Hypothalamus and Pituitary gland��By Prof. Dr. S. T. Abbas

Key Points

1. Hormones and neurotransmitters are integrated, and they coordinate cellular functions in the body.

2. The physiologic response to hormones can be autocrine, paracrine, or endocrine.

3. Hormones can be amino acid-derived amines, peptides, proteins or glycoproteins, steroids, or eicosanoids.

4. The nervous and endocrine systems function in a coordinated manner to promote growth, homeostasis, and reproductive competence.

5. Feedback regulation of an endocrine system (usually negative) involves both simple feedback loops (e.g., insulin secretion regulated by plasma glucose levels) and complex feedback loops (e.g., hypothalamic, pituitary, thyroid in the secretion of thyroxine). Some of the feedback loops can be positive.

6. Hormone secretion can be pulsatile, episodic, daily, monthly, or seasonal.

7. Steroid hormones and thyroid hormones (T3 and T4) require transport proteins in the blood to reach the target sites.

8. Some hormones have multiple physiologic effects at a given target site (e.g., insulin), and some hormones have different physiological effects at different sites (e.g., testosterone).

9. The physiological response to a hormone (ligand) is determined by the presence of a specific receptor at the target cell. The receptors may be located on the plasma cell

membrane, in the cytosol, or in the nucleus.

10. Hormone recognition and binding at their specific receptor binding site initiate the signal transduction amplification pathways, which culminates in an appropriate biological

response.

11. Nuclear receptors are responsible for the action of the thyroid hormone tetraiodothyronine (T3). T3 binding to the nonhistone receptor proteins stimulates transcription at the target sites. However, it can also inhibit transcription of thyroid stimulating hormone (TSH) at the pituitary (a negative feedback process).

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12. All steroid hormones, like T3, mediate their action via nuclear receptors. However, glucocorticoids and aldosterone initially bind to cytosolic receptors.

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13. Amine, polypeptide, and protein hormones (either growth promoting or inhibiting) initiate their action by binding to plasma membrane receptors on the cell surface.

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14. Cell surface receptors can be G-protein-coupled receptors (GPCR), tyrosine kinase receptors, or guanylyl kinase receptors. GPCR pathways include the heterotrimeric G-protein-coupled adenylate cyclase cAMP system and the G-protein-coupled phosphatidyl-inositol- Ca+2 pathway.

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15. G-protein-coupled receptor signaling pathways affect diverse metabolic processes and are regulated by several different mechanisms involving the regulation of GTPase activity of the Gα subunit. Some bacterial toxins act by activating or inhibiting Gα subunit activity.

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16. Monomeric G-proteins anchored to the inner cytoplasmic membrane also participate in the normal cellular functions when activated by external stimuli. Some of these are proto-oncogenes and, when mutated, become oncogenes that promote cancer.

17. Tyrosine kinase receptors are of two types. The first type contains an extracellular receptor domain and an intracellular domain with tyrosine kinase activity (e.g.,insulin). The second type consists of the extracellular hormone-induced dimerization with resultant activation of constitutively associated tyrosine kinases known as Janus kinases (JAK) and involves cytosolic signal transducer and activator of transcription pathway (STAT). These signal amplifications of JAKSTAT pathways are involved in several other pathways of the cytokines of growth factors (e.g., growth hormone, prolactin).

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18. Nonreceptor tyrosine kinases are found in the cytosol and are involved in the signal transduction pathways of normal cellular processes. Abnormalities in these pathways can lead to cancer (e.g., chronic myelogenous leukemia, BCRABL tyrosine kinase).

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19. Specific inhibitions at the receptor sites using monoclonal antibodies or tyrosine kinase inhibitors are therapeutic targets used in the management of some cancers.

HYPOTHALAMUS and Pituitry

Key Points

1. The endocrine systems of the hypothalamus and pituitary (hypophysis) have an integrated anatomical and functional relationship.

2. The afferent signals received by the hypothalamus are transmitted to the pituitary by two hypothalamic_pituitary axes: (1) portal venous blood circulation, which transports hypothalamic (hypophysiotropic) hormones to target sites at the anterior lobe of the pituitary, and (2) hypothalamic nerve tracts in which neuro-hormones are synthesized and then stored in the posterior lobe of the pituitary.

3. The hypophysiotrophic hormones are all peptides, except for dopamine, which is synthesized from tyrosine. These hormones either inhibit or stimulate the synthesis and release of hormones from specific cells of the anterior pituitary. The pituitary hormones belong to three families: somatomammotropin (GH and PRL), the glycoproteins (LH, FSH, and TSH), and opiomelanocortin (ACTH, β-endorphin, and related peptides).

4. The anterior pituitary hormones regulate growth (GH), milk production (PRL), and secretions of hormones from the adrenal glands , thyroid gland , and the glands of the reproductive system.

5. The neurohypophyseal hormones, antidiuretic hormone (ADH), and oxytocin regulate water balance and milk production, respectively.

6. The brain contains several peptides that share homology with gastrointestinal hormones and affect eating behavior.

7. The perception of pain in the CNS is regulated by peptides known as endogenous opioids; they are derived from posttranslational processing of three prohormones: proopiomelanocortin (POMC), proenkephalin A, and proenkephalin B.

8. Growth hormone (GH) is synthesized in pituitary somatotroph cells and is the most abundant of the anterior pituitary hormones. It is a nonglycosylated globular protein and consists of 191 amino acid residues (M.W. 22 kDa). Its secretion is pulsatile and is stimulated by GHRH and ghrelin, and inhibited by somatostatin.

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9. The effect of growth hormone on growth and the metabolic activity of somatic cells consists of both direct and indirect actions. The indirect actions are mediated by insulin-like growth factors (IGFs) synthesized and released from the liver.

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10. The action of growth hormone at the target site is initiated by its binding to specific cell surface receptors followed by activation of intracellular Janus tyrosine kinase-signal transducing activators of transcription (JAK-STAT), leading to a protein phosphorylation cascade .

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11. Growth hormone deficiency leads to short stature and can occur due to defects in its synthesis by the pituitary cells, whereas growth hormone insensitivity occurs due to

mutations of the GH receptor or in the STAT proteins of the signal-transducing system. Recombinant human GH is used to treat primary GH deficiency, and recombinant IGF-I is used to treat growth hormone insensitivity disorders.

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12. Growth hormone_secreting tumors result in gigantism during childhood.

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13. Prolactin is secreted by pituitary lactotroph cells and inhibited by the neurotransmitter dopamine originating from the hypothalamus. It is a globular protein of 199 amino acid residues. Its action at the target site involves the JAK-STAT pathway. Its functions include mammary gland development and milk production.

14. Hyperprolactinomas (e.g., pituitary lactotroph adenoma), which can cause hypogonadism, are treated with dopamine agonists, radiotherapy, or surgery.

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Hypothalamus

Anterior pituitary

Posterior pituitary

Neurosecretory

neurons

Systemic

arterial

inflow

Hypothalamic-hypophyseal

portal system

System

venous

outflow

Hypophysiotropic H.:

Anterior pituitary hormones:

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HYPOTHALAMUS

The hypothalamus is a small region of the brain in the ventral aspect of the diencephalon. In the adult human, it is about 2.5 cm in length and weighs about 4 g.

Ventromedially, it surrounds the third ventricle and is continuous with the infundibular stalk of the pituitary (hypophysis). The cone-shaped region of the hypothalamus,

the median eminence, consists mainly of axonal fibers from hypothalamic neurons, which either terminate in the median eminence or continue down into the posterior

lobe of the pituitary. It is perfused by a capillary network (primary plexus) derived from the carotid arteries. Blood from the primary plexus is transported by portal vessels (hypophyseal portal vessels) to another capillary network (secondary plexus) in the anterior lobe of the pituitary (adenohypophysis) .

The hypothalamus contains a high density of nerve cell bodies clustered into nuclei which participate in a variety of functions, such as integrating neurons and

endocrine systems. Neurons in each of these nuclei tend to send their axons to the same regions in the form of tracts. These nuclei innervate the median eminence, other

hypothalamic nuclei, the posterior pituitary, and various structures in the extrahypothalamic central nervous system. Many of the hypothalamic neurons are presumably monoaminergic as they synthesize and release the neurotransmitter

amines norepinephrine, serotonin, or dopamine.

Many are also peptidergic as they synthesize and release neuropeptides. At least 12 hypothalamic neuropeptides have been identified.

The hypothalamus is an important integrating area in the brain. It receives afferent signals from virtually all parts of the central nervous system (CNS) and sends efferent fibers to the median eminence, the posterior pituitary, and certain areas of the central nervous system. In the median eminence, a number of peptidergic fibers terminate in close proximity to the primary plexus, which transports their neuropeptide hormones via the portal blood flow to the anterior pituitary. Since these neuropeptide hormones affect the function of the anterior pituitary cells, they are called hypophysiotropic. Two hypothalamic nuclei, the paraventricular nucleus (PVN) and the supraoptic nucleus (SON), consist of two populations of, neurons that differ in size: the parvicellular (small-celled) neurons and the magnocellular (large-celled) neurons.,The parvicellular neurons of the paraventricular nucleus produce a peptide that is transported by axoplasmic flow to the median eminence and then released into the hypophyseal portal blood. The magnocellular neurons of the paraventricular and supraoptic nuclei send their long axons directly into the posterior pituitary (neurohypophysis), where their dilated nerve endings are closely positioned next to capillaries that drain the tissue. Peptide hormones synthesized in these magnocellular neurons are transported to the neurohypophysis by axoplasmic flow and then released into the general circulation. These neuropeptide hormones are called neurohypophyseal. Other hypothalamic neurons, called neuroregulatory, make synaptic contact with other neurons, and their neuropeptide products function as neurotransmitters or as neuromodulators.

Hypophysiotropic Hormones of the Human Hypothalamus

PeriVN5periventricular nucleus; PVNparv5parvicellular paraventricular nucleus; PON5preoptic nucleus; OVLT5organum vasculosum of the lamina terminalis; VMN5ventromedial nucleus; TIDA5tuberoinfundibular dopaminergic system; LHRH5luteinizing hormone-releasing hormone; POMC5pro-opiomelanocortin 2AA5amino acid residue; M.W.5molecular weight; n.a.5not applicable.

§ Introduction

1. The “master gland”— controls three other endocrine glands

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• Better to think of the pituitary gland as the relay center—

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• Its function covers both endocrine target glands and nonendocrine target glands

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§ The Posterior Pituitary

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Neurohypophyseal Peptide Hormones

The magnocellular neurons of the paraventricular and supraoptic nuclei synthesize antidiuretic hormone (ADH, vasopressin, or arginine vasopressin) and oxytocin, neuropeptide hormones that are released into the general circulation in significant amounts . These neuropeptides are synthesized in separate cells and transported by axoplasmic flow to nerve endings in the neurohypophysis. Cholinergic signals to the magnocellular neurons stimulate the release of ADH and oxytocin via nerve impulse propagation along the axon and Ca21- dependent exocytosis of secretory granules. Release mechanisms for ADH and oxytocin are under separate control.ADH is a nonapeptide that contains an intrachain disulfide bridge. ADH is synthesized as part of a precursor glycoprotein (propressophysin), whose gene is located on chromosome 20. Propressophysin is packaged into secretory granules &transported to the neurohypophysis. During transit, propressophysin is split by proteases in the granule wall yielding ADH and a “carrier” polypeptide called neurophysin II, or nicotine-sensitive neurophysin (NSN), whose release is stimulated by nicotine. On neural stimulation, ADH and NSN are released in equimolar amounts. NSN has no known biological activity. In the collecting ducts of the kidney, ADH acts by a Gs-protein coupled cAMP-mediated mechanism to increase the permeability of ductal cells to water by mobilizing aquaporin proteins to the apical membrane, which prevents diuresis . At relatively high concs. ADH is a potent vasoconstrictor. High concentrations are attained after massive hemorrhage, when constriction of blood vessels prevents further blood loss. Major stimuli for ADH release are (1) an increase in plasma osmolality, monitored by hypothalamic osmoreceptors; and (2) a decrease in blood volume, monitored by baroreceptors in the carotid sinus and in the left atrial wall. Afferent fibers to the vasomotor center in the hindbrain sense a fall in blood volume, and diminished noradrenergic signals from this center to the hypothalamic magnocellular neurons stimulate ADH release. Because norepinephrine inhibits ADH release, a decrease of this inhibition results in stimulation of ADH.

Oxytocin _ a nonapeptide : differs from ADH at the amino acids in positions 3 and 8.

Synthesized in separate magnocellular neurons; The gene codes for pro-oxyphysin, __ precursor of oxytocin and its “carrier” (neurophysin I, or estrogen-sensitive neurophysin). Neurons in the paraventricular and supraoptic nuclei synthesize pro-oxyphysin, which is packaged and processed during transit to the neurohypophysis. The principal action of oxytocin is ejection of milk from the lactating mammary gland (“milk let-down”), and it also participates in parturition. Oxytocin is released by a neuroendocrine reflex mechanism and stimulates contraction of estrogen-conditioned smooth muscle cells. The mechanism of action of oxytocin does not involve cAMP but may involve regulation of increased intracellular Ca++. The oxytocin receptor belongs to a sevenmembrane-spanning receptor family.

Neuroregulatory Peptides

Neuronal projections from the hypothalamus to other regions of the brain relay important output information that influences blood pressure, appetite, thirst, circadian rhythm, behavior, nociception (pain perception), and other factors. Although many of these neurons release neurotransmitter amines at synapses, some of them are known to release neurotransmitter peptides. These include, among others, peptides that closely resemble hormones formed in the gastrointestinal system, as well as endogenous opiates.

Brain Gut Peptides

Gut hormone-like neurotransmitters have been detected in the brain and are believed to function in a manner that complements their counterparts in the gastrointestinal tract . For example, cholecystokinin (CCK) functions in the gut to promote digestion by acting on the gallbladder and exocrine pancreas. The gut-derived CCK is a large peptide (33 amino acid residues), the last 8 of which confer biological activity. In the brain, a smaller CCK with the same 8 carboxy terminal amino acids functions as a neurotransmitter for appetite suppression. Thus, in the brain and in the gut, CCK influences some facet of eating. Gastrin, a 17-residue hormone in the gut that stimulates gastric acid secretion and that has the same five carboxy terminal residues as CCK, has also been detected in the brain, where it is believed to have aneffect on appetite.

Vasopressin and oxytocin

• Synthetized in the hypothalamus (nucleus supraopticus and paraventricularis)
• Axonal transport with transport proteins (neurophysins)
• Nonapeptides with disulfide bridge

Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH₂

Arginine vasopressin

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Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH₂

Lysine vasopressin

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Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Arg-Gly-NH₂

Oxytocin

Structural similarity, overlapping functions

Oxytocin: causes milk ejection in lactating female

Vasopressin: increases water reabsorption from distal kidney tubule

Endogenous Opiates: Opioid neurotransmitters in the brain are peptides that modulate pain perception and/or the reaction to perceived pain; they include the enkephalins, endorphins, dynorphins, and neoendorphins. All exert their effects by binding to specific types of opiate receptors that are located in various parts of the CNS, but particularly in those regions that function in pain perception. Derivatives of opium, the extract of the poppy Papaver somniferum, exert their analgesic and psychological effects through these opiate receptors. The endogenous opiates include β-endorphin, the enkephalins (met enkephalin and leu-enkephalin), the dynorphins, and the neoendorphins. All are peptides varying in size from 5 to 31 amino acid residues. All have in common an amino terminus consisting of either of two pentapeptide sequences: TyrGlyGlyPheMet (the met-enkephalin sequence) or TyrGlyGlyPheLeu (the leu-enkephalin sequence). The fundamental endogenous opioid peptides are the pentapeptides, met-enkephalin and leu-enkephalin, which function as neurotransmitters in the CNS. All of the known endogenous opioids are derived from three different prohormones: proopiomelanocortin (POMC); proenkephalin A; and proenkephalin B (prodynorphin).

