HORMONES

Raymond Oliver A. Cruz, MD

WHAT ARE HORMONES?
Hormones are chemical substances, present in very low concentrations in the blood, that regulate the metabolism of at least one specific organ or tissue n The site of secretion is distant from the target organ
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WHAT ARE GLANDS?
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A gland is a group of cells specialized to secrete hormones into the bloodstream

WHAT ARE RECEPTORS?
Receptors are proteins or glycoproteins that specifically binds a hormone and produces a biologic action after such binding n Have high specificity n May be found on the plasma membrane or inside the nucleus of the cell
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Comparison of Receptors with Transport Proteins
Feature Receptors Concentration Very low (thousands/cell) Binding affinity High (pmol/L to nmol/L Binding specificity range) Very high Saturability Yes Reversibility Yes Signal Yes transduction Transport Proteins Very high (billions/ Low (µ mol/L range) µ L) Low No Yes No

Feedback mechanisms are usually the means by which hormones are regulated n Before we discuss the individual hormones, we will first look into how these hormones work
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HORMONES CAN AFFECT ANY OF THE FOLLOWING STEPS:

Hormones can be thought of as signals, and receptors are signal detectors n Each component serves as a link in the communication process between extracellular events and chemical changes within the cell
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General Features of Hormone Classes
Types Solubility Transport Plasma half-life proteins Receptor Mediator Group I Steroids, Lipophilic iodothyronines, Yes calcitriol, retinoids Long (hours to days) Intracellular Receptor-hormone complex Group II Polypeptides, proteins, glycoproteins, Hydrophilic catecholamines No Short (minutes) Plasma membrane cAMP, cGMP, Ca2+ , metabolites of complex phosphoinositols, kinase cascades

Classification of Hormones