The cells of the human body depend on receiving signals—they need to know when to store glucose, when to divide, when muscles should contract, when neurons should fire, etc.  The molecules that send these signals typically do not enter the cell.  How can a hormone, or a neurotransmitter, or a growth factor, or whatever stimulate cells that they do not enter?  They activate a second messenger system so that activated second messenger molecules stimulate changes inside a cell.  Molecules of adenylate cyclase create the second messenger cAMP (cyclic AMP which is produced by removing two phosphate groups from ATP).  Adenylate cyclase is activated by stimulated G proteins.  Normally, G proteins bind GDP and are unable to bind adenylate cyclase; when G proteins are themselves activated, they bind GTP and are able to activate adenylate cyclase.  G proteins are activated by G-protein coupled receptors which have bound their specific ligand.

     In the following illustration, the G-protein coupled receptor has not bound its ligand; the G protein has not been activated, which means that adenylate cyclase has not been activated, which means that the second messenger cAMP is not being made to initiate changes in the cell.

G-protein coupled receptors belong to a giant gene superfamily.  The cells of the body react to different stimuli because different cells express different GPCRs. 
G PROTEIN COUPLED RECEPTORS

     The hormones of the endocrine system cannot affect the cells of the body unless the cells of the body have receptors which can perceive them.  Many hormone receptors are G protein coupled receptors.  This superfamily of proteins shares a set of 7 hydrophobic transmembrane regions connected by hydrophilic sections which form either intracellular or extracellular loops.  This is a very old family found even in bacteria; bacteriorhodopsin is homologous to GPCRs of higher organisms although exon shuffling has changed the order of the transmembrane regions. Gene duplication had produced many of the subfamilies of the  G proteins and protein tyrosine kinases before the lineages leading to modern sponges separated from those leading to higher animals (Suga, 1999).  Unicellular yeast respond to mating pheromones through G-protein coupled receptors, reminiscent of homone-receptor interactions of animals (Blumer, 1988).

     This family of receptors is actually the largest gene family known in vertebrate genomes (including that of humans).  These receptors mediate the activity of major hormones such as ACTH, anti-Mullerian hormone, melatonin, calcitonin, FSH, CRH, GIP, GnRH, glucagons, LRH, MSH, oxytocin, parathormone, secretin, VIP, and ADH; local hormones such as bradykinin, histamine, leukotrienes, prostaglandins, cytokines, purinergic hormones, endothelin, adenosine, formyl peptide, and platelet signals;  most neurotransmitters and neuropeptides; and the sensory stimuli of taste, smell, and sight.  A number of these receptors are expressed in the human body whose ligands are not yet known.

STEROID HORMONE RECEPTORS

     Other hormones, such as estrogen and testosterone, are not perceived by G protein coupled receptors but by a family of zinc finger transcription factors known as nuclear receptors.  Zinc finger proteins are metal-binding proteins which control the transcription of other genes in eukaryotes. There are more than 500 zinc finger proteins in the human genome.  Nuclear receptors are a family of related zinc finger proteins which include receptors for estrogen, testosterone, glucocorticoids, thyroid hormones, and retinoic acid (Zilliacus, 1994) and a large number of orphan receptors whose function is not yet known (Detera, 1994). Unlike most hormones, steroid and thyroid hormones enter cells rather than binding only on the outside.  Once they have bound the receptor, the hormone-receptor complex travels to the nucleus where it binds DNA and effects gene transcription. Nuclear hormone receptors are known from vertebrates, echinoderms, arthropods and nematodes.  The receptor subunits can form homodimers with themselves or heterodimers with other subunits to bind DNA molecules.  The vertebrate retinoic acid receptor (RXR) is homologous to the invertebrate receptor for juvenile hormone III. Sponges produce both retinoic acid and its receptor (Schacke, 1994b).  Jellyfish possess a receptor which is similar to vertebrate RXR which binds retinoic acid and then binds the DNA of crystallin genes, just as in both vertebrates and invertebrates (Kostrouch, 1998).