PITUITARY GLAND (HYPOPHYSIS)

The pituitary is a small, bilobed gland connected to the base of the hypothalamus by the infundibular process (pituitary stalk). Embryologically, it derives from Rathke’s pouch (buccal epithelium) and the infundibulum (neuroectoderm). The former gives rise to the anterior lobe (anterior pituitary or adenohypophysis). The latter is a projection of the hypothalamus and gives rise to the posterior lobe (posterior pituitary/ neurohypophysis). In many species, an “intermediate lobe” also exists, but in humans, this is rudimentary and apparently nonfunctional. The pituitary in an average-sized adult weighs only about

0.5 g, 75% of which is anterior pituitary.

The anterior pituitary is not innervated by nerve fibersfrom the hypothalamus but is well vascularized by the portal blood that drains the median eminence. The portal blood

flows primarily from the median eminence to the anterior pituitary; however, some vessels may transport blood in the opposite direction (retrograde flow). The posterior pituitary consists mainly of nerve endings of hypothalamic magnocellular neurons and contains no portal connections with the hypothalamus; its vascular connections are largely independent of those in the anterior pituitary. The hormones of the posterior pituitary (neurohypophyseal hormones) have been discussed previously. The anterior pituitary has five endocrine cell types, each of which produces different hormones. In humans, at least seven are produced: growth hormone (GH); prolactin (PRL); luteinizing hormone (LH); follicle-stimulating hormone (FSH); thyroid-stimulating hormone (TSH); adrenocorticotropic hormone (ACTH, corticotropin); and β-endorphin. β-Lipotrophic hormone (β-LPH) is also secreted, but it serves mainly as a precursor of β-endorphin

and is not regarded as a hormone. In species that possess a prominent intermediate lobe, the pituitary also secretes α- and β-melanocyte-stimulating hormones (MSH), which affect skin coloration. Anterior pituitary hormones are classified into three

families: the somatomammotropin family (GH and PRL); the glycoprotein hormones (LH, FSH, and TSH); and the opiomelanocortin family (ACTH, β-endorphin, and related peptides). These three families appear to have evolved from three separate ancestral polypeptides, because homologous members of each family occur in other parts of the body. For example, human placental lactogen (hPL) is somatomammotropin, human chorionic gonadotrophin (hCG) is a glycoprotein hormone, and the brain and gut produce substances related to endorphins (enkephalins and dynorphin).

Somatomammotropin Family

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Somatomammotropin

Members of the somatomammotropin family are single chain proteins with two or three intrachain disulfide bridges. Their molecular weight is about 20,000, and they function mainly to promote protein synthesis .The hypothalamus produces both a stimulating and an inhibiting hormone to regulate secretion of the adreno-hypophyseal hormone. Growth Hormone (Somatotropin) Human growth hormone consists of 191 amino acid residues (M.W. 22,000) and contains two disulfide bridges. It is a globular protein and does not undergo glycosylation. It exhibits extensive sequence homology with prolactin (76%) and placental lactogen (94%). The gene encoding growth hormone (GH) is on chromosome 17, q22-q24, and its expression is regulated by a transcription factor (Pit-1/ GHF-1) that is promoted by hormones that stimulate GH synthesis (e.g., GHRH, glucocorticoids, thyroid hormone). GH is the most abundant hormone in the human pituitary gland, averaging about 6 mg per adult gland. Growth hormone secretion is pulsatile, with about 10 pulses per day; its basal blood level averages 2 ng/mL in adults and 6 ng/mL in preadolescent and adolescent boys. GH is cleared from circulation with a half-life of about 25 minutes in lean adults, but is cleared more rapidly in obese subjects. GH is inactivated mainly by the liver but also by the kidney. About 40% of the hormone is bound to GH-binding protein (GHBP), a fragment of the GH receptor. It serves to prolong the half-life of GH 10-fold. Its primary structure is species-specific and antigenic.

Actions of GH

The actions of GH are initiated by its binding to the membrane receptor of target cells. The GH and PRL receptors are single-membrane-bound proteins that belong to class I of the cytokine receptor superfamily . Each receptor contains an extracellular, a transmembrane, and an intracellular domain. Receptor activation begins when one molecule of growth hormone (with its two binding sites) binds to the first receptor, followed by binding to the second receptor, resulting in receptor dimerization. The hormone receptor complex activates a tyrosine kinase known as Janus kinase 2 (Jak-2) that is associated with the proximal region of the intracellular domains of the dimerized receptor. Two Jak-2 kinases transphosphorylate each other and also phosphorylate tyrosine residues of the receptor. Subsequent downstream single transduction pathways are many and involve signal transducer and activator of transcription (STAT) proteins, activation of mitogen-activated protein (MAP) kinase, and phosphoinositide-3-kinase (PI kinase) pathways. GH promotes the transport and incorporation of amino acids into skeletal muscle, cardiac muscle, adipose tissue, and liver, and is responsible for the proportional growth of visceral organs and lean body mass during puberty. Linear growth during childhood requires the presence of GH. GH acts directly on cartilage tissue to promote the endochondral growth that results in skeletal growth. Although GH has a direct effect on chondrocyte stem cells, the growthpromoting effect of GH is due to its stimulation of the chondrocytes to produce insulin-like growth factor I (IGFI, discussed later), which then acts locally to stimulate cellular replication in the distal proliferative zone of the epiphyseal plate. Thus, the growth-promoting effect of GH can be abolished by blocking the IGF-I receptor, and can be duplicated by exogenous IGF-I treatment in the absence of GH.

The importance of GH is in its ability to stimulate IGF-I production within bone cartilage, an ability that is unique to GH. This explains why GH deficiency results in growth retardation, despite the fact that bone cartilage has the ability to produce IGF-I. GH exerts a “protein-sparing” effect by mobilizing the body’s energy substrates, such as glucose, free fatty acids, and ketone bodies, in the same tissues in which it stimulates protein synthesis. GH elevates blood glucose levels by lowering glucose uptake by skeletal muscle by means of inhibiting hexokinase activity and desensitizing the tissue to the actions of insulin. In addition, GH increases the activity of hepatic glucose-6-phosphatase, and thereby increases glucose secretion. GH promotes lipolysis in adipocytes, possibly by increasing the synthesis of hormone-sensitive lipase (HSL), and by increasing ketogenesis in the liver. These protein-sparing effects of GH are diabetogenic and explain how GH functions as an insulin antagonist.

REGULATION OF GH: The protein-anabolic and protein-sparing actions of GH

require the metabolic effects of insulin, glucagon, cortisol, and thyroid hormone in the unstressed individual. These actions depend on fine-tuned control of GH release, which is achieved mainly by substrate feedback to the hypothalamus . A fall in blood glucose level stimulates GH release, whereas a rise inhibits release. GH release also occurs in response to certain amino acids, the most potent being L-arginine, with a latency period of about 30 minutes. Circulating hormones exert their effects at the level of the hypothalamus or the pituitary.

GH influences its own secretion by way of IGFs that exert a negative feedback effect at the median eminence. However, it is not known if this feedback involves a decrease in GHRH, an increase in somatostatin, or both. Other hormones promote the synthesis and release of GH at the level of the anterior pituitary. While estrogen promotes an increase in somatotroph numbers and GH mRNA levels, androgens increase and IGF-I decreases the somatotroph response to GHRH. Glucocorticoids and thyroid hormone act in concert to stimulate GH gene expression. However, pharmacological concentrations of glucocorticoids strongly inhibit GH release in response to GHRH Superimposed on this fine regulation of GH secretion by substrates and hormones is the coarse regulation by higher brain centers that operate on an open-loop, substrate-independent basis. These influences are dramatic and result in a several-fold increase in GH levels during stress and during deep sleep. GH is one of several hormones released in response to stress . It is also one of the few released during deep sleep (EEG stages III and IV) irrespective of the time of day. The amount of GH released during deep sleep is substantial, accounting for about 75% of the daily output of GH. In children who are unable to achieve deep sleep because of emotional disturbances, the absence of sleep-induced GH results in growth retardation.

Insulin-Like Growth Factors

Insulin-like growth factors (IGFs) are GH-dependent polypeptide hormones that promote cell replication in most mesenchymally derived tissues, and are responsible for the growth-promoting effects of GH. There are two IGFs, I and II, both of which are 7 kDa proteins that resemble proinsulin in structure. The IGFs exert insulin like biological effects when tested in insulin bioassay systems in vitro and account for the nonsuppressible insulin-like activity (NSILA) in plasma that had been described before the discovery of the IGFs.

Six serum proteins, produced mainly in the liver, that bind IGFs in the circulation have been identified. They are designated IGF-binding proteins (IGFBPs) 1 through 6. IGFBP-1 appears to retard target tissue uptake of IGF-I, while IGFBP-3 appears to enhance it; the latter accounts for most of the IGF found in blood. About 80%90% of the IGF-I in circulation is bound to IGFBP-3, along with an 88 kDa acid-labile subunit (ALS). This complex confers protection on the IGF and prolongs its half-life to 12-15 hours. About 5% of the IGF is unbound, and the remaining 5% 15% is bound to IGFBP-1, -2, or -4 as smaller complexes. Unlike insulin and other peptide hormones that are released from storage granules, IGFs are released as they are produced. Most tissues produce IGFs in small amounts that are sufficient for local (paracrine / autocrine) effects and do not contribute significantly to the circulating pool of IGFs. The highest concentration of IGF-I and -II is found in the circulation and is primarily derived from the liver. GH and insulin are positive regulators of IGF-I synthesis in the non fasting state. During mild starvation when GH levels increase, there is a decline in hepatic production of IGF-I due, in part, to the decline in insulin. Re feeding, which causes insulin to rise and GH to fall, promotes IGF-I production only if the diet is adequate in calorie and protein content.

The circulating IGF-I does not mediate the growth-promoting effect of GH but is an important feedback regulator of GH. The indispensability of IGF-I for linear growth and the fact that it mediates the effect of GH are firmly established. IGF-I, locally produced in endochondral bone in response to GH, promotes skeletal growth by stimulating clonal chondrocyte expansion of the distal proliferative zone of the epiphyseal plate. Under physiological conditions, IGF-I is a relatively minor regulator of fuel homeostasis. It does not mediate the effects of GH on intermediary metabolism. In fact, many of the effects of IGF-I resemble those of insulin, not GH. IGF-I promotes the production and actions of erythropoietin and is responsible for the increased packed volume of blood that results from elevated GH levels.

Disturbances in GH and IGF

Only rarely has a condition of IGF deficiency or excess been described that is not accompanied by a disturbance in GH production or responsiveness. Thus, a GH deficiency results in IGF-I deficiency, whereas a GH excess results in IGF-I excess. GH deficiency in children, due to defects of the GH gene and its related genes, results in reduced growth rate and growth retardation (dwarfism) due to secondary IGF-I deficiency. Insensitivity to GH action, which is accompanied by phenotypic features consistent with GH deficiency, occurs due to either defects in GH receptors at the target site or defects in the post-GHR signal transduction pathways. These disorders are characterized by normal or high levels of serum GH and low levels of IGF-I and IGF binding protein-3. The main cause of GH resistance is a genetic defect in the growth hormone receptor (GHR); the resultant condition is known as Laron-type dwarfism. This is an autosomal recessive disorder characterized by normal-to-high levels of serum growth hormone and low levels of IGF-I. Analysis of the GHR gene in Laron-type dwarfism has revealed point mutations, deletions, and splicing defects. Adults who are deficient primarily in GH have decreased lean body mass,

increased adiposity, and are at increased risk of cardiovascular disease. The STAT5b mutation is an example of how a postreceptor molecular abnormality causes dwarfism due to insensitivity to GH action .Growth hormone deficiency in children can be treated by administration of recombinant GH or, in some cases, growth hormone-releasing hormone. Recombinant IGF-I is used in the treatment of children with GH insensitivity syndrome.

Potential targets for recombinant GH use that are undergoing clinical investigation include children with idiopathic short stature, persons with wasting syndrome associated with human immunodeficiency virus infection, critically ill patients, and sick elderly individuals. GH hypersecretion in children causes increased growth rate and can result in gigantism. However, GH excess occurs infrequently in childhood. GH excess occurs most frequently in the middle-aged and leads to acromegaly (akros=extremities, plus megas=large), a condition in which the cartilaginous tissues proliferate, resulting in distorted overgrowth of the hands, feet, mandibles, nose, brow, and cheek bones. Because epiphyseal cartilage is absent in long bones, there is no gain in height. Acromegaly promotes insulin resistance and results in cardiovascular complications.

Resistance to the effects of GH results in a condition similar to GH deficiency. Excess production of GH due to somatotroph adenomas may be treated by surgical resection, irradiation, or in some cases with somatostatin analogues (e.g., octreotide) that suppress GH secretion, or by a combination of these treatments. GH has been abused by athletes to enhance their physical performance for its purported anabolic and metabolic effects. GH has also been touted as an anti-aging drug. Studies have not substantiated any of the presumed beneficial effects of GH. Recombinant and endogenous GH are chemically identical 22 kDa proteins. Normal serum contains endogenous 22 kDa GH protein and other molecular species of GH (20 kDa GH and their dimers and multimers). Since the injected recombinant 22 kDa GH increases its proportion relative to other normal GH species in the serum, the determination of the proportions of 22 kDa protein with its other forms by sensitive immunochemical analysis has been used in the detection of GH doping in sports.

§ Hormones secreted by anterior pituitary

• FSH (follicle stimulating hormone)
• LH (luteinizing hormone)

The above two are called gonadotropins

• TSH (thyroid stimulating hormone, thyrotropin)
• ACTH (adrenocorticotropic hormone)
• GH (growth hormone; somatotropin or somatotropic hormone)
• PRL (prolactin)
2. Tropic (trophic) hormones-- target other endocrine glands to release their own hormones.

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3 hormonal families of the anterior lobe: (ALL proteins)

§ Glycoprotein hormone family– TSH, FSH, LH

1. TSH– to stimulate the secretion of thyroid hormone
2. FSH & LH– important for the function of the testes and the ovaries
• FSH– growth of ovarian follicles and formation of sperm
• LH (in women)– induce ovulation and the formation of the corpus luteum; stimulate the ovarian production of estrogen and progesterone
• LH (in men)– stimulates the production of Testosterone; what cells?

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§ Glycoprotein hormone family (continued)

1. 2 peptide subunits– alpha + beta
2. The three glycoprotein hormones and hCG (Human chorionic gonadotropin; a placental hormone) all share the same alpha subunit.
3. Both subunits need to be present to be functional.
4. Beta subunits are encoded in separate genes located on different chromosomes.

