negative regulatory mechanism for its secretion. However, vasoactive intestinal polypeptide (VIP) positively regulates PRL secretion in birds. Further, regular milking has a positive effect on its secretion.

15.3.2.4 Adrenocorticotropic Hormone (ACTH)

ACTH targets different adrenocortical zones to stimulate the production of three different classes of steroid hormones collectively known as corticosteroids. Primarily, it is impor­tant for the secretion of glucocorticoids to alleviate the harm­ful effects of various kinds of stressors in animals.

15.3.2.4.1 Chemical Structure and Mechanism

of Action

The release of hypothalamic CRH stimulates corticotropes in anterior lobe and neuroendocrine cells in intermediate lobe to synthesise a large precursor known as pro-opiomelanocortin (POMC). The POMC is cleaved in both anterior and inter­mediate lobes of pituitary, generating a single-chain polypep­tide hormone of 39 amino acids length known as ACTH. ACTH binds to melanocortin 2-receptor (MC2-R), a mem­brane localised GPCR localised in adrenal cortical cells. It results in the production of cAMP, activating protein kinase A (PKA) with subsequent initiation of downstream cellular pathways.

15.3.2.4.2 EffectonAdrenalCortex

The activation of PKA leads to generating an acute steroido­genic response characterised by increased de novo choles­terol synthesis by activating hormone-sensitive lipase (HSL), StAR, and CYP11A1 (p450scc). Their co-activation leads to increased conversion of cholesterol to pregnenolone, a rate­limiting step in the synthesis of corticosteroids. Additionally, the activation of zone-specific hydroxylases results in the production of distinct classes of corticosteroids.

15.3.2.4.3 Regulation of Secretion

The CRH has a positive effect on ACTH levels whereas it is negatively regulated by an increased level of corticosteroids especially cortisol.

15.3.2.5 Thyroid Stimulating Hormone (TSH)

With thyroid gland as the target organ, TSH plays a key role in stimulating it to produce thyroid hormones (T_3/T₄) and in regulating metabolism to cater the needs of animals during various physiological states.

15.3.2.5.1 Chemical Structure and Mechanism of Action

TSH is a heterodimeric glycoprotein with α and β chains, composed of 92 and 112 amino acids, respectively. It binds to specific GPCRs known as TSH receptors (TSHR) that are present on the cell membrane of thyroid follicular cells. The signal transduction involves the activation of adenylyl cyclase resulting in elevated cAMP levels with the subsequent trigger­ing of PKA and downstream signalling pathways. They mainly effect the rate of transcription and translation of genes that are linked to the production of T3/T4.

15.3.2.5.2 EffectonThyroidGland

It positively affects all the steps involved in synthesis and secretion of T3/T4 from the thyroid gland. Briefly, it increases the synthesis of sodium-iodide symporter protein (NIS), thyroid peroxidase, and thyroglobulin. It also increases the endocytosis of stored colloid followed by iodin­ation to produce and secrete thyroid hormones.

15.3.2.5.3 Regulation of Secretion

The TRH and GH are two principal stimulators for the secretion of TSH. Whereas, rise in T3/T4 circulatory levels inhibit its release.

15.3.2.6 Pituitary Gonadotropins: LH and FSH

Pituitary gonadotropins stimulate gonadal steroidogenesis and gametogenesis in post-pubertal animals. Therefore, nor­mal secretion of gonadotropins helps in maintaining optimal reproduction, which is very essential in farm animals.

15.3.2.6.1 Chemical Structure and Mechanism

of Action

Gonadotropins are heterodimeric glycoprotein hormones with a common α sub-unit (92 amino acids) and distinct β sub-units that determine their specific biological activity. The β sub-units of LH and FSH consist of 121 and 109 amino acids. The glycosylation of asparagine residues in α and β sub-units plays a vital role in determining specific biological effects and half-life of gonadotropins in circulation. Gonadotropins bind to their respective membrane-bound GPCRs, i.e. luteinising hormone receptor and follicle-stimulating hor­mone receptor (LHR and FSHR) to initiate signal transduction by activating adenylyl cyclase enzyme and followed by a rise in cAMP production. The increased cAMP levels stimulate PKA, thereby initiating downstream signalling pathways that stimulate cholesterol synthesis, cholesterol side chain cleavage by CYP11A1, StAR, and various hydroxylases. In addition, they also activate MAPK and AKT pathways that help in regulating cell cycle, proliferation, and apoptosis.