     Mammals possess a number of major receptors for steroid hormones including 2 estrogen receptors, a protesterone receptor, an androgen receptor, a glucocorticoid receptor, and a mineralocorticoid receptor.  All these receptors seem to have evolved from an ancestral receptor in primitive vertebrates.  None of these receptors have yet to be identified in invertebrates although Drosophila and tunicates possess a receptor which is homologous to estrogen receptors whose ligand is unknown (Dehal, 2002).  Several nuclear receptors are known from insects (such as ecdysone, ftz regulatory factor 1, and the products of the genes knirps, embryonic gonald, tailless, knirps, and ultraspiracle) and worms (the C. elegans differentiation activating factor).  They all form part of a gene family derived from an ancestral protein with ligand-binding and DNA-binding domains (Amero, 1992).   Ftz-F1, a protein which activates the ftz homeodomain gene in Drosophila which is involved in the segmentation of the embryo is a member of the nuclear receptor superfamily.    Some members of the family only contain the DNA-binding region of the mammalian nuclear hormone receptors (such Knirps and Embryonic gonald) while Ftz-F1 possesses both the DNA-binding and ligand binding domains found in the mammalian hormone receptors (Lavorgna, 1991)

     There were already several different subfamilies of nuclear proteins at the time when protostomes and deuterostomes separated (Laudet, 1992).  Tunicates possess genes for all major peptide hormone receptors (such as insulin and gonadotropins), except growth hormone.  Tunicates lack steroid hormones (and the P450 enzymes which synthesize them) but they do possess nuclear receptors, such as those which bind thyroid hormones and retinoic acid (which protostomes lack).  (Dehal, 2002; Christiaen, 2002).

      A single indeterminate steroid hormone receptor is present in hagfish, 3 are known to date from lampreys (named ER, CR, and PR) and sharks (ER, GR, and AR), and all 6 are known in bony vertebrates (lamprey CR is similar to both gnathostome GR and MR) (Thornton, 2001).   Lampreys lack estradiol 17b, progesterone, and testosterone  but do produce a variety of steroid hormones, including estrogens and androgens.  Small amounts of estradiol are made (Lowartz, 2003).

     The endocrine system is composed of organs called glands whose major function is the secretion of hormones (such as the pituitary, thyroid, parathyroid, and adrenal glands) in addition to hormone-secreting endocrine cells inside organs which have other primary functions (such as the hypothalamus, heart, kidney, pancreas, and stomach).  Each of these endocrine regions has its own evolutionary history.

HYPOTHALAMUS

     The vertebrate hypothalamus is not only an important part of the nervous system, it is an important part of the endocrine system because of its regulation of the secretion of hormones by the pituitary, control of the epinephrine release by adrenal glands, and production of circulating hormones such as oxytocin and ADH (vasopressin).     Most metazoan animals use sex steroids in differentiation of male and female reproductive structures and oxytocin for the majority of the acute events that occur at these structures structures.  Oxytocin and vasopressin family members are known from 4 invertebrate phyla and all groups of vertebrates (Youson, 1999).  Cnidarians produce oxytocin/vasopressin (Thorndyke, ).  A number of peptides similar to oxytocin/vasotocin are known in invertebrates such as Arg-conopressin-S in mollusks, Lys-conopressin-G in mollusks, cephalotocin in mollusks, annetocin in annelids, Lom-DH in arthropods, and Stp-OLP in tunicates.  Mollusk conopressin genes are homologous to those of vasoticn/oxytocin in vertebrtates (Hoyle, 1998; Youson, 1999; Kesteren, 1992).    In worms, annetocin functions in egg-laying and the contraction of neprhidia (which propel both wastes and gametes) (Ivell, 1999).

     In vertebrates, these hormones are produced in the hypothalamus, travel through the axons of hypothalamic neurons to the posterior pituitary (the neurohypohysis), and are secreted from the neurohypophysis.  Ascidians possess a neural gland which has been compared to the vertebrate neurohypophysis although its relationship to vertebrate structures is not clear. (Burighel, from Harrison, 1997, p. 270).  The human neurohypophysis is depicted below.

     The vertebrate hypothalamus is not only an important part of the nervous system, it is an important part of the endocrine system because of its regulation of the secretion of hormones by the pituitary, control of the epinephrine release by adrenal glands, and production of circulating hormones such as oxytocin and ADH (vasopressin).     Most metazoan animals use sex steroids in differentiation of male and female reproductive structures and oxytocin for the majority of the acute events that occur at these structures structures.  Oxytocin and vasopressin family members are known from 4 invertebrate phyla and all groups of vertebrates (Youson, 1999).  Cnidarians produce oxytocin/vasopressin (Thorndyke, ).  A number of peptides similar to oxytocin/vasotocin are known in invertebrates such as Arg-conopressin-S in mollusks, Lys-conopressin-G in mollusks, cephalotocin in mollusks, annetocin in annelids, Lom-DH in arthropods, and Stp-OLP in tunicates.  Mollusk conopressin genes are homologous to those of vasoticn/oxytocin in vertebrtates (Hoyle, 1998; Youson, 1999; Kesteren, 1992).    In worms, annetocin functions in egg-laying and the contraction of neprhidia (which propel both wastes and gametes) (Ivell, 1999).