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4 Glycoproteins– all of them share a common alpha subunit

§ Growth hormone and prolactin

1. Growth hormone (GH) is required for proper adult stature.
• Species specificity: primates for primate GH
• Metabolic effects
2. Prolactin (PRL) is required for milk production in post-partum women.
• In men or nonlactating women-- not clear; however, evidence suggests it may has to do with the immune function.
3. Human placental lactogen (HPL) = human chorionic somatomammotropin

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3 single-stranded peptides are similar in their structures and functions

(lactogen)

2 GH & 3 human placental lactogen genes

§ Adrenocorticotropin family

1. ACTH (adrenal corticotropic hormone) regulates hormone secretion by the cortex of the adrenal glands.
2. The gene produces ACTH is called POMC (pro-opiomelanocortin) in corticotropes and other cells by prohormone convertases.
• (Corticotropes) ACTH is the only one has an established physiological role in humans
• (melanocytes and keratinocytes)– pigmentation by MSH
• (Melanotrope in arcuate neurons)– food intake

Pro-opiomelanocortin (POMC), a gene, products

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Melanocyte-stimulating hormone (MSH)

Corticotropin-like intermediate lobe peptide (CLIP)

P. convertases

Prolactin

Human prolactin (PRL) contains 199 amino acid residues (M.W. 23,500) and three intramolecular disulfide bridges. In healthy adults, the anterior pituitary releases very little PRL under nonstressed conditions, primarily because PRL release is under hypothalamic inhibition. This inhibition is exerted by dopamine, or prolactin-inhibitory hormone (PIH). The hypothalamus also secretes PRF, but the major regulator appears to be PIH. The biological actions of prolactin are initiated by its membrane receptor, followed by the associated intracellular signal transduction pathways. These actions are similar to growth hormone . In humans, the function of PRL may be restricted to promotion of lactation, but there is some evidence that PRL suppresses gonadal function in females. There is no consensus regarding a physiological role for PRL in males. During late pregnancy, the maternal pituitary releases increasing amounts of PRL in response to rising levels of estrogen, a stimulator of PRL synthesis. Elevated levels of PRL stimulate milk production in the mammary gland . After parturition, PRL promotes milk secretion via a neuroendocrine reflex that involves sensory receptors in the nipples. In mammary tissue, it binds to alveolar cells and stimulates the synthesis of milk-specific proteins (casein, lactalbumin, and lactoglobulin) by increasing production of their respective mRNAs. Accordingly, there is a lag of several hours before this effect of PRL is seen. In the liver, PRL stimulates the synthesis of its own receptors. PRL receptors occur in the mammary gland, liver, gonads, uterus, prostate, adrenals, and kidney. Disturbances in Prolactin In women, hyperprolactinemia is often associated with amenorrhea, a condition that resembles the physiological situation during lactation (lactational amenorrhea).

Excess PRL may inhibit the menstrual cycle directly, by a suppressive effect on the ovary, or indirectly, by decreasing the release of GnRH . In men, hyperprolactinemia is not associated with altered testicular function, but is often accompanied by diminished libido and impotence. This finding suggests that PRL may serve an important role in regulating certain behavior patterns. Prolactinomas are the most common hormone-secreting pituitary adenomas and, in addition to the previously mentioned clinical characteristics, the patient may exhibit visual field defects. Prolactinoma may be treated by surgery, radiotherapy, or pharmacotherapy. This last method consists of using a dopamine D2 receptor agonist such as bromocriptine or cabergoline to suppress prolactin secretion. Hyperprolactinemia can also occur due to loss of function mutations in the prolactin receptor, causing downstream signaling dysfunctions in JAK2-STAT5 receptor pathways.

The Opiomelanocortin Family : All members of this family are derived from a single prohormone, pro-opiomelanocortin (POMC). The prohormone molecule contains three special peptide sequences: enkephalin (opioid), melanocyte-stimulating hormone (MSH), and corticotropin (ACTH). After translation, POMC is processed by proteases contained in tissue. In the adenohypophyseal corticotrophs, there is no further processing of ACTH and β-endorphin, whereas in the intermediate lobe of other species, ACTH can be processed to form α-MSH; γ-LPH can be processed to form β-MSH. The human hypothalamus and/or brain may be capable of forming α- and β-MSH from POMC. Inherited defects in POMC production result in deficiency or a complete lack of secretion of ACTH, MSH (α-, β-, γ-), and β-endorphin. These patients exhibit adrenal insufficiency, red hair pigmentation, and early-onset obesity that have been related to a deficiency of α-MSH production. Animal studies have shown that α-MSH regulates food intake by activation of melanocortin receptor-4. In mice, a POMC gene defect also leads to adrenal deficiency, altered pigmentation, and obesity with loss of a significant portion of the animal’s excess weight when treated with a stable α- MSH preparation. Other genetic causes of obesity include defects in genes encoding prohormone convertase-1 (i.e., inability to convert POMC to various peptides), leptin, and leptin receptor. ACTH is a polypeptide of 39 residues, the first 24 of which are required for corticotropic activity and which do not vary among species. ACTH124 has been synthesized and is used for diagnostic purposes. Because it contains the MSH sequence in residues 69 (HisPheArgTrp), ACTH has intrinsic melanocyte-stimulating activity and can thus cause skin darkening if present in high concentrations. In normal adults, the pituitary contains about 0.25 mg of ACTH, and the basal level of ACTH in blood is approximately 50 pg/mL. ACTH acts mainly on the cells of the zona fasciculata of the adrenal cortex to stimulate the synthesis and release of cortisol .

It also stimulates the secretion of adrenal androgens from the zona reticularis. Binding of ACTH to receptors activates the formation of cAMP, which mediates cortisol formation and secretion, as well as protein synthesis. Deficiency of ACTH leads to a reduction in the size and activity of adrenocortical cells in the inner two zones. ACTH secretion is regulated to ensure constant, adequate levels of cortisol in the blood. Corticotrophs in the pituitary are under tonic stimulation by CRH and are modulated by the negative feedback effect of blood cortisol, which inhibits POMC synthesis by repression of the POMC gene. Although cortisol also exerts an effect on the hypothalamus and related areas in the brain (limbic system, reticular formation), this activity may involve the regulation of emotion and behavior and not regulation of CRH release. Secretion of POMC in the intermediate lobe is not regulated by CRH and glucocorticoids because the intermediate lobe is poorly vascularized and contains no glucocorticoid receptors. However, the intermediate lobe is rich in dopaminergic fibers so that dopamine agonists (ergocryptine) decrease—and antagonists (haloperidol) increase—the synthesis and release of POMC-derived peptides. β-Endorphin is a 31-amino acid polypeptide released together with ACTH. When it is introduced into the third ventricle of the brain, it produces dramatic behavioral changes, but it does not when injected systemically. Thus, the function of circulating β-endorphin remains unclear. The CNS and gastrointestinal effects of the hormone are probably induced by that secreted locally. Circulating β-endorphin may act in conjunction with enkephalins released by the adrenal medulla to produce stress analgesia. Human N-terminal fragment (hNT) and γ-melanocyte- stimulating hormone (γ-MSH) are released with ACTH and β-endorphin. γ-MSH, a fragment of hNT, may be the putative aldosterone-stimulating hormone of the pituitary. hNT and γ-MSH may also be major stimulators of adrenocortical proliferation, whereas ACTH is the regulator of adrenocortical steroidogenesis.

Regulation of GHs secretion in

humans. + =stimulation, - =inhibition.

Pituitary Independent Cutaneous POMC Production and Ultraviolet-Induced Formation of Melanin Ultraviolet (UV) radiation induces skin pigmentation (sun tanning) by stimulating production of melanin. This process is mediated by the following sequence of events. UV damage to keratinocytes leads to activation of transcription factor tumor suppressor protein, p53, which upregulates the pro-opiomelanocortin (POMC) gene leading to multicomponent precursor POMC production. Enzymatic post-translational processing of POMC yields three biologically active peptides: adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (MSH), and opioid peptide β-endorphin. MSH, by binding to melanocortin-1 receptors located on the cell membrane of melanocytes, stimulates the production of melanin, which is packaged in melanosomes, which, in turn, are subsequently transported out and deposited in keratinocytes. The cutaneous production of POMC and its processing is independent of anterior pituitary processing. The addictive potential for indoor tanning among young individuals may be attributed to the release of β-endorphin. A beneficial action of UV is the production of vitamin D . It should be emphasized that UV radiation, whether due to indoor skin tanning or exposure to excessive sunlight, is a risk factor for melanoma and nonmelanoma cutaneous cancers.

Keratinocsytes _+UV irradiation___ Transcription factor tumor suppression protein (p53) Activated Upregulation of POMC gene

​

Preopeomelanocorten production proteases ACTH +α MSH + β-endorphin

Glycoprotein Hormones

The glycoprotein hormones may have evolved from a single ancestral polypeptide . In the anterior pituitary, the thyrotrophs produce thyrotropin, and the gonadotrophs produce LH and FSH. Each glycoprotein hormone is composed of two dissimilar subunits (α and β) that are glycosylated and noncovalently bound. Synthesis of β-subunits is rate-limiting. Glycosylation takes place post-translationally on the endoplasmic reticulum membranes at about the time when disulfide bridges form in each subunit. “Mature” subunits then dimerize and are packaged in secretory granules. The α-subunits of all pituitary glycoprotein hormones are identical but show minor differences from the α-subunit of hCG. The β-subunits of all these hormones are different and confer hormonal specificity

Regulation of ACTH secretion in

humans. + =stimulation, - =inhibition

§ Development of the anterior pituitary

1. Several transcription factors determine the different cellular lineages
1. Corticotropes lineage
2. GH, PRL, and TSH lineage
3. Gonadotropes lineage
2. Disorders:
• Genetic absence of Pit-1 results in failure of the somatotropes, lactotropes, and thyrotropes to develop
• Absence of prop-1 results in deficiencies of these three hormones as well as deficiencies in gonadotropin production

​

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§ Regulation of anterior pituitary function

1. Primarily by the CNS– All pituitary hormones except PRL would decline in the absence of the hypothalamus
• Experiment--Pituitary gland is removed . . . and in vitro . . .
2. By hormones produced in peripheral target glands—
• Example– inhibin secreted from gonads
3. All anterior pituitary hormones secreted in a diurnal pattern.

§ Gonadotropin releasing hormone (GnRH)

1. A decapeptide
2. Is synthesized primarily in the arcuate nucleus in the hypothalamus and secondary in the preoptic area
• GnRH gene is also expressed in the placenta

​

• Function– GnRH regulates FSH and LH secretion
• How? Pulses of GnRH release determines the ratio of FSH and LH Secreted
• Secretions (Examples: Testosterone and inhibin) of the FSH/LH target organs regulate FSH/LH output

§ Dopamine and control of prolactin secretion

1. Dopamin (an amine) is a prolactin inhibitory factor which can inhibit PRL secretion
2. Dopamine is synthesized in tuberohypophyseal neurons
3. PRL releasing hormone’s existence is unclear

§ Secretion and actions of hypophysiotropic hormones

1. (ONE to ONE) In general, the hypophysiotropic hormones affect the secretion of one or another pituitary hormone specifically; not always this way
• Example: TRH increases PRL and TSH secretion; suckling at the breast increases both PRL and TSH secretion
2. Many factors impact neurons that secrete hypophysiotropic hormones– internal and external environment
3. (Action Mechanism on pituitary hormones)– all appear to act through G-protein

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Feedback control of anterior pituitary function

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§ Feedback regulation of anterior pituitary hormone secretion

1. Interplay of the following two:
1. Stimulatory effects of releasing hormones
2. Inhibitory effects of target gland hormone

​

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2-56

B

A

C

§ Posterior Pituitary Hormones

• OT (oxytocin– rapid birth; mainly from paraventricular nuclei) and ADH (vasopressin– contraction of blood pressure- to _______ blood pressure; mainly from supraoptic nuclei)
• These two are from a single ancestral gene; both are nonapeptides and differ by only two amino acids
• Neurophysins– cosecreted with AVP or oxytocin but no known hormonal actions.
• Fig. 2.9

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Hormone Actions: Posterior Lobe

• ADH (Antidiuretic Hormone; i.e. vasopressin)– through different G-proteins
• Reabsorption of water– through cAMP
• Vascular muscular contraction– through inositol tris-phosphate/diacylglycerol
• Oxytocin
• labor contractions, lactation (milk ejection)
• Through a single class of G-protein– through the inositol trisphosphate/diaclglycerol

2-58

59

60

VOCC= Vescular Smooth Muscle Cells

SOCE= Store operated Ca entry

TRP Genes = code for transient receptor potential (TRP) channels

ROCK= rho associated protein kinase

MLCP : myosin II DTNB light chain phosphatase .

MLCK= myosin light chain Kinase. �ERK=Extracellular Receptor Kinase

LTCC=L-type Ca channel

​

FIGURE 2.10

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2-62

Adrenal Glands

​

The outer part is called the adrenal cortex, which produces many different hormones called corticosteroids. This includes cortisol. These hormones regulate the salt and water balance in the body, prepare the body for stress, regulate metabolism, interact with the immune system, and induce sexual function.

​

The inner part, which is called the adrenal medulla, produces

catecholamines, such as epinephrine. Epinephrine also known as adrenaline, increase the blood pressure and heart rate during times of stress.

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Steroid Hormones Produced by Adrenal Cortex:

About 50 steroids have been isolated from the adrenal cortex. But out of them only 7 (seven) are important and known to possess physiologic activity. They are all

derived from cholesterol which can be synthesised from “active” acetate, and they contain the steroid nucleus, called “cyclo-pentano perhydro phenanthrene” nucleus.

Seven important hormones are:

• 11-dehydro corticosterone (DOC) (Earlier called as

compound A)

​

• Corticosterone (Compound B)

​

• Cortisone (Compound E)

​

• Cortisol (17-OH corticosterone, Compound F)

​

• Aldosterone (mineralo-corticoid)

​

• Androstenedione Two

​

• Dehydroepiandrosterone androgens

(DHE)

Cortisol is the major free-circulating adrenocortical hormone

(gluco-corticoid) in human plasma.

Hormones of adrenal cortex

​

Three general classes of steroid hormones based on predominant functions

​

Mineralocorticoids: 21 carbon containing steroids , synthesized by zona glomerulosa, regulate water and electrolyte balance. Aldosterone is the most prominent mineralocorticoid.

​

Glucocorticoids: Also 21 carbon steroids, produced mostly in zona fasciculata and affect glucose (hence the name), amino acid and fat metabolism. Cortisol (also known as hydrocortisone) is most important GC in humans.

​

Androgens: The zona reticularis and fasciculata produce significant amounts of androgen precursor DHEA (dehydroepiandrosterone) and androstenedione (both 19 carbon).

65

Synthesis of adrenocorticosteroids

All steroid hormones have in common the 17-carbon cyclopentao-perhydrophenanthrene nucleus. Additional carbons can be added at positions 10 and 13 or as a side chain attached to C17. STEROL

Synthesis of adrenocorticosteroids

Steroid hormones and their precursors and metabolites differ in

1. number and type of substituted groups,

2. number and location of double bonds,

3. stereochemical configuration.

3

17

18

19

18

21

Synthesis of adrenocorticosteroids

1. Uptake of cholesterol by the adrenal cortex is mediated by the LDL receptor. With long-term stimulation of the adrenal cortex by ACTH, the number of LDL receptors increases. Much of the cholesterol in the adrenal is esterified and stored in cytoplasmic lipid droplets.

Synthesis of adrenocorticosteroids

2. Upon stimulation of the adrenal by ACTH or cAMP, an esterase is activated, and the free cholesterol formed is transported into the mitochondria.

3. In the mitochondria, a cytochrome P450 side chain cleavage enzyme (P450SCC) converts cholesterol to pregnenolone.

Synthesis of adrenocorticosteroids

4. Pregnenolone may be converted by dehydrogenase/isomerase to progesterone or else by P450c17 (17-α-hydroxylase) to 17α-hydroxypregnenolone. Progesterone can also be converted to 17α-hydroxyprogesterone by P450c17.

Synthesis of adrenocorticosteroids

17-α-hydroxylase

17-α-hydroxylase

dehydrogenase/isomerase

5. After the synthesis of progesterone and 17-hydroxyprogesterone, P450c21(21-hydroxylase) can hydroxylate these steroids at the 21 position, resulting in 11-deoxycorticosterone and 11-deoxycortisol, respectively.