15.3.2.6.2 Biological Effects of LH

In female animals, LH acts on thecal cells of the growing follicles to stimulate synthesis and secretion of testosterone that later gets converted into oestrogen. The granulosa cells develop LHRs during the late phase of follicular growth and when stimulated with LH are responsible for developing critical changes that ensues ovulation. Moreover, LH essen­tially causes the transition of granulosa cells into luteal cells in most of the mammals and hence known as the chief luteotrophic factor. However, LH acts on the Leydig cells (hence it is also referred to as interstitial cell stimulating hormone (ICSH)) stimulating the production of testosterone, which is a principal regulator of male fertility. Therefore, the LH-dependent production of oestrogen, testosterone, and progesterone regulates key processes such as oestrous cycle, libido, and gestation.

15.3.2.6.3 Biological Effects of FSH

FSH stimulates the granulosa cells in ovarian follicles to produce oestrogen. The testosterone produced by theca cells is converted by FSH activated aromatase enzyme in granulosa cells. The dominant follicle that shows high sensitivity to FSH becomes the graafian follicle. In males, FSH acts on Sertoli cells to regulate their proliferation and differentiation. It also helps in sequestering testosterone in seminiferous tubules by producing androgen-binding protein (ABP) from Sertoli cells. Further, FSH dependent conversion of testosterone to estrogen in Sertoli cells is obligatory for the spermatogenesis and maintaining libido in male animals (Fig. 15.11).

15.3.2.6.4 Regulation of Secretion

GnRH is a chief stimulator for the secretion of pituitary gonadotropins. The rise in oestrogen levels has a negative effect on FSH and a positive effect on LH surge. Activin and inhibin are large proteins produced in gonads; respectively, they exert positive and negative regulation on the secretion of FSH. Higher levels of testosterone and progesterone impose a negative effect on the secretion of LH in male and females correspondingly.

Know More...

• All the glycoprotein hormones (TSH, LH, and FSH) of pituitary origin and placenta (eCG/hCG) are com­posed of a common α sub-unit composing 92 amino acids. Thus, their respective biological effects reside in the β sub-units.

Fig. 15.11 Biologicaleffectsof gonadotropins on different somatic cells present in male and female animals. [Pituitary gonadotropins stimulate the production of gonadal steroids, i.e. testosterone and oestrogen in male and female animals, respectively. [LH luteinising hormone; FSH follicle­stimulating hormone]

15.3.3 PosteriorPituitary

Derived from neural ectoderm, posterior pituitary is com­posed of axons arising from magnocellular (MC) neurons present in PVN and SON of hypothalamus. Up on appropri­ate stimulus, these nerve terminals in the posterior pituitary secrete oxytocin (OT) and anti-diuretic hormone (ADH). In addition, glial cells present in the neurohypophysis com­monly referred to as pituicytes.

15.3.3.1 Chemical Structure of Oxytocin and ADH

Both oxytocin and ADH are nonapeptides with minor differences in their amino acid composition. They are synthesised in MC neurons along with their specific precur­sor transport protein known as neurophysin and stored as secretory granules. However, during the axonal transport, the transport protein moiety is cleaved to produce the active hormone. The action potential propagated in response to an afferent neural stimulus on MC neurons results in the release of hormones from their nerve terminals.

15.3.3.2 Oxytocin

Widely known for its role in parturition, oxytocin also has an effect on milk ejection, sperm transport, social bonding, and ovulation in animals.