     In vertebrates, these hormones are produced in the hypothalamus, travel through the axons of hypothalamic neurons to the posterior pituitary (the neurohypohysis), and are secreted from the neurohypophysis.  Ascidians possess a neural gland which has been compared to the vertebrate neurohypophysis although its relationship to vertebrate structures is not clear. (Burighel, from Harrison, 1997, p. 270). 

     Vasopressin and oxytocin are related hormones produced from the duplication of an ancestral gene.  Oxytocin exists in mammals (including echidna) while the similar hormone mesotocin is produced in nonmammalian tetrapods.  The opossum Didelphis marsupialis secretes only oxytocin while Didelphis virginiana secretes both oxytocin and mesotocin.  Other marsupials secrete only mesotocin.  Although most marsupials produce mesotocin rather than oxytocin (which differ by one amino acid), the precursor of mesotocin in marsupials is more similar to that of oxytocin in placental mammals than to the mesotocin of nonmammals.  While mesotocin is not as effective in inducing uterine contractions in placental mammals, the mesotocin and oxytocin are functionally equivalent in marsupials.  In both marsupials and placental mammals, oxytocin influences the physiology of the ovary with its receptors expressed in the preovulatory follicles. (Parry, 2000).

     The hypothalamus secretes a number of hormones which regulate the hormone secretion of the pituitary.  Teleosts have two forms of TRH and are conserved between bony fish and humans (Harder, 2001).  Neurohypophysial hormone sequences in lungfish are more similar to those of amphibians than to teleosts (Shinohara-Ohtani, 1998).  The hypothalamic hormone GnRH (gonadotropin releasing hormone) controls the release of two important pituitary hormones collectively referred to as the gonadotropins: FSH (follicle stimulating hormone) and LH (leutenizing hormone).

Gn RH

GnRH genes are not part of a larger gene family (Fernald, 1999).  GnRH is known in a number of mollusks where it is affects neural function and gonadal function (Zhang, 2000a).  There are three GnRH genes known which appear to have resulted from an ancestral gene which was duplicated in ancestral vertebrates.  Two of the three resulting decapeptides have the same amino acid sequence in all known species.  Basal actinopterygians, lungfish, amphibians, marsupials, and primitive placental mammals possess two GnRH genes.

GnRH3 is known only in fish to date (Fernald, 1999; King, 1995; Lovejoy, 1992). 

     In humans, GnRH1 is produced in the spleen, lymphocytes, liver, muscle, kidney, placenta.  Expression is also widespread in fish.  GnRH2 is expressed in the human brain, prostate, bone marrow, and kidney.  The terminal nerves in many fish release GnRH and lesions of these neurons interferes with specific aspects of male reproductive behavior.  There is one report of abnormal reproductive behavior after terminal nerve damage in mammals (Yamamoto, 1997).

GROWTH HORMONE RELEASING HORMONE; GHRH

GHRH is produced by the hypothalamus to affect the secretion of growth hormone from the pituitary.  Homologs of gene family members are known in flies.  It is also a paracrine/autocrine hormone produced by the lung and gastrointestinal tract (the latter is pictured in the photo below).

     In all vertebrates, the pituitary gland (often referred to as the “master gland”) is composed of 2 parts: a neurohypohysis from the hypothalamus and an adenohypophysis from the ectoderm of the embryonic oral cavity known as Rathke’s pouch.  The pituitary of the hagfish is the most primitive: there is no distinction between the pars distalis and intermedius and although neurons of the hypothalamus send long axons to a lobe ventral to the adenohypohysis, connective tissue separates neurohypophysis from the adenohypohysis.  There is a portal system in this region in hagfish, but it doesn’t unite the neurhypophysis and the adenohypophysis as in gnathostomes.  As a result, the two regions of the vertebrate pituitary have neither neural nor vascular connections in hagfish.  In lampreys these two regions are separate but they may have neural connections.  There is no portal system in lampreys.  Cartilaginous fish possess a portal system to the adenohypophysis  (Hoar, Vol. 2).  In cartilaginous fish, the adenohypohysis is still thin but blood vessels cross the distance between them.  In teleosts, the adenohypohysis is thin and approaches the neurohypophysis at multiple points so that materials can diffuse between them.  In primitive bony fish, there is still a connection between the adenohypohysis and the roof of the mouth. Once a portal system was more completely developed, the adenohypohysis could become a more globular structure (Gorbman, 1995).