Synthesis of adrenocorticosteroids

21-hydroxylase

21-hydroxylase

6. The final step in the synthesis of adrenal mineralocorticoids and glucocorticoids is mediated by P450c11 (11-β-hydroxylase), which also mediates the final steps in the synthesis of aldosterone from deoxycorticosterone.

11-β-hydroxylase

11-β-hydroxylase

11

7. P450c17 has two activities, that of a 17α-hydroxylase and that of a C-17,20 lyase capable of breaking up the C-17,20 carbon bond of 17α-hydroxypregnenolone or 17α-hydroxyprogesterone, yielding dehydroepiandrosterone (DHEA) or androstenedione, respectively.

Synthesis of adrenocorticosteroids

Synthesis of adrenocorticosteroids

8. 17-hydroxysteroid dehydrogenase converts androstenedione to testosterone. P450 aromitase mediates the aromatisation of androgens to estrogens in the gonads. In peripheral target tissues, testosterone can further be converted to 5α-dihydrotestosterone by 5α-reductase.

Biosynthesis

Of human steroid Hormones

Synthesis of Adrenocortical Hormones

Storage and secretion

• Little (if any) storage of steroid hormones , directly go into circulation as and when they are produced
• Cortisol release follows the diurnal rhythm of ACTH release. Highest levels in the morning shortly after awakening and lowest in the evening and early morning.

Plasma Transport

• Cortisol circulates in plasma bound to proteins or as free.
• Transcortin or corticosteroid binding globulin (CBG) binds cortisol.
• Most of the steroid hormones bind to CBG.
• Cortisol binds CBG and has a half life of 1.5 - 2 hrs. 8-10% Cortisol is free.
• Progesterone and deoxycorticosterone also bind CBG strongly.
• Corticosterone binds CBG with less affinity.
• Aldosterone does not have a specific protein but binds weekly with albumin

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Degradation and Excretion

• Glucocorticoids: Cortisol, Cortisone and 11-deoxycortosol are reduced by NADPH dependant enzymes and conjugated with either glucoronate or sulfate which render them water soluble. About 70% of the conjugated steroids are excreted in the urine , 20% in feces and rest exit through the skin.

​

• Mineralocorticoids: Aldosterone is very rapidly cleared from the plasma by liver because it lacks a specific protein carrier. It is converted to tetrahydroaldosterone 3-glucoronide which is excreted in urine.
• Androgens: are excreted as 17-keto compounds including DHEA (sulfate) as well as androstenedione and its metabolites. Small amounts of testosterone secreted by adrenals are also converted to 17-keto compounds like androsterone and etiocholanolone which are excreted in urine.

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Metabolic functions of adrenal corticosteroids

Glucocorticoid hormones: the most important are Cortisol, cortisone and Corticosterone

​

• Effects on Carbohydrate metabolism:
• ↑es Gluconeogenesis and glucose output
• ↑es amino acid utilization
• ↑es glycogenolysis
• ↓es glucose uptake by tissues other than liver

​

• Effects on Lipid metabolism:
• ↑es lipolysis
• ↑es circulating free fatty acids (FFA)
• ↓ es utilization of FFA for TG synthesis.

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Metabolic functions of adrenocorticosteroids

• Effects on Protein metabolism:
• ↑es degradation of proteins in extra hepatic tissues
• ↑es protein synthesis in liver

​

• Effects on Nucleic acid metabolism:
• promotes transcription of specific genes in liver.

​

• Effects on water and electrolyte metabolism:
• Mediated through ADH ,Deficiency causes ↑ ADH which decreases glomerular filtration and leads to water retention.

​

• Other biochemical functions:
• Suppress immune response in high doses (esp. cortisol)
• Modulate response of catecholamines
• Increase the production of gastric HCl and pepsinogen
• Inhibit the bone formation- increases the risk of osteoporosis.

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Biochemical actions of adrenocorticosteroids

A. Mineralocorticoids: aldosterone

It promotes Na⁺ reabsorption at the distal convoluted tubules of kidney. Na⁺ retention is accompanied by corresponding excretion of K⁺,H⁺ and NH₄⁺ ions.

Biochemical actions of adrenocorticosteroids

B. Glucocorticoids: Cortisol

Biochemical actions of adrenocorticosteroids

1. Effects on glucose metabolism: They promote gluconeogenesis.

They work in tandem with insulin from the pancreas to maintain blood glucose levels in the proper balance.

2. Effects on lipid metabolism: They increase lipolysis in adipose tissue and reduce synthesis of TAG.

3. Effects on protein and nucleic acid metabolism: They promote transcription and protein synthesis in liver. They also cause catabolic effects in extrahepatic tissues results in enhanced degradation of protein.

B. Glucocorticoids: Cortisol

4. Effects on water and electrolyte metabolism: Deficiency of them cause increased production of ADH which can decrease glomerular filtration rate causing water retention in the body.

5. Effects on immune system: Cortisol suppress the immune response directly and indirectly by affecting most cells that participate in immune reactions and inflammatory reactions. It is powerful anti-inflammatory even when secreted at normal levels. It also reduces the rate at which lymphocytes multiply and accelerates their programmed cell death to further protect the body from this overreaction. This is one of the reasons why strong corticosteroids (prednisone, prednisolone, etc.) are used with all diseases involving inflammatory processes, including auto-immune diseases.

6. Effects on cardiovascular system: Cortisol could control the contraction of the walls of the mid-sized arteries in increasing blood pressure, but this hypertensive effect is moderated by calcium and magnesium. It also directly affects the heart by regulating sodium and potassium in the heart cells and increasing the strength of contraction of the heart muscle.

7. Effects on central nervous system: The changes of behavior, mood, excitability and even the electrical activity of neurons in the brain frequently occur in cases of excess and deficient cortisol levels. Many signs and symptoms of adrenal fatigue involve moodiness, decreased tolerance, decreased clarity of thought and decreased memory. These occur because the brain is affected by both too little and too much cortisol.

• There are four major categories of stress:

1. Physical stress: such as overwork, lack of sleep, athletic overtraining. 2.Chemical stress: environmental pollutants, allergies to foods, diets high in refined carbohydrates, endocrine gland imbalances.

3. Thermal stress: over-heating or over-chilling of the body

4. Emotional and mental stress

Stress

• Adrenal glands are the anti-stress glands of the body.

Stress: During stress cortisol must simultaneously provide more blood glucose, mobilize fats and proteins for a back-up supply of glucose, modify immune reactions, heartbeat, blood pressure, brain alertness and nervous system responsiveness. If cortisol level cannot rise in response to these needs, maintaining your body under stress is nearly impossible.

Hypothalamopituitary adrenal (HPA) axis

Fasting

People have considerable difficulty when on a prolonged fasting. They will always rationalize the problems encountered on a fasting as being due to the body detoxifying.

During a fasting, the body will call on the adrenals to produce glucocorticoids to maintain blood glucose level which is adequate for normal level of activity. The glucocorticoids can elevate blood glucose by breaking down protein into carbohydrates through the process of gluconeogenesis.

Regulation of glucocorticoids

The Secretion of glucocorticoids from the adrenal cortex is regulated by negative feedback involving the CRH secretion by the hypothalamus. CRH then acts on the anterior pituitary to stimulate ACTH secretion, which then stimulates the adrenal cortex into cortisol secretion. About 70% of blood cortisol is bound to a carrier protein called corticosteroid-binding globulin. Another 15% is bound to albumin, the remaining 15% exists free in solution.

The HPA axis or HPA system, a negative feedback system, is one of the most important elements of homeostasis, the process that maintains a steady internal biochemical and physiological balance in your body. The HPA Axis adjusts cortisol level according to the needs of the body, under normal and stressed conditions, via ACTH. ACTH is secreted from the pituitary gland in response to orders form the hypothalamus and travels in the bloodstream to the adrenal cortex.

• The Hypothalamus/Pituitary/Adrenal (HPA) Axis

Primary Addison Disease= Damaged Adernal Gland

Secondary Addison Disease= Deficiency in ACTH

People who suffer from adrenal fatigue almost always have some form of irregular blood sugar pattern, of which hypoglycemia is the most common.

When your adrenals are fatigued, their cortisol output is diminished and you have lower levels of circulating blood cortisol, your liver has a more difficult time converting glycogen into glucose.

Addison's Disease: Primary Chronic Adrenocortical Insufficiency

Cushing's syndrome (hyperadrenocorticism or hypercorticism) is a endocrine disorder caused by high levels of cortisol (hypercortisolism) in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or ACTH.

CAH (congenital adrenal hyperplasia): For P450c21 is deficiency, cortisol synthesis decreases, leading to overproduction of ACTH. When this occurs adrenal steroid synthesis is stimulated and 17-hydroxyprogesterone is converted to androstenedione and further to testosterone, leading to severe virilization of the female fetus. This disorder is known as CAH which disrupts the synthesis of all adrenal and gonadal steroids. Affected genetic males are born with normal female external genitalia.

Some autosomal recessive mutations in biosynthetic enzymes responsible for converting cholesterol to androgens generally lead to partial male-to-female sex reversal.

Effect of cortisol during stress

Effect of cortisol after 2 - 4 hours

​

1. inhibits glucose uptake by many cells
2. stimulates gluconeogenesis
3. stimulates protein catabolism
4. vascular effect – sensibilization of vessels to the effect of noradrenaline - vasoconstriction

5) Effect on memory – ACTH facilitates learning and memory in experimental animals – helps to cope with the stress

…however, long-lasting stress impairs learning

cortisol damages neurons in hippocampus

Hormones of adrenal medulla

Norepinephrine (noradrenaline) 20% 1.2 - 3.4 nmol/l

• 5 - 6 fold increase exerts biological action

​

Epinephrine (adrenaline) 80% 0.1 - 0.8 nmol/l

• 2 fold increase can elicit physiological response

Effect of catecholamines during stress

Alarm reaction - immediate

1) increased hepatic and muscle glycogenolysis

2) increased breakdown of adipose tissue - lipolysis

3) blockade of insulin

4) increased cardiac output (increased contractility, heart rate)

5) shunting blood from visceral to skeletal muscles by means of vasoconstriction in visceral and vasodilatation in skeletal

6) increased ventilation

7) decreased fatigue of skeletal muscle

8) Increased coagulability of blood

The Adrenal Medulla

The functional unit of the adrenal medulla is the chromaffin cell, which functions as a neuroendocrine cell. In response to stimulation, chromaffin cells secrete the hormones epinephrine (adrenaline) and norepinephrine (noradrenalin) directly into the blood.

The medulla is involved in extreme stress and, within this context, epinephrine and norepinephrine both work with cortisol from the adrenal cortex. Epinephrine and norepinephrine are important mainly in crisis situations.

​

Physiological actions of the catecholamines

​

•Diverse.

•Norepinephrine functions primarily as a neurotransmitter.

•Both norepinephrine and epinephrine influence the vascular system, whereas epinephrine affects metabolic processes such as carbohydrate metabolism.

•The biological actions of the catecholamines are initiated through their interaction with two different types of specific cell membrane receptors, the alpha-adrenergic and beta-adrenergic receptors.

•These receptors have different affinities for norepinephrine and epinephrine and cause opposing physiological effects.

•Norepinephrine primarily interacts with alpha-adrenergic receptors, whereas epinephrine interacts with both alpha-and beta-receptors.

​

Effect of catecholamineson different receptors

​

•Stimulation of alpha-adrenergic receptors results in:

–vasoconstriction,

–decrease in insulin secretion,

–sweating,

–piloerection(hair standing on end),

–and stimulation of glycogenolysis in the liver and skeletal muscle leading to an increase in blood glucose concentration.

•Stimulation of beta-receptors leads to:

–vasodilatation;

–stimulation of insulin release;

–increased cardiac contraction rate;

–relaxation of smooth muscle in the intestinal tract;

–bronchodilatation by relaxation of smooth muscles in bronchi;

–stimulation of renin release, which enhances sodium resorption from the kidney;

–and enhanced lipolysis.

​

Factors Regulating release

​

•The synthesis of epinephrine and norepinephrine is regulated by the intracellular concentrations of these hormones by negative-feedback inhibition, as stated previously.

•The catecholamines are released from the adrenal medulla in response to hypotension, hypoxia, expsoure to cold, muscular exertion, pain, and emotional disturbances.

​

Storage and secretion

​

-Norepinephine and epinephrine are stored in electron-dense granules, which also contain ATP and several neuropeptides.

-Secretion of these hormones is stimulated by:

-acetylcholine release from preganglionic sympathetic fibres innervating the medulla.

-Many types of "stresses" stimulate such secretion, including exercise, hypoglycaemia and trauma.

-Following secretion into blood, the catecholamines bind loosely to and are carried in the circulation by albumin and perhaps other serum proteins.

Source of circulating catecholamines

​

Circulating catecholamines, epinephrine and norepinephrine, originate from two sources.

​

•Epinephrine is released by the adrenal medulla upon activation of preganglionic sympathetic nerves innervating this tissue.

–This activation occurs during times of stress (e.g., exercise, heart failure, hemorrhage, emotional stress or excitement, pain).

•Norepinephrine is also released by the adrenal medulla (about 20% of its total catecholamine release is norepinephrine). The primary source of circulating norepinephrine is spillover from sympathetic nerves innervating blood vessels.

–Normally, most of the norepinephrine released by sympathetic nerves is taken back up by the nerves (some is also taken up by extra-neuronal tissues) where it is metabolized.

–A small amount of norepinephrine, however, diffuses into the blood and circulates throughout the body.

–At times of high sympathetic nerve activation, the amount of norepinephrine entering the blood increases dramatically.

​

Adrenergic Receptors and Mechanism of Action

​

•The physiologic effects of epinephrine and norepinephrine are initiated by their binding to adrenergic receptors on the surface of target cells. These receptors are prototypical examples of seven-pass transmembrane proteins that are coupled to G proteins, which stimulate or inhibit intracellular signalling pathways.

•Complex physiologic responses result from adrenal medullary stimulation because there are multiple receptor types, which are differentially expressed in different tissues and cells. The alpha and beta-adrenergic receptors and their subtypes were originally defined by differential binding of various agonists and antagnonists and, more recently, by analysis of molecular clones.

​

Circulating epinephrine causes:

​

•Increased heart rate and inotropy(ß1-adrenoceptor mediated)

•Vasoconstrictionin most systemic arteries and veins (postjunction α 1 and α 2 adrenoceptors)

•Vasodilation in muscle and liver vasculatures at low concentrations (b2-adrenoceptor); vasoconstriction at high concentrations (a1-adrenoceptor mediated)

•The overall cardiovascular response to low-to-moderate circulating concentrations of epinephrine results in increased cardiac outputand a redistribution of the cardiac output to muscular and hepatic circulations with only a small change in mean arterial pressure.

•Although cardiac output is increased, arterial pressure does not change much because the systemic vascular resistance falls due to b2-adrenoceptor activation.

•At high plasma concentrations, epinephrine increases arterial pressure because of binding to a-adrenoceptorson blood vessels, which offsets the b2-adrenoceptor mediated vasodilation

Effect of cortisol during stress

Effect of cortisol after 2 - 4 hours

​

1. inhibits glucose uptake by many cells
2. stimulates gluconeogenesis
3. stimulates protein catabolism
4. vascular effect – sensibilization of vessels to the effect of noradrenaline - vasoconstriction

5) Effect on memory – ACTH facilitates learning and memory in experimental animals – helps to cope with the stress

…however, long-lasting stress impairs learning

cortisol damages neurons in hippocampus

Catecholamines Biosynthesis

1. Tyrosine is precursor for the synthesis of catecholamines.

2. The catecholamine are produced in response to fight, fright and flight (3F). These include emergencies like shock, cold, fatigue, emotional condition like anger.