15.3.3.2.1 MechanismofAction

It binds to specific GPCRs known as oxytocin receptors (OTR), and then activate PLC system to produce the second­ary messengers DAG and IP₃. The secondary messengers in turn activates PKC and stimulates the release of Ca+² from endoplasmic reticulum. The increased Ca⁺² levels activate myosin-light chain kinase (MLCK), whereas activated PKC inhibit myosin-light chain phosphatase (MLCP) resulting in an increased formation of actin-myosin bridges. This leads to the initiation of smooth muscular contraction process.

15.3.3.2.2 Biological Effects

15.3.3.2.2.1 EffectsonUterus

The afferent neural stimuli due to the entry of foetus in to cervical region leads to the release of oxytocin, and this particular neuroendocrine reflex is known as Ferguson’s reflex. This stimulates smooth muscle cells present in myometrium to initiate uterine contractions, which leads in the expulsion of foetus. Hence, it is also known as the “birth hormone”. It is released while/after mating in male and female animals, aiding in the transport of spermatozoa in male and female reproductive tracts.

15.3.3.2.2.2 Effects on Mammary Gland

The contraction of myoepithelial cells around the alveoli leads to the ejection of milk from the mammary gland. In dairy animals, afferent neural stimuli due to tactile stimula­tion of udder, visual, or auditory stimuli leads to the secretion of oxytocin with subsequent ejection of milk.

15.3.3.2.2.3 EffectsonOvulation

Oxytocin stimulates the synthesis of PGF2α, which has a significant role in rupture of follicular membrane resulting in ovulation.

15.3.3.3 Anti-diuretic Hormone

Responsible for conserving body water during periods of extreme dehydration, ADH opposes water excretion (anti­diuresis) through urine and prevents increase in ECF osmolality.

15.3.3.3.1 MechanismofAction

Anti-diuretic hormone binds to transmembrane GPCRs known as vasopressin receptors (VR). Three different types of vasopressin receptors are found, namely V₁, V₂, and V₃. The signal transduction pathway and effects of ADH depend on the type of receptors present on the target tissue.

15.3.3.3.2 Biological Effects

15.3.3.3.2.1 Effects on Kidney

It binds to V₂ receptors on tubular epithelial cells present in the distal collecting tubules and collecting ducts. This leads to the production of cAMP levels by activating the adenylyl cyclase enzyme, thereby initiating transcription, translation of the aquaporin gene. Consequent incorporation of aquaporins on tubular epithelial cells leads to the reabsorption of water resulting in the classic anti-diuretic effect of ADH.

15.3.3.3.2.2 Effects on the Vascular System

ADH binds to V₁ receptors present on the arteriolar smooth muscle cells to activate PLC resulting in the production of DAG and IP₃. The further activation of various kinases and rise in intracellular Ca⁺² levels lead to the smooth muscle contraction. Due to its potent vasoconstrictor ability, ADH is also known as vasopressin. This particular vasoconstriction in reducing the GFR to conserve water and maintaining systemic blood pressure during periods of acute water loss or prolonged dehydration.

15.3.3.3.3 Regulation of Secretion

Residing in the supra-optic nucleus (SON), cells that detect osmolality of ECF are known as the osmoreceptors. An increase in the osmolality results in the shrinking of osmoreceptors and stimulates the secretion of ADH. While a decrease in osmolality of ECF has an opposite effect on its secretion. In addition to the osmoreceptors, the stretch receptors in heart stimulate the secretion of ADH in response to a 5-10% reduction of blood volume (Fig. 15.12).

Fig. 15.12 Mechanism of secretion of ADH and its actions. [Osmoreceptors in the hypothalamus responds to the hyperosmolality of ECF by secreting ADH, which drives the thirst behaviour and conservation of body water by decreased excretion in animals. [ADH anti­diuretic hormone; ECF extracellular fluid; SON supra­optic nucleus; GFR glomerular filtration rate]

Know More...

• Neurophysin-I is the transport protein for the oxyto­cin, whereas the neurophysin-II is required for the axonal transport of ADH.

• All mammals have arginine vasopressin except in pigs, where lysine vasopressin is found.

• Vasotocin: Found in birds, a nonapeptide hormone possess both the biological activities of oxytocin and ADH.

15.4