     Preliminary evidence suggests that the neural gland of tunicates produces hormones similar to prolactin, beta-endorphin, and MSH and thus is homologous to the pituitary gland. (Burighel, from Harrison, 1997, p. 279).  The tunicate Pitx (pituitary homeobox) homolog is expressed in the neural complex (part of the embryonic pharynx) comparable to where the pituitary forms in vertebrates.  The Pitx family of homeodomain proteins is related to the Aristaless-related, goosecoid, and Otx families (Christiaen, 2002).  Tunicates possess genes for all major peptide hormone receptors (such as insulin and gonadotropins), except growth hormone (Christiaen, 2002).. 

     In Amphioxus, the dorsal portion of the oral region includes Hatschek’s pit and groove which are homologous to the hypothalamus and pituitary of vertebrates.    Hatschek’s pit contains hormones similar to GnRH, LH, human chorionic gonadotropin, substance P, met-enkephalin, CCK, and gastrin.  It is not only capable of stimulating the gonads in Amphioxus, but also in toads. The homology of the pituitary to Hatschek’s pit supports the hypothesis that the pituitary evolved from a chemosensitive olfactory region (Gorbman, 1995; Ruppert, from Harrison, 1997, p. 413.; Stach, 2000).      Islet1 expression also reveals that Amphioxus may have homologs of the pineal gland and adenohypophysis (Jackman, 2000). 

     In the cartilaginous fish, the pituitary makes gonadotropins, TSH, ACTH. The pars nervosa is defined in many cartilaginous fish and in bony fish ( Hoar, Vol. 2)186-7).  Growth hormone in cartilaginous fish has both growth and diabetogenic effects (Hoar, Vol. 2).   In teleosts, the pituitary consists of different cell types which secrete prolactin, TSH, ACTH, GH, and the 2 gonadotropins.  MSH is also secreted. (Hoar, Vol. 2).  The hypothalamo-hypophysial structure of lungfish is comparable to that of tetrapods.  Lungfish produce peptides related to TSH, prolactin, and somatotropin in their pituitary glands (Hansen, 1998).

     Growth hormone, prolactin, and somatolactin are members of a gene family.  GH is the only member of the family known to exist in agnathans.  While there is only a single growth hormone gene in most vertebrates, gene duplications have produced multiple copies in teleost fish, goats, and primates (the latter of which have four genes) (Chuzhanova, 2000).

     Prolactin and growth hormone are known in mammals and bony fish.  (Sower, 2001).  Prolactin is known to have more than 300 functions in vertebrates, more than the roles of all other pituitary hormones combined.  One of its major roles in fish is the control of osmotic balance (Manzon, 2002).  Prolactin is involved in parental behavior in some fish, as in higher vertebrates. In the sea horse Hippocampus, prolactin promotes secretions from the epithelium of the brood chamber which holds the young.  In some fish, prolactin increases the production of epithelial mucus cells.   In one cichlid fish, this mucus is eaten by the young (Hoar, Vol. 2, p. 219-20).  Somatolactin is a hormone of the growth hormone and prolactin family.  To date, it is known only from actiopterygian and sarcopterygian fish (Amemiya, 1999; Sower, 2001)

     The POMC gene is interesting in that its product is cut to form separate signal molecules.  In other words, this single gene encodes a number of hormones: ACTH (which stimulates secretion of hormones from the adrenal cortex), a MSH, bMSH, g MSH (which affect melanocytes and pigmentation), b lipotropin, g lipotropin, corticotropin-like intermediate lobe peptide (CLIP), and b endorphin.  In humans, mutations have been shown to cause obesity, red hair, and adrenal insufficiency.  Cartilaginous fish possess a POMC gene which may contain an additional dMSH sequence (Alrubaian, 2003).  Processing of a-MSH and b-endorphin occurs before they are secreted in bony fish and mammals (Dores, 1994).  The lungfish POMC gene possesses a g-MSH sequence like the gene in tetrapods and unlike the gene in other fish (Lee, 1999).  Lungfish POMC is more similar to that of tetrapods, in both its sequence and the presence of g-MSH, than to teleosts.  Primitive actinopterygians also have a similar sequence and a g-MSH-like sequence (Amemiya, 1999b).

ANTERIOR PITUITARY

POSTERIOR PITUITARY

THYROID

     In humans, the thyroid gland secretes hormones such as calcitonin which regulate blood calcium levels (and effect many tissues ranging from skeletal tissues to the heart) and thyroxine which is essential for development and helps humans to maintain a constant body temperature.  Hormones equivalent to those of the thyroid gland existed in primitive organisms long before the evolution of warm-bloodedness, a bony skeleton, and the regulatory mechanisms of the vertebrate heart.