​

Site of synthesis of catecholamines

​

•Adrenal medulla: the main secretory products are epinephrine and norepinephrine.

•Neurons of the sympathetic and central nervous systems (CNS):

•and in scattered groups of chromaffin cells found in other regions of the abdomen and neck.

–Norepinephrine is the principal product synthesized in the CNS,

–and epinephrine is the principal catecholamine produced by the adrenal glands.

In humans, catecholamines are derived from the amino acid L-phenylalanine.�L-Phenylalanine is converted into L-tyrosine by an aromatic amino acid hydroxylase (AAAH) enzyme (phenylalanine 4-shydroxylase), with molecular oxygen (O₂) and tetrahydrobiopterin as cofactors. L-Tyrosine is converted into L-DOPA by another AAAH enzyme (tyrosine 3-hydroxylase) with tetrahydrobiopterin, O₂, and ferrous iron (Fe²⁺) as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC), with pyridoxal phosphate as the cofactor. Dopamine itself is also used as precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine. Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase (DBH), with O₂ and L-ascorbic acid as cofactors. Norepinephrine is converted into epinephrine by the phenylethanolamine N-methyltransferase (PNMT) with S-adenosyl-L-methionine as the cofactor.

Biochemical function of catecholamine

1. Effect on carbohydrate metabolism: Both of them can increase glycogenolysis and gluconeogenesis and decrease glycogenesis.

①Catecholamine promote the release of glucose from liver and decrease its utilization by muscle; ②Epinepherine inhibits insulin secretion but promote glucagon secretion.

2. Effect on lipid metabolism: Both of them enhance the breakdown of TAG in adipose tissue. This cause increase in the free fatty acid in the circulation which are effectively utilized by the heart and muscle as fuel source.

3. Effect on physiological function: Cateccholamines increase cardiac output, blood pressure and oxygen consumption. They cause smooth muscle relaxation in bronchi, GIT and blood vessels supplying skeletal muscle.

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Metabolism of Catchecolamines

Most of the NE released by sympathetic nerves

•(a) is removed by neuronal uptake

•(b) and a much smaller amount is removed by extraneuronal uptake

•(c) so that only a small portion escapes to enter the bloodstream

•(d). Most of the NE recaptured by sympathetic nerves is sequestered into storage vesicles by the vesicular monoamine oxidase(MAO) transporter

•(e) and a smaller proportion is metabolized intraneuronally to 3,4-dihydroxyphenylglycol (DHPG).

•However, considerably more of the NE that is sequestered into storage vesicles or metabolized intraneuronally to DHPG is derived from transmitter leaking from storage vesicles (e) than from reuptake (b).

•Very little circulating DHPG is derived from metabolism of circulating NE, whereas a significant proportion of the small amounts of circulating free Normetanephrine (NMN) is formed from circulating NE.

•MHPG is mainly derived from O-methylation of DHPG before and after its entry into the bloodstream. Vanillylmandelic acid (VMA) is mainly derived from metabolism of MHPG and DHPG in the liver. COMT, Catechol-O-methyltransferase

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Vanillylmandelicacid (VMA),

​

•Vanillylmandelic acid (VMA), the major end-product of norepinephrine and epinephrine metabolism, is produced almost exclusively from the removal and metabolism by the liver of catecholamines and their metabolites that circulate in the bloodstream.

•VMA is a relatively insensitive marker for pheochromocytoma compared with the precursors norepinephrine, epinephrine, normetanephrine and metanephrine

phaeochromocytoma (PCC) or pheochromocytoma:

a neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells), or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually adrenaline (epinephrine) if in the adrenal gland and not extra-adrenal, and noradrenaline (norepinephrine).

17% of adrenal cases are bilateral (suggesting hereditary disease)

18.4% in children (also suggesting hereditary disease)

5% are extra-adrenal (located in any orthosympathetic tissue): of these 9% are in the abdomen and 1% are located elsewhere. Some extra-adrenal phaeochromocytomas are probably actually paragangliomas, but the distinction is only possible after surgical resection.

11.1% malignant, but this rises to 30% for extra-adrenal cases

26% are hereditary

3% recur after being resected

14% of affected individuals do not have arterial hypertension

1. Within the sympathetic nerve chain along the spinal cord (orange spots)

2. Overlying the distal aorta (the main artery from the heart) (green spots)

3. Within the ureter (collecting system from the kidney (yellow spot)

4. Within the urinary bladder (blue spot)

5. Remember, 90% are in the adrenal glands (red spots on the kidneys)

Here's a look at the extra-adrenal sites of pheochromocytomas

124

Primary Enzyme Activities of Steroid Hormone Biosynthesis

��

The conversion of pregnenolone to testosterone requires the action of five

enzyme activities contained in three proteins:

(1) 3β-hydroxysteroid dehydrogenase (3β-HSD) and ∆5,4-isomerase;

(2) 17α-hydroxylase and C17-20 Lyase and

(3) 17β-hydroxysteroid dehydrogenase (17β-OHSD).

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The ∆5 route appears to be most used in human testes.

​

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Regulation:

• The production of androgens is under the control of LH and FSH.
• Regulated by negative feedback mechanism
• The rate limiting step is the delivery of cholesterol to IMM by StAR.

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Steroidogenic acute regulatory protein (StAR)

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�Testosterone is metabolized by two pathways. �

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• First pathway involves oxidation at the 17 position, occurs in many tissues, including liver and produces 17-ketosteroids that are generally inactive or less active than the parent compound.
• Second pathway (Dihydrotestosterone Is Formed From Testosterone in Peripheral tissues) occurs primarily in target tissues involves reduction of the A ring double bond and the 3 Ketosterone, a reaction catalyzed by the NADPH-dependent 5 α reductase
• Some estradiol is formed from the peripheral aromatization of testosterone.

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• 5 mg of testosterone is produced daily by testes. Approximately 400 µg of DHT is produced daily

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126

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Transport of androgens:

In the plasma testosterone and DHT bind to two proteins-

1. Sex hormone binding globulin ( SHBG) binds 97 to 99% and

2. Testosterone-estrogen binding globulin( TEBG).

A small fraction is in free form.

Both these proteins are synthesized in liver.

The plasma testosterone level in normal men is about 0.7 µg/dl while in women it is < 0.1 µg/dl.

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Mode of action:

Group I hormone

Both testosterone and dihydrotestosterone bind to a single class of receptors on the target tissues. The affinity of DHT for the receptor is much higher compared to testosterone.

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Receptor sites for androgens are found in muscle, brain, and other target tissues.

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127

Physiological and biochemical functions of androgen:

The androgens influence

1. Growth, development and maintenance of male reproductive organs.

2. Sexual differentiation and secondary sexual characteristics.

3. Spermatogenesis.

4. Male pattern of aggressive behavior.

5. pubertal transformation:

• Enlargement of testes, penis and scrotum
• Pubic and axillary hair
• Bone growth
• Red cell mass increase
• Skeletal muscle mass increase
• Larynx enlarges - deepening of the voice
• Increase in sebaceous glands - often cause of acne
• Development of Beard

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128

Biochemical functions:

Protein retention ( Anabolic action)

Effect on protein metabolism:

Androgens promote

• RNA synthesis( transcription)
• Protein synthesis( translation).
• Rapid growth of musculo-skeletal system associated with puberty.

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Effect on carbohydrate and fat metabolism-

• Glycolysis,
• Production of D-fructose from D-glucose by seminal vesicles.
• fatty acid synthesis and
• citric acid cycle.

Effects on mineral metabolism-

Androgens promote

• Mineral deposition and bone growth
• Kidney reabsorption of Na+, Cl- and water.

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129

METABOLIC ROLE: Both testosterone and dihydrotestosterone are protein anabolic and growth promoting hormone.

1. Protein Metabolism Dominant general metabolic effect is stimulation of protein anabolism. This is reflected in: • A decrease in urinary N2 (urea) ↓ without an increase in blood NPN. Decrease in hepatic arginine synthetase activity ↓, the enzyme that catalyses conversion of citrulline to arginine.

• Creatine metabolism: Creatine is virtually absent from the urine of normal men, increases after castration. This increase is abolished by administration of testosterone, owing to increased storage of creatine in the muscles.

• There is increase in body weight, due chiefly to an increase in skeletal muscle. The associated increase in O2 consumption by muscle tissue is due to increased activity of NADH cytochrome- C reductase.

2. Protein Synthesis: Androgens promote protein synthesis in male accessory glands. It causes increased RNA and RNA polymerase in the nucleus, and increased amino acyl transferase at the ribosomal level. Androgens also act at the mitochondrial level to increase the respiratory rate, the number of mitochondria and the synthesis of mitochondrial membrane.

3. Carbohydrate Metabolism: Androgens increase the fructose production ↑ by seminal vesicles and utilisation of this sugar by the seminal plasma by enhancing the activity of both aldose reductase as well as ketoreductase.

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4. Skeletal Growth: In the growing organism, a growth spurt is induced with increase in bone matrix and skeletal length. Androgens stimulate the growth of bones before the closure of epiphyseal cartilage.

Mineralisation of added skeletal tissue is accompanied

by decreased excretion of Ca and PO4, i.e. a more +ve

balance in respect of these.

5. Renotropic Action: Androgens cause a rather selective increase in size and weight of the kidneys (“renotropic” action). This is accompanied by a decrease in renal alkaline phosphatase activity and by increase in activity of D-amino acid oxidase, arginase and acid phosphatase in the kidney. The relation of these phenomena to metabolic activity of testosterone is not

clear.

6. Mineral Metabolism: The decreased excretion of urinary N2 (chiefly urea) that follows administration of androgens is accompanied by a lower urine volume and diminished excretion of Na, Cl, K, SO4 and PO4, with no increase in their concentration in blood plasma. The tissue retention of K, SO4, PO4 is probably

related to the increased storage of proteins. The retention of Na, Cl and water are due to increased tubular reabsorption.

7. Citrate Excretion: Androgen reduces (and oestrogen increases) the excretion of citrates in the urine. This is due to increased reabsorption of citrate by renaltubular epithelium.

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Abnormalities associated with male sex hormones:

Hypogonadisn is a disorder characterized by a defect in testosterone synthesis. It may be of two types.

1. Primary hypogonadism is caused by a failure of testes to produce testosterone.

2. Secondary hypogonadism is due to an impairment in the release of gonadotropins.

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Transport of Sex Hormones in the Bloodstream

Testosterone & estradiol bind to sex hormone binding globulin (SHBG).

Progesterone binds to transcortin.

Affinity of SHBG for testosterone is higher than for estradiol.

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• Before puberty - the level of SHBG is about the same in males and females .
• At the puberty - there is a small decrease in the level of circulating SHBG in females and larger decrease in males, insuring relatively greater amount of the unbound, biologically active sex hormones.

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• In adults, males have half of the amount of SHBG than females.

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• Testosterone lowers SHBG levels in blood, whereas estradiol raises SHBG levels.

Mechanism of Steroid Hormone Action

• Steroid hormones are soluble in the plasma membrane and readily enter the cytosol.

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• Steroids bind to intracellular receptor either in the cytosol or in the nucleus.

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• The hormone-receptor complex acts as a transcription factor which turns on / turns off the genes.

Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations

Mechanism of Steroid Hormone Action

• Messenger RNA is transcribed, leaves the nucleus, and is translated into a specific protein by ribosome.

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• The specific proteins then carry out function in the target cell.

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• Because steroid hormones initiate protein synthesis their effects are produced more slowly, but are more long-lasting than those produced by other hormones.

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Intracellular receptors

Model of typical steroid hormone receptor

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1. Variable domain – interacts with other transcription factors
2. DNA-binding domain – „zinc finger“
3. Domain for dimerization – a site of dimerization of two receptor-hormone complexes
4. Hormone- binding domain

„zinc finger structure“

FEMALE SEX HORMONES

Two main types of female hormones are secreted by the

ovary:

1. The follicular or estrogenic hormones: Produced by cells of developing Graffian follicles; and

2. The progestational hormone: Derived from the corpus luteum that is formed in the ovary from the ruptured follicles.

ESTROGENS

Estrogens are hormones capable of producing certain biological effects, the most characteristic of which are the changes which occur in mammals of estrus. They include:

• Growth of female genital organs,

• The appearance of female secondary sex characteristics

• Growth of the mammary duct system and numerous other phenomena which vary somewhat in different species.

The naturally occurring estrogens in humans are:

• β-Estradiol • Estrone and • Estriol

The principal estrogenic hormone in circulation and the most active form of the estrogen is β-estradiol, which is in metabolic equilibrium with estrone. Estriol is the principal estrogen found in the urine of pregnant women and in the placenta.

Essential Features:

• Aromatic character of ring A (three double bonds)

• Absence of –CH3 group at C10

• OH GR at C3 possesses the properties of a phenolic–OH group (weakly acid). All naturally occurring estrogens are C18 steroids.

• Estriol is produced from estrone by hydroxylation of estrone at C16 and reduction of the ketone group at C17. It is the principal metabolite found in urine.

• Estrone is the hormone produced in the follicles but released into the blood as β-estradiol. In the liver, it is converted to estriol. β-estradiol and estrone are interconvertible.

• Potency: β-Estradiol is 10 times more potent than estrone and 300 times more potent than estriol.

• Site of Formation

In the ovary estrogens are produced by the maturing Graffian follicles, both thecal cells and granulosa cells are involved, and also in Corpus luteum. All the three pituitary gonadotropins—FSH, LH and LTH are involved in stimulation of estrogen secretion.

Estrogens are also formed in the adrenal cortex, placenta and testes in small amounts.

BIOSYNTHESIS

Androgenic steroids—testosterone and androstenedione— are precursors for the synthesis of estrogens in testes, ovaries, adrenal cortex and placenta. Transformation of the natural C19 steroids, e.g. testosterone and androstenedione to β-estradiol and estrone involves:

• Removal of the angular –CH3 group at C10, and

• Aromatisation of ring A.

The above is achieved by:

• Enzymes: Aromatase, hydroxylases (mono-oxygenases)

and dehydrogenases.

• Hydroxylase: Requires mol O2 and NADPH.

Biosynthesis Steps

• Cholesterol is converted to pregnenolone and progesterone by the ovarian steroidogenic cells similar to pathway operating in adrenal cortex. Luteal cells also provide certain amount of progesterone.

• Theca interna cells of graafian follicles converts both pregnenolone and progesterone to testosterone andandrostenedione, which are the precursors.

• In granulosa cells of the follicle → testosterone is converted to β-estradiol, catalysed by a microsomal enzyme aromatase, which brings about aromatisation of ring A. The enzyme contains a mono-oxygenase as a component, it contains Cyt. P450 and requires molecular O2 and NADPH. It brings about three successive hydroxylations of testosterone and the final hydroxylated product loses C18 nonenzymatically and converted to β-estradiol.

• Androstenedione can be converted to estrone by the

enzyme aromatase, with molecular O2 and NADPH.

• β-Estradiol and estrone are interconvertible by the

enzyme β-estradiol dehydrogenase.

• Estrone is converted to 16-α-OH-estrone by the enzyme 16-α-hydroxylase, also a mono-oxygenase which has Cyt. P450 and requires molecular O2. Subsequently 16-α-OH-estrone is reduced to form estriol by the enzyme reductase.

Note

• β-Estradiol and estrone can be produced in extraovarian tissues, viz. liver, muscles, adipose tissue, etc. from DHEA, androstenedione and testosterone.

• β-Estradiol and estrone are interconvertible in extraovarian tissues like liver and placenta, catalysed by the specific enzyme 17-β-estradiol dehydrogenase.

Mechanism of Action (Similar to Androgens): After entering the target cells, it binds to a specific ‘receptor’ present in cytosol, “receptor-steroid complex” then binds to hormone-responsive element (HRE) associated with

specific nuclear genes, which translates for synthesis of specific proteins and enzymes (Refer to mechanism of action of glucocorticoids).

METABOLIC ROLE

I. After Administration of Estrogens: The following biochemical changes are observed to occur:

• Proliferation of vaginal epithelium and endometrium, an increase in glycogen ↑ in the cells, and increase in alkaline phosphatase activity ↑ in endometrium. Glycogen also increases in vaginal epithelial cells.

• Rate of glycolysis increases with accumulation of lactic acid (LA). The vaginal glycogen is probably the source of LA, which by increasing the acidity of the vaginal secretion (pH 4.0 to 5.0), favours a homogeneous flora of acid bacteria.

• Acceleration of incorporation of amino acids into proteins of uterus, increased protein synthesis ↑, which is preceded by an increase in RNA polymerase activity and RNA synthesis.

Metabolism Effects

• Favours retention and elevation of Ca and P and skeletal deposition of Ca producing hypercalcaemia and hyperphosphataemia and calcification and ossification of bones.

• Estrogens also stimulate the closure of bone epiphyses.

• β-Estradiol prevents osteoporosis, which is frequently seen in menopausal women, when estrogens decrease. Menopausal women are liable to get fractures due to weakness of bones from osteoporosis.

• An increase in O2 - consumption in endometrium, placenta, mammary gland and adenohypophysis, owing to a specific effect on estradiol-sensitive

Isocitrate dehydrogenase enzyme (ICD).

• Estrogens also produce an effect on mineral metabolism. β-Estradiol particularly causes a slight retention of Na, Cl and water.

• In certain mammalian species, estrogens may exert a ‘lipotropic effect’, i.e tendency to prevent accumulation of fats in the liver.

• Estrogens also have a cholesterol lowering effect ↓ and reduces plasma cholesterol level and a fall in the level of β-lipoproteins ↓ (LDL).

BIOMEDICAL IMPORTANCE

The estrogen dependent transhydrogenase which catalyses the transfer of H+ from NADPH to NAD+ may bring about an increased rate of biologically useful energy in two ways:

• Considering that concentration of NADP+ in the cells is ordinarily very low, increased oxidation of NADPH would maintain availability of NADP+ for the activity of those dehydrogenases which require the oxidised form of this cofactor.

• Because direct oxidation of NAPD yields no high energy PO4, a method of deriving high energy PO4 would be made available by transfer of H+ to NAD+, thus forming NADH which can be oxidised in electron transport chain.

CLINICAL ASPECT

Young women are protected against myocardial infarction whereas women in menopause, with decline in estrogenic activity are more susceptible to myocardial infarction.

Estrogenic activity in pre-menopause is associated with increased HDL.

II. Transhydrogenation Reaction

Estrogens may also act as cofactor in transhydrogenation reaction in which H+ ions and electrons are transferred from reduced NADP+ to NAD+.

PROGESTATIONAL HORMONES: (LUTEAL HORMONES)

PROGESTERONE

• Progesterone is the hormone of the corpus luteum, the structure which develops in the ovary from the ruptured graafian follicle. It is also formed by the placenta, which secretes progesterone, during the later part of pregnancy. It is also formed in the adrenal cortex, as a precursor of both C19 and C21 corticosteroids. It is also formed in the testes.

Chemistry: Progesterone may be regarded as a derivative

of “pregnane” and is designated chemically as “4- pregnane-3, 20-dione”. It is a C21 steroid and has a– CH3 group at C10 and C13.

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Biosynthesis: Progesterone has a role as an intermediate

in the biogenesis of adrenocortical hormones and of androgens. Indirectly via androstenedione and testosterone, it also serves as precursors for estrogens also. Progesterone is formed from acetate via cholesterol, ‘Pregnenolone’ is the immediate precursor.

Mechanism of action: It is similar to estrogen.

METABOLIC ROLE

In the humans, progesterone produces characteristic changes (progestational) in the estrogen primed endometrium.It appears after ovulation and causes:

• Extensive development of the endometrium preparing the uterus for the embedding of the embryo and for its nutrition.

• It causes an increase in glycogen ↑, mucin ↑ and fat ↑ in the lining epithelial cells. Alkaline phosphatase ↓ decreases in activity.

• It also suppresses estrus, ovulation and production of pituitary luteinizing hormone (LH). During menstrual cycle modifies the action of estrogen on the vaginal epithelium, causing desquamation and basophilia of the superficial

layer of cells and leucocytic infiltration.

• Hormone also stimulates the mammary glands. In conjunction with estrogen, progesterone causes development of the alveolar system of the breasts and sensitizes them for the action of lactogenic hormone.

• Progesterone is responsible for the rise in basal temperature ↑, which occurs during the corpus luteum phase of the normal menstrual cycle. This is due to increase in basal metabolic rate (BMR ↑ ).

• In large doses, progesterone exerts androgenic effects, perhaps by conversion to androgenic metabolites.

• The hormonal effects on electrolyte and water metabolism vary in different species. In dogs and rodents, it appears to favour retention of Na, Cl and water. In humans, there is evidence that it exerts an opposite effect.

RELAXIN

Relaxin is a hormone concerned with the relaxation of pelvic tissues and cavity operating in conjunction with other factors. Relaxin is produced, during pregnancy, in tissues of the reproductive system, e.g. principally by corpus luteum and also by placenta. Its production is stimulated by progesterone, pregnenolone and related adrenocortical steroids, e.g. deoxy corticosterone.

Chemistry: Porcine relaxin is made up of two peptide chains, consisting of 22 and 26 amino acid residues. It has two S–S bonds linking its two chains and one intra-chain S–S bond in the A-chain. Approximate mol. wt. = 9000. It is inactivated by proteolytic enzymes or by reagents which breaks the S–S bond (reduction) to form –SH groups.

METABOLIC ROLE

The specific effect of relaxin consists of:

• Increased vascularity of the connective tissue of the symphysis.

• Followed by imbibitions of water, dissolution and splitting of collagen fibres, and disorganization of the fibrous structures. There is depolymerization of MPS of ground substance.

• The above makes separation of the symphysis pubis and, a dilatation and softening of uterine cervix, facilitating child birth.

PLACENTAL HORMONES

Pregnancy activates the placental hormones. The implanted blastocyst forms the trophoblast which is subsequently organised into the placenta. The placenta provides the nutritional connection between the embryo and the maternal circulation.

Human placenta produces and secretes:

(a) Peptide hormones Mainly two:

1. Human chorionic gonadotropin hormone (hCG) and

2. Chorionic somatomammotropin (CS) or placental lactogen).

(b) Ovarian steroid hormones

1. Progestins 2. Estrogens, chiefly Estriol.

1. Human Chorionic Gonadotropin (hCG):

Chemistry

It is a glycoprotein, a heterodimer consisting of two subunits α β.

• α-chain is made up of 92 amino acids and is identical to human FSH, LH and TSH.

• β-chain is made up of 145 amino acids.

• Carbohydrate moieties present are as follows:

– α-chain carries two asparagine linked oligosaccharides

– β-chain has more carbohydrate and contains two asparagine-linked oligosaccharides and four serine-linked oligosaccharides

Origin: It is formed by the syncytiotrophoblast of chorionic villi within 12 to 14 days of fertilization.

Mechanism of Action: The hormone binds to “specific receptor” on the cell membrane of target tissues like ovaries and testes, activates adenyl cyclase, which in turn increases cyclic AMP level ↑ . Cyclic AMP acts as “second messenger” to produce the biological effects.

METABOLIC ROLE

• Luteotrophic effect: The hormone produces enlargement of corpus luteum and stimulates its secretion. It maintains secretory corpus luteum in first three months of pregnancy.

• Testosterone secretion: Like LH, the hormone stimulates the growth of interstitial cells (Leydig cells) of embryonic testes and produces testosterone. This helps in virilisation of the reproductive system of male embryo.

2. Chorionic Somatomammotropin (CS): (Placental Lactogen)

The hormone has biologic properties of prolactin and growth hormone of anterior pituitary. It is a peptide hormone and amino acid sequences are similar to GH and prolactin (85% homology). The hormone is secreted by the syncytiotrophoblast from about the second week of pregnancy, rises slowly and reaches a peak approximately by 36 weeks of pregnancy.

METABOLIC ROLE

The exact role of this hormone is not clear, because pregnant women lacking this hormone have normal pregnancies and deliver normal babies. But as the hormone has similar structure to anterior pituitary GH and prolactin, it exerts similar effects:

• Somatotrophic effect: May promote growth of maternal tissues.

• Luteotrophic effect: Stimulates the enlargement, growth and secretion of corpus luteum and helps to maintain a secretory corpus luteum.

• Mammotrophic effect: Stimulates alveolar growth of mammary glands during pregnancy.

• Lactogenic effect: Also stimulates lactation.

• Anabolic effect: Stimulates foetal and maternal tissue growth. Promotes retention of N, Ca++ and inorganic P.

• Anti-insulin effect: May decrease glucose utilisation, decreased carbohydrate tolerance and hyperglycaemic effect.

3. Ovarian Steroids

A. Progestins: The corpus luteum is the major source of progesterone for the first 6 to 8 weeks of pregnancy and then placenta takes over this function. The corpus luteum though continues to function, but in third trimester onwards, the placenta

produces 30 to 40 times more progesterone than the corpus luteum. Placenta cannot synthesize cholesterol from ‘active’ acetate, hence for cholesterol it has to depend on maternal supply.

B. Estrogens: Plasma concentrations of estradiol, estrone and estriol gradually increase throughout pregnancy. Estriol is produced in the largest amount. Adrenal cortex of foetus produces DHEA and DHEA SO4, which are converted to 16 α-OH derivatives by the foetal liver, and these are subsequently converted to estriol by the placenta. After its formation, travels via the placental circulation to the maternal liver, where they are

conjugated to glucuronides, and then are excreted in the urine.

CLINICAL SIGNIFICANCE

1. Feto-placental function: As estriol is formed by placenta, the measurement of urinary estriol levels has been used as a test of feto-placental function. Failure of urinary estriol or total estrogens to rise in late pregnancy reflects the integrity of the feto-placental unit and may indicate imminent fetal death or placental insufficiency, e.g preeclamptic toxaemia.

Note: Urinary pregnanediol (or plasma progesterone)

reflects placental function only as does estimation of plasma

placental lactogen. A falling titre of urinary estrogens or plasma placental lactogen is serious.

2. Pregnancy tests: Increased urinary excretion of HCG

which occurs in early pregnancy (as early as 10th day of

gestation) forms the basis for pregnancy tests.

Insulin

• Insulin is a protein hormone, secreted by β-cells of islets of Langerhans of pancreas. It plays an important role in
• metabolism causing increased carbohydrate metabolism,
• glycogenesis and glycogen storage; FA synthesis/TG
• storage and amino acid uptake/protein synthesis. Thus
• insulin is an important anabolic hormone which act on
• variety of tissues. Major target tissues of insulin are the
• muscles, liver, adipose tissue and heart.
• RB cells, GI tract epithelial cells and renal tubular
• epithelial cells are rather generally unresponsive to insulin.

Insulin Structure

1- Large polypeptide 51 AA (MW 6000)

2- Two chains linked by disulfide bonds.

A chain (21 AA) B chain (30 AA) 3 disulfide bonds.

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A heterodimeric protein; has been isolated from pancreas and prepared in crystalline form. For crystallisation, it requires Zn++. Zinc is also a

constituent of stored insulin and normal pancreatic tissue is relatively rich in Zn.

A-chain, N-terminal amino acid is glycine and C-terminal is asparagine. In B-chain, N-terminal amino acid is phenyl alanine and C- terminal is threonine.

Disulfide bridges: Both the chains are held together by two S S linkages. Cys 7 and Cys 20 of A-chain are joined to Cys 7 and Cys 19 of B-chain respectively. In addition, the ‘A’ chain carries an “intra-chain” S-Slinkage between Cys 6 and Cys 11

Insulin Structure

Importance of S–S bridges: Breaking of the disulfide

bonds with alkali or reducing agents inactivate insulin. Digestion of insulin protein with proteolytic enzymes also inactivates the hormone. This is the reason why insulin cannot be given orally.

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• Molecular Weight of Insulin: Minimum calculated molecular wt. is 5734. Most estimates of mol. wt. by physical measurements range from 12,000 to 48,000. Insulin can exist in different ‘polymeric’ forms

(dimers, trimers, etc.) depending on pH, temperature and concentration.

Insulin from Other Species:

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Porcine insulin: Porcine insulin is similar to human insulin. It differs by only terminal amino acid No.-30 of B-chain.

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• In humans: It is threonine.

• In porcine: It is alanine in place of threonine.

Removal of alanine (de-alaninated) retains the biologic activity.

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• De-alaninated insulin has been used in treatment of

diabetes mellitus because of its low antigenicity.

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• It is of interest to note that human insulin has been produced by recombinant DNA technology.

3. Conversion of Pro-Insulin to Insulin:

• Pro-insulin containing small vesicles detatch from ER

Fuses with the cisternae of Golgi apparatus.

• Here proinsulin acted upon by a trypsin-like protease

Hydrolysis of peptide chain at two sites

Inactive connective ‘C’-peptide is liberated

Two active peptide left to form the A-and-B chain.

• A carboxypeptidase B like enzyme splits the

C-terminal peptide bonds in the two intermediates

to release two C-terminal basic amino acids from

each of them viz. “Arg 63-Lys 62” to form ‘A’ chains

and “Arg 31 Arg 32” to form B-chain.

C-peptide which is split off has 31 aa.

• Condensing vacuoles are pinched off from

Golgi cisternae with equimolar amounts of

insulin and C-peptide in their lumen.

Insulin molecules form dimers by hydrogen bonding between the peptide

groups of Phe 24 and Tyrosine 26 residues of their B-chains. Gradually with increasing concentrations, condensing vacuoles change into secretory granules. In them, insulin forms crystalloid form of hexamers with two Zn++. C-peptides remain in the fluid spaces surrounding the crystalloid granules

Pro-insulin is comparatively inactive biologically, but it can cross-react with anti-sera prepared against insulin.

• Plasma pro-insulin is not elevated in human diabetes or in normals after glucose stimulation, but it may be the predominant circulating form in some subjects with islet-cell tumours.

Insulin Synthesis

• Insulin synthesis is stimulated by glucose or feeding and decreased by fasting
• Threshold of glucose-stimulated insulin secretion is 100 mg/dl.
• Glucose rapidly increase the translation of the insulin mRNA and slowly increases transcription of the insulin gene

Glucose is the primary stimulator of insulin secretion

Regulation of Insulin Secretion

Regulation of Insulin Secretion

• No insulin is produced when plasma glucose below 50 mg/dl
• Half-maximal insulin response occurs at 150 mg/dl
• A maximum insulin response occurs at 300 mg/dl
• Insulin secretion is biphasic:
• Upon glucose stimulation– an initial burst of secretion (5-15 min.)
• Then a second phase of gradual increment that lasts as long as blood glucose is high

INSULIN RECEPTORS

Insulin acts on target tissues by binding to specific “insulin receptors”, which are ‘glycoproteins’. The human insulin receptor gene is found on chromosome 19.