     Hypothalamic control over the production of TSH may be lacking in jawless fish.  In hagfish, the follicles of the thyroid tissue are separate and many of the follicles are avascular.  In lampreys, like higher fish, the follicles are concentrated in the ventral pharynx and have an ample blood supply.  In hagfish, alone among vertebrates, iodine is concentrated in the cytoplasm of follicular cells but not in the colloid around them. TSH has not been definitely identified in fish more primitive than bony fish. (Hoar, Vol. 2)

     Calcitonin and the ultimobranchial body are known in all gnathostomes (Hoar, Vol. 2; Shinohara-Ohtani, 1998).  The ultimobranchial glands of lungfish produce calcitonin and are structurally more similar to those of salamanders than to teleosts (Shinohara-Ohtani, 1998).  Mammals process the calcitonin gene to produce calcitonin and calcitonin gene-related peptide GGRP.  At high concentrations, CGRP reduces calcium levels as does calcitonin.  CGRP’s primary role is to control cardiovascular system and inhibit stomach secretion of acid (La Font, 2004).  Studies from fish and invertebrates indicate CGRP is the ancestral molecule.  In eels, CGRP is found in the brain, heart, as in mammals (La Font, 2004).

     The expression of the thyroid hormone distributor protein transthyretin in the liver and its release into the blood has evolved separately in different vertebrate groups.  The earliest eutherians apparently began to express transthyretin in the liver and release it into the blood, unlike the many marsupials, monotremes, reptiles, and amphibians.  Albumin and thyroxine binding globulin also bind thyroid hormones (Prapunpoj, 2000).

The following images are of the follicles of the human thyroid gland.

OPOSSUM

CAT

THE PARATHYROID

PANCREAS

    Although the human pancreas is primarily an exocrine structure which secretes digestive enzymes, about 1% of the cells secrete hormones and are an important part of the endocrine system.  Alpha cells secrete the hormone glucagons and beta cells secrete the hormone insulin, both of which control blood glucose levels.  These hormones were functional long before an organ homologous to the pancreas existed.

     Beta cells and the insulin they secrete are known in basal deuterostomes and some protostomes (Hoar). Mollusks have an insulin–like protein and the insect hormone bombyxin is also similar to insulin. (Chan, 1990).  Lancelets have a molecule which shares characteristics of insulin and insulin-like peptide and may be a transitional form between the two (Chan, 1990).  In lancelets, the endocrine cells which produce this insulin-like hormone are located in the GI tract but not until hagfish do they form a separate islet organ (Youson, 1999).

     Hagfish possess an islet organ where the extrahepatic bile duct empties into the intestine which is separated from the exocrine tissue.  Thus, the endocrine pancreas is older than the exocrine portion.  This islet organ does not synthesize glucagon and pancreatic peptides; the cells which do so are dispersed in the intestinal epithelia (Youson, 1999).  In hagfish B and D cells are present in the pancreatic islet tissue while in lampreys B, D, and F cells are present in those of adult lampreys.  Gnathostomes possess these three cell types plus A cells (Youson, 1999).  The endocrine pancreatic islets possess an ample blood supply from hagfish up.  The islets in hagfish are not innervated, unlike those of higher forms (Jansson, 1998).

   The pancreas has existed as a composite organ composed of endocrine islets dispersed in compact exocrine tissue since cartilaginous fish. (Hoar, Vol. 2; Biemar, 2001; Youson, 1999).  In some teleosts, the endocrine cells of the pancreas can form as two separate rows, only to fuse into one solid islet.  In other teleosts, the endocrine tissue may be distributed throughout the exocrine tissue similar to the condition in mammals (Biemar, 2001).

The following images depict the islets of the frog pancreas.

HUMAN PANCREAS

EXOCRINE TISSUE

ENDOCRINE TISSUE

ADRENAL GLANDS

     In humans, the adrenal glands are located over the kidneys.  The adrenal cortex secretes a number of hormones, such as the androgens which function in puberty, hair growth and sex drive, aldosterone which regulates salt reabsorption at the kidney, and the glucocorticoids which are anti-inflammatory and mediate many aspects of stress responses.  The adrenal medulla is the site where epinephrine and neurepineprhine are secreted into the blood during the fight or flight response.     In jawless fish, the cells corresponding to the adrenal cortex are diffuse.  Cartilaginous fish possess an adrenal gland near the kidney but it lacks chromaffin tissue which secretes epinephrine (Hoar, Vol. 2)  Chromaffin-like cells are present in the hearts of lampreys and higher vertebrates including mammals. (Webster, 1974, p. 127). 

The human adrenal gland is depicted below.

CAT

MONKEY