The insulin receptors are being constantly synthesised and degraded. Their 1/2 life is 6 to 12 hours only. It is synthesised as a single-chain polypeptide, “Pro-receptor” in the rough endoplasmic reticulum (RER) and is rapidly glycosylated in Golgi region. The ‘pro-receptor’ has 1382

amino acids and mol. wt. of 190,000.

The pro-receptor is cleaved to form mature ‘α’ and ‘β’ subunits (α2 β2), which is a heterodimer, linked by S-S bonds. Both subunits are extensively glycosylated and removal of sialic acid and galactose decreases insulin binding and insulin action. Insulin receptors are found

in target cell membrane, up to 20,000 per cell.

Binding of insulin to the receptor, stimulates its tyrosine kinase activity. Tyrosine kinase enzyme phosphorylates the phenolic-OH group of tyrosine residues in specific protein including that of a tyrosine in the β-chain of insulin receptor itself to modulate their activities,

ATP+ tyrosine protein → ADP + phospho-tyrosine protein.

Regulation of Insulin Receptors

A high blood insulin level decreases the number of insulin receptors on target cell membrane, probably through internalisation of the insulin-receptor complex into the cell and thus decreases the insulin sensitivity of the target tissues.

Chief differences in structure and function of α and β

subunits are tabulated below:

α-Subunit β-Subunit

• The heavy chain • The lighter chain

• Entirely extracellular • Transmembrane protein

• Mol. wt. = 135,000 • Mol. wt. = 95,000

• Binds insulin via ‘cyst-eine rich’ domain • Functions as “Signal transducers” (insulin binding site)

• Inter-linked by S-S to a b-chain • Its N-terminal third on outer linkage surface of the membranes, a narrow 23 aa domain in the membrane and C-terminal 2/3 possesses tyrosine kinase activity and ATP-binding activity.

MECHANISM OF ACTION OF INSULIN

When insulin binds to the specific receptor, several events of actions take place:

• A conformational change of the receptor

• The receptors cross-link and form “microaggregates”.

• The receptor complex is internalised, and

• One or more signals are generated.

But nature of the intracellular signal and intracellular “second messenger” remains still uncertain and vague.Various mechanisms have been proposed:

1. Role of Cyclic AMP: It is proposed that insulin promotes the phosphorylation of cyclic AMP phosphodiesterase. The “active” phosphodiesterase hydrolyses c-AMP and lowers the c-AMP level ↓ in the cells. The consequent fall in activities of c-AMP dependent protein kinase reduce phosphorylation of specific enzymes.

2. Role of Cyclic - GMP: The insulin-receptor binding

may activate guanylate cyclase which forms cyclic GMP. Increased concentration of cyclic GMP act as “second messenger” to activate cyclic-GMP dependent protein kinase. These may phosphorylate some enzymes to modulate their activities.

Cyclic AMP and cyclic GMP function in a reciprocal relationship which has been called the “yin-yang hypothesis”.

3. Role of Protein-phosphatases: Insulin may act through the protein-phosphatase 1 which may dephosphorylate certain key enzymes thereby

activating them. Best examples are the key enzyme glycogen synthase and PDH (pyruvate dehydrogenase complex). On the other hand, it inhibits phosphorylase enzyme and triacyl glycerol lipase.

4. Action through ‘Tyrosine Kinase’ Activity of β-Subunit

of Receptor: The binding of insulin to its receptor enhances tyrosine kinase activity. Tyrosine kinase inturn phosphorylates phenolic-OH group of tyrosine residues of specific proteins leading to changes in enzyme activities.

5. Role in m-RNA Translation: Insulin is known to affect the activity or amount of at least more than 50 proteins in a variety of tissues and many of these effects involve covalent modification. A role of insulin in the translation of m-RNA has been proposed largely based on studies of ribosomal protein 6S, a component of the 40S ribosomal unit. Such a mechanism accounts for the general effect of insulin on protein synthesis

in liver, heart muscle and skeletal muscle.

6. Role on Gene Expression (Nuclear Action): Insulin also affects the rate of transcription of specific genes, thereby regulates the synthesis of specific m-RNAs and thus changing the rate of synthesis of specific

proteins coded by them.

Example: Insulin decreases the transcription of gene involved in synthesis of the enzyme phosphoenol-pyruvate carboxy kinase (PEPCK), the key enzyme for gluconeogenesis. On the other hand, insulin induces the synthesis of phosphofructokinase and pyruvate kinase required for

glycolysis, by increasing the transcription of these genes.

ACTION ON CARBOHYDRATE METABOLISM

Net effect is (1) lowering of blood glucose ↓ level and (2)

increased glycogen store ↑. It is achieved by several mechanisms:

1. Increases glucose uptake:

• Insulin increases glucose uptake from EC fluid by the various tissues, viz. muscles, adipose tissue, mammary glands, lens, etc.

• In adipose tissue and probably other extrahepatic tissues, insulin stimulates translocation of glucose ‘transporters’ from their intracellular pool in Golgi cisternae to the plasma membrane where they participate as “carriers” in transportation of D-glucose and D-galactose across the membrane.

• Also in hepatocytes, insulin increases hepatic uptake of glucose (freely permeable to liver cells). It induces the synthesis of the enzyme glucokinase, which simultaneously phosphorylates glucose, thereby lowering intracellular concentration.

2. Increases glycolysis Increases utilisation of glucose for providing energy which takes place in muscles, liver and many other tissues. Insulin enhances glycolysis ↑ because it induces the synthesis of key enzyme phosphofructokinase and also “pyruvate kinase”.

3. Increases conversion of pyruvate to acetyl-CoA:

Insulin increases aerobic oxidative decarboxylation of pyruvate to acetyl-CoA↑, because it causes dephosphorylation of pyruvate dehydrogenase complex (PDH) which is thus converted to ‘active’ form.

4. Stimulates glycogenesis:

Insulin stimulates glycogenesis ↑ in the liver and muscles by increasing dephosphorylation of the key and rate limiting enzyme “glycogen synthase”, thus converting to its ‘active’ form. Insulin stimulates the protein-phosphatase-1 directly, which brings about dephosphorylation.

5. Decreases gluconeogenesis:

Insulin reduces gluconeogenesis ↓ :

• By repressing the synthesis of the key rate limiting enzyme PEP-carboxykinase (PEPCK), by decreasing the transcription rate of the gene.

• Also inhibits allosterically fructose-1, 6-bi-phosphatase, another key enzyme for gluconeogenesis.

• Insulin dephosphorylates fructose-2, 6-bi-phosphatase so that it is converted to ‘inactive’ form, which increases the concentration of “fructose-2, 6-bi-P” in the cell, which in turn allosterically inhibit fructose-1, 6-bi-phosphatase.

6. Decreases glycogenolysis:

Insulin decreases glycogenolysis ↓

• By dephosphorylating the key and rate limiting enzyme glycogen phosphorylase thus converting it to “inactive form”.

• Also represses the enzyme glucose-6-phosphatase.

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7. Increasing HMP-shunt:

Insulin stimulates HMP-shunt producing more

NADPH (required for FA synthesis), by inducing the

synthesis of glucose-6-P- dehydrogenase (G-6-PD) and 6- Phosphogluconate dehydrogenase.

ACTION ON LIPID METABOLISM

Net effects are: (1) lowering of FFA level ↓ and

(2) increase in TG store ↑. The above is achieved as follows:

1. Decreases Lipolysis:

Insulin decreases lipolysis ↓ in adipose tissue cells and consequently lowers plasma FFA ↓.

Lipolysis is reduced due to:

• Insulin activates phosphoprotein phosphatase which dephosphorylates the triacyl glycerol lipase and thus is converted to ‘inactive’ form.

• At the same time, insulin activates phosphodiesterase which degrades cyclic-AMP and prevents phosphorylation and reactivation of TG lipase.

2. Increases FA Synthesis:

Insulin increases the extramitochondrial de novo FAsynthesis ↑, by making available of more substrate acetyl-CoA and also increasing the activity of acetyl- CoA carboxylase.

The above is done as follows:

• Insulin promotes dephosphorylation of pyruvate dehydrogenase complex and converts into “active form” so that more acetyl-CoA is available from pyruvate.

• Insulin induces the synthesis of ATP-citrate lyase to increase cleavage of citrate, so that more acetyl- CoA is available in cytosol.

• Insulin lowers the plasma FFA level, so prevents long-chain acyl-CoA from inhibiting acetyl-CoA carboxylase.

• It induces the synthesis of acetyl-CoA carboxylase and fatty acid synthase, the cytosolic enzymes required for FA synthesis.

• Insulin activates acetyl-CoA carboxylase by dephosphorylation of the enzyme (converting to “active” form).

• Provides more NADPH for the reductive steps in FA synthesis by stimulating HMP-shunt pathway.

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3. Increases Synthesis of TG:

Insulin enhances TG synthesis ↑ in adipose tissue by:

• Providing more α-glycero-p, as glucose uptake and utilisation is enhanced in adipocytes.

• Increased synthesis of FA provides the acyl-CoA (FFA pool 1), required for TG synthesis.

• Insulin also induces the synthesis of lipoprotein lipase. This enzyme hydrolyses TG of circulating chylomicrons and VLDL and releases FFA (FFA pool-2), which are taken up by adipocytes and used for TG synthesis.

4. Decreases Ketogenesis:

As plasma FFA level is decreased, less is oxidised by β-oxidation and less acetyl-CoA will be available for cholesterol synthesis and ketogenesis.

ACTION ON PROTEIN METABOLISM

Net effect is that insulin promotes protein synthesis ↑as follows:

• Insulin increases amino acids uptake by the tissues,by enhancing the rate of synthesis of membrane“transporters” for amino acids.

• Adequate supply of insulin is necessary for protein anabolic effect of GH (permissive effect).

• Insulin increases protein synthesis by providing more amino acids in cells, by affecting gene transcription (nuclear level), by regulating specific m-RNA synthesis and affecting translation at ribosomal level.

• Regulation of ribosomal translation is done by two ways:

• Increases the synthesis of polyamines, required for ribosomal RNA synthesis, by increasing the synthesis of key and rate limiting enzyme ornithine decarboxylase.

• Secondly, insulin modulates ribosomal activity by causing phosphorylation of 6S ribosome (a component of 40S).

Action on Mineral Metabolism

Decrease in concentration of K+ ↓ and inorganic P ↓ in blood due to enhanced glycogenesis and phosphorylation of glucose.

Actions on Growth and Cell Replication:

Insulin stimulates growth in vivo and also cell proliferation in vitro. Cultured fibroblasts have been used most frequently in studies of cell proliferation. It has been found that insulin potentiates the ability of fibroblast growth factor (FGF), platelet-derived growth factor

(PDGF) and epidermal growth factor (EGF), etc. The effects on growth and cell proliferation are seen in many tissues such as liver, mammary glands and adrenals and also in embryogenesis and tissue differentiation. These effects are largely due to stimulation of DNA replication, gene transcription, protein synthesis and modulation

of various enzyme activities through phosphorylation dephosphorylation.

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RELATION OF TYROSINE KINASE

ACTIVITY WITH GROWTH FACTORS

Insulin receptors along with receptors of many other growth promoting peptides including those of EGF, PDGF, IGF-I, etc. have tyrosine kinase activity. It is of interest to note that at least ten or more “oncogene”

products, many of which are suspected to be involved in stimulating malignant cell replication are also tyrosine kinases. Tyrosine kinase activity is now thought to be an essential factor in the action of a number of viral oncogene products. Mammalian cells contain analogous of these

‘oncogenes’, as proto-oncogenes which may be involved in the replication of normal cells.

Glucagon

• A 29-amino-acid polypeptide hormone containing only 15 different amino acids that is a potent hyperglycemic agent.
• Histadine is N-terminal and threonine is C-terminal amino acid. Mol. Wt. is 3485. Does not contain cystine, proline or isoleucine, rather have tyrosine, methionine and tryptophane.
• Does not require Zn or other metal for crystalization.
• Produced by α cells in the pancreas
• Its major target is the liver, where it promotes:
• Glycogenolysis – the breakdown of glycogen to glucose
• Gluconeogenesis – synthesis of glucose from lactic acid and noncarbohydrates
• Release of glucose to the blood from liver cells

Glucagon Signaling

SYNTHESIS

GLUCAGON HYPERGLYCAEMICGLYCOGENOLYTIC FACTOR (HGF)

Glucagon is a hormone produced by α-cells of islet of Langerhans of pancreas and is an important hormone involved in:

• Rapid mobilisation of hepatic glycogen to give glucose by glycogenolysis, and

• To a lesser extent FA from adipose tissue.

Thus, it acts as a hormone required to mobilise metabolic substrates from storage depots.

SYNTHESIS

It is synthesised first as a pro-hormone, “proglucagon” in α-cells. Lysosomal enzymes peptidases like carboxypeptidase B and trypsin-like peptidases in α-cells hydrolyse pro-glucagon from both its N-terminal end and C-terminal end to yield glucagon and inactive peptides.

Entero-glucagon or glucagon-like immune reactive factor (GLI) has been identified in gastric and duodenal mucosa, is immunologically similar but not identical to the pancreatic hormone. It is less active in stimulating adenyl cyclase and cannot duplicate many of the functions of pancreatic hormone. GLI is stimulated by absorbed glucose causing elevation of circulating pancreatic glucagon. Recently, two different molecular fractions • One with mol. wt. = 3500, hyperglycaemic, and glycogenolytic activity but far less potent than pancreatic glucagon. • The other fraction, mol. wt. = 7000, is devoid of the above activity both with insulin releasing activity have been identified.

DNA in α cells

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mRNA

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Preproglucagon

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Proglucagon

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glucagon

Factors Affecting Glucagon Secretion:

MECHANISM OF ACTION

Glucagon binds to specific receptors on the plasma membranes of hepatocytes and adipocytes and activates adenyl cyclase to produce c-AMP in these cells, which is the principal “second messenger” and duplicates the functions of the hormone. c-AMP in turn activates c-AMP dependent protein kinases which further phosphorylates specific enzymes to increase/decrease their activities. c-AMP also induces synthesis of certain specific enzymes like glucose-6-phosphatase by increasing the

transcription of their genes.

METABOLIC ROLE

1. Action on Carbohydrate Metabolism: Net effect of the hormone is to increase the blood sugar level (hyperglycaemia) ↑. Hyperglucaemic effect is due to various causes:

• Glycogenolysis: Glucagon increases glycogenolysis in liver. In muscles, it cannot bring about glycogenolysis as muscle cell membrane lacks the glucagon specific receptors. Glucagon also induces the synthesis of glucose-6-phosphatase enzyme.

By increasing gluconeogenesis in liver: Glucagon stimulates the conversion of LA and glucogenic amino acids to form glucose.

• The increased hepatic cAMP produced after glucagon action increases protein kinases that catalyse nuclear histone phosphorylation in liver cell nucleus. Thus histones repressive action on DNA is inhibited and initiation of a sequence of events leading to the synthesis of new enzyme proteins involved in gluconeogenesis takes over. Thus, glucagon induces all key enzymes for gluconeogenesis the PEP-carboxykinase, pyruvate carboxylase and fructose-1, 6-biphosphatase enzyme,.

• It increases the pool of hepatic glucogenic amino acid for gluconeogenesis. by increasing protein breakdown by reducing hepatic protein synthesis& increasing breakdown.

2. On Lipid Metabolism: • Lipolysis: In adipose tissue and also possibly in

liver, glucagon increases the breakdown of TG to produce FFA ↑ and glycerol ↑. FA undergo β-oxidation, increased breakdown may lead to Ketone bodies formation and Ketosis. Thyroid hormones help in the lipolytic action of glucagon, probably the hormones increase the number of glucagon specific receptors on adipocytes.

• Anti-lipogenic Action: Glucagon reduces FA synthesis in 2 ways: • Increased lipolysis raises the concentration of FFA in blood. Long-chain acyl-CoA inhibits the rate-limiting enzyme acetyl-CoA carboxylase.

• Increased c-AMP level in cells activates the c-AMP-dependent protein kinase which phosphorylates acetyl-CoA carboxylase. Phosphorylated form of the enzyme is “inactive”.

3. On Protein Metabolism: • Glucagon reduces protein synthesis by depressing incorporation of amino acids into peptide chains through inactivation of some ribosomal component by a protein kinase whose activity is enhanced by glucagon-induced rise in c-AMP.

• Glucagon also stimulates protein catabolism ↑ specially in liver, increases the hepatic amino acid pool for gluconeogenesis. Also ↑ urinary NPN &urea.

4. Action on Heart:

Glucagon exerts a +ve ionotropic effect on heart without producing increased myocardial irritability. Hence, use of glucagon in treatment of heart disease, viz. in cardiac failure and in cardiogenic shock. Advantage over nor-epinephrine: Glucagon increases the force of contraction, but does not produce any arrhythmias, tachycardia or increase in O2 consumption.

5. Calorigenic Action:

Glucagon increases heat production and rise in BMR. The calorigenic action is not due to hyperglycaemia Perse but is probably due to increased hepatic deamination of amino acids, with thyroid hormones stimulating the utilisation of deaminated residues. The calorigenic action needs the presence of thyroid and adrenocortical hormones.

6. On Mineral Metabolism: • Potassium: Glucagon increases K+ release from the liver, an action which may be related to its glycogenolytic activity.

• Calcium: Recently it has been shown that glucagon can increase the release of calcitonin from the thyroid, thus have calcium lowering affect.

CLINICAL ASPECTS /Clinical and Therapeutic Uses

• Most important use is in treatment of severe insulin induced hypoglycaemia.

• Long acting Zinc glucagon has been used in inoperable pancreatic cell tumours.

• Has been used in heart failure and cardiogenic shock due to its direct ionotropic effect on cardiac muscle.

• It also improves the renal perfusion by decreasing renal vascular resistance. It is mainly indicated in low output failure and in toxicity of β-blockers (as its action is not blocked by α-blockers).

• Recently it has been used also in treatment of Acute Pancreatitis due to inhibitory effect on exocrine secretions of pancreas.

Glucagon Action on Cells:

Thyroid Hormones

• There are two biologically active thyroid hormones:

- tetraiodothyronine (T4; usually called thyroxine)

- triiodothyronine (T3)

• Derived from modification of tyrosine.

Differences between T4 and T3

• The thyroid secretes about 80 microg of T4, but only 5 microg of T3 per day.
• However, T3 has a much greater biological activity (about 10 X) than T4.
• An additional 25 microg/day of T3 is produced by peripheral monodeiodination of T4.

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T4

T3

Thyrotropic hormone (TTH).

Chemical structure: glycoprotein.

This hormone is necessary for the normal functions of thyroid glands.

Thyrotropic hormone promotes:

• accumulation of iodine in thyroid;
• inclusion of iodine into the tyrosine;
• synthesis of thyroxine and triiodothyronine.

Synthesis of thyroid hormones

• Active uptake of iodide into follicular cell
• Iodide iodine - H₂O ₂ (catalysed by TPO)
• Active uptake of iodine at follicular/ colloid interface
• Incorporation of iodine onto tyrosine residues of thyroglobulin
• Coupling of iodinated tyrosines
• Storeage of T₃ and T₄

Iodine Metabolism

• Dietary iodine is absorbed in the GI tract, then taken up by the thyroid gland (or removed from the body by the kidneys).
• The transport of iodide into follicular cells is dependent upon a Na⁺/I^- cotransport symport system an active transport system.
• Iodide taken up by the thyroid gland is oxidized by peroxidase in the lumen of the follicle:

• Oxidized iodine can then be used in production of thyroid hormones.

The Next Step: Production of Thyroglobulin

• Pituitary produces TSH, which binds to follicle cell receptors.
• The follicle cells of the thyroid produce thyroglobulin.
• Thyroglobulin is a very large glycoprotein.
• Thyroglobulin is released into the colloid space, where it’s tyrosine residues are iodinated by I⁺.
• This results in tyrosine residues which have one or two iodines attached (monoiodotyrosine or diiodotyrosine).

Formation and Secretion of Thyroglobulin by the Thyroid Cells.

The thyroid cells are typical protein-secreting glandular cells. The endoplasmic reticulum and Golgi apparatus synthesize and secrete into the follicles a large glycoprotein molecule called thyroglobulin, with a molecular weight of about 335,000.

Each molecule of thyroglobulin contains about 70 tyrosine amino acids, and they are the major substrates that combine with iodine to form the thyroid hormones.

4) Release of T4 and T3 into circulation -

100μg T4 & 10μg T3/day

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3) ~ 10% T4 undergoes mono-deiodination to T3 before secretion

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2) Fusion of colloid droplets with lysosomes --> hydrolysis and release of thyroid hormones

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1) Stimulated by TSH colloid droplets with the bound thyroid hormones are taken back into follicular cells by pinocytosis

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They combine mainly with

Thyroxin-binding globulin <90%

Thyroxin-binding pre-albumin

Thyroxin-binding albumin.

Transport of thyroxine and triiodothyronine to tissues:

Utilization of Thyroglobulin to Secrete Thyroid Hormones

• In order to secrete T3/T4, the thyroglobulin in the colloid space is internalized by endocytosis back into the follicle cell.
• This internalized vesicle joins with a lysosome, whose enzymes cause cleavage of T3 and T4 from thyroglobulin. Some T4 is converted to T3 at this point. [this is the peripheral monoiodination of T4 mentioned earlier].
• T3 and T4 are then released into the extracellular space by diffusion.
• Only minute amounts of thyroglobulin are released into the circulation. extracellular spacecolloid droplet

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iodinated tyrosines (gets deiodinated,

Lysosome recycled)

follicle

cell

endocytosis

colloid space

Thyroglobulin T3 T4

MEHANISM OF ACTION OF THYROID HORMONES:

The thyroid hormone receptors are either attached to the DNA genetic strands or located in proximity to them.

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The thyroid hormone receptor usually forms a heterodimer with retinoid X receptor (RXR) at specific thyroid hormone response elements on the DNA.

MEHANISM OF ACTION OF THYROID HORMONES:

On binding with thyroid hormone, the receptors become activated and initiate the transcription process.

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Then large numbers of different types of messenger RNA are formed, followed within another few minutes or hours by RNA translation on the cytoplasmic ribosomes to form hundreds of new intracellular proteins

More on Receptor Coactivators and Corepressors

• When not bound to hormone, the thyroid hormone receptor binds to target DNA (TRE on 5’ flanking region). It is associated with corepressor proteins that cause DNA to be tightly wound and inhibit transcription.
• Binding of hormone causes a conformational change, resulting in loss of corepressor binding and association with coactivator proteins, which loosen DNA structure and stimulate transcription.

Expression and Regulation of Thyroid Hormone Receptors

• Thyroid hormone receptors are found in many tissues of the body, but not in adult brain, spleen, testes, uterus, and thyroid gland itself.
• Thyroid hormone inhibits thyroid hormone receptor expression.

One Major Target Gene of T3: The Na⁺/K⁺ ATPase Pump

• Pumps sodium and potassium across cell membranes to maintain resting membrane potential
• Activity of the Na⁺/K⁺ pump uses up energy, in the form of ATP
• About 1/3rd of all ATP in the body is used by the Na⁺/K⁺ ATPase
• T3 increases the synthesis of Na⁺/K⁺ pumps, markedly increasing ATP consumption.
• T3 also acts on mitochondria to increase ATP synthesis
• The resulting increased metabolic rate increases thermogenesis (heat production).

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Endemic goiter (occurs in the deficit of iodine in water, soil and air)

Connective tissue is enlarged in gland and it is increased in size markedly

Endemic goitre is a type of goitre that is associated with dietary iodine deficiency. Some inland areas where soil and water lacks in iodine compounds and consumption of marine foods is low are known for higher incidence of goitre.

Hyperfunction of gland – diffuse toxic goiter (thyrotoxicosis, Graves disease)

• Goiter – hyperplasia of gland
• Hypermetabolism
• Increase of body temperature
• Sweating, muscle weakness
• Weight loss with good appetite
• Tremor, emotional lability, insomnia
• Exophtalm

Grave’s disease (1⁰)

• Autoimmune - activating AB’s to TSH receptor
• High concentrations of circulating thyroid hormones, low TSH
• Weight loss, tachycardia, tiredness
• Diffuse goitre - TSH stimulating growth
• Opthalmompathy and dermopathy

How is Hypothyroidism Related to Goiter?

• During iodine deficiency, thyroid hormone production decreases.
• This results in increased TSH release (less negative feedback).
• TSH acts on thyroid, increasing blood flow, and stimulating follicular cells and increasing colloid production.

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Midwest – the Goiter Belt

• If goiter is due to decreased I, then thyroid gland enlarges – called endemic or colloidal goiter.
• Pituitary gland 🡪 TSH to stim thyroid gland to produce TH, but the only result is that the follicles accumulate more and more unusable colloid.
• Cells eventually die from overactivity and the gland atrophies.

How is Goiter Related to Hyperthyroidism?

• Due to excessive stimulation by TSH (thyroglobulin production, enlarged follicles…).
• In this case, excessive stimulation of the thyroid gland by TSH DOES result in thyroid hormone secretion, since iodine is available.

Hashimoto’s (1^o)

• Autoimmune - AB’s destruction of thyroid gland
• Low concentrations of thyroid hormones, high TSH
• Lethargy, intolerance to cold
• Lack of growth and development
• Diffuse goitre - lymphocytic infiltration of gland + TSH stimulated growth

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Symptoms and signs of hypothyroidism

Parathyroid Hormone

• PTH is synthesized and secreted by the parathyroid gland which lie posterior to the thyroid glands.
• The blood supply to the parathyroid glands is from the thyroid arteries.
• The Chief Cells in the parathyroid gland are the principal site of PTH synthesis.
• It is THE MAJOR REGULATOR of Ca homeostasis in humans.

Parathyroid Glands

Synthesis of PTH

• PTH is translated as a pre-prohormone.
• Cleavage of leader and pro-sequences yield a biologically active peptide of 84 aa.
• Cleavage of C-terminal end yields a biologically inactive peptide.

Regulation of PTH

• PTH secretion responds to small alterations in plasma Ca²⁺ within seconds.
• A unique calcium receptor within the parathyroid cell plasma membrane senses changes in the extracellular fluid concentration of Ca²⁺.
• This is a typical G-protein coupled receptor that activates phospholipase C and inhibits adenylate cyclase—result is increase in intracellular Ca²⁺ via generation of inositol phosphates and decrease in cAMP which prevents exocytosis of PTH from secretory granules.

• The dominant regulator of PTH is plasma Ca²⁺.
• Secretion of PTH is inversely related to [Ca²⁺].
• Maximum secretion of PTH occurs at plasma Ca²⁺ below 3.5 mg/dL.
• At Ca²⁺ above 5.5 mg/dL, PTH secretion is maximally inhibited.

Regulation of PTH

• When Ca²⁺ falls, cAMP rises and PTH is secreted.
• 1,25-(OH)₂-D inhibits PTH gene expression, providing another level of feedback control of PTH.
• Despite close connection between Ca²⁺ and PO₄, no direct control of PTH is exerted by phosphate levels.

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Calcium regulates PTH secretion

PTH action

• The overall action of PTH is to increase plasma Ca²⁺ levels and decrease plasma phosphate levels.
• PTH acts directly on the bones to stimulate Ca²⁺ resorption and kidney to stimulate Ca²⁺ reabsorption in the distal tubule of the kidney and to inhibit reabosorptioin of phosphate (thereby stimulating its excretion).
• PTH also acts indirectly on intestine by stimulating 1,25-(OH)₂-D synthesis.

Actions of PTH: Bone

• PTH acts to increase degradation of bone (release of calcium).

- causes osteoblasts to release cytokines, which stimulate osteoclast activity

- stimulates bone stem cells to develop into osteoclasts

- net result: increased release of calcium from bone

- effects on bone are dependent upon presence of vitamin D

Actions of PTH: Kidney

• PTH acts on the kidney to increase the reabsorption of calcium (decreased excretion).
• Also get increased excretion of phosphate (other component of bone mineralization), and decreased excretion of hydrogen ions (more acidic environment favors dimineralization of bone)
• ALSO, get increased production of the active metabolite of vitamin D3 (required for calcium absorption from the small intestine, bone demineralization).

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• NET RESULT: increased plasma calcium levels

Mechanism of Action of PTH

• PTH binds to a G protein-coupled receptor.
• Binding of PTH to its receptor activates 2 signaling pathways:

- increased cyclic AMP

- increased phospholipase C

• Activation of PKA appears to be sufficient to decrease bone mineralization
• Both PKA and PKC activity appear to be required for increased resorption of calcium by the kidneys

Regulation of PTH Secretion

• PTH is released in response to changes in plasma calcium levels.

- Low calcium results in high PTH release.

- High calcium results in low PTH release.

• PTH cells contain a receptor for calcium, coupled to a G protein.
• Result of calcium binding: increased phospholipase C, decreased cyclic AMP.
• Low calcium results in higher cAMP, PTH release.

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• Also, vitamin D inhibits PTH release (negative feedback).

PTH-Related Peptide

• Has high degree of homology to PTH, but is not from the same gene.
• Can activate the PTH receptor.
• In certain cancer patients with high PTH-related peptide levels, this peptide causes hypercalcemia.
• But, its normal physiological role is not clear.

- mammary gland development/lactation?

- kidney glomerular function?

- growth and development?

Primary Hyperparathyroidism

• Calcium homeostatic loss due to excessive PTH secretion
• Due to excess PTH secreted from adenomatous or hyperplastic parathyroid tissue
• Hypercalcemia results from combined effects of PTH-induced bone resorption, intestinal calcium absorption and renal tubular reabsorption
• Pathophysiology related to both PTH excess and concomitant excessive production of 1,25-(OH)2-D.

Hypercalcemia of Malignancy

• Underlying cause is generally excessive bone resorption by one of three mechanisms
• 1,25-(OH)2-D synthesis by lymphomas
• Local osteolytic hypercalcemia
• 20% of all hypercalcemia of malignancy
• Humoral hypercalcemia of malignancy
• Over-expression of PTH-related protein (PTHrP)

PTHrP

• Three forms of PTHrP identified, all about twice the size of native PTH
• Marked structural homology with PTH
• PTHrP and PTH bind to the same receptor
• PTHrP reproduce full spectrum of PTH activities

PTH receptor defect

• Rare disease known as Jansen’s metaphyseal chondrodysplasia
• Characterized by hypercalcemia, hypophosphotemia, short-limbed dwarfism
• Due to activating mutation of PTH receptor
• Rescue of PTH receptor knock-out with targeted expression of “Jansen’s transgene”

Hypoparathyroidism

• Hypocalcemia occurs when there is inadequate response of the Vitamin D-PTH axis to hypocalcemic stimuli
• Hypocalcemia is often multifactorial
• Hypocalcemia is invariably associated with hypoparathyroidism
• Bihormonal—concomitant decrease in 1,25-(OH)2-D

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Your questions are proof of your studies , intellect and reasoning. These are cordially invited and much appreciateds.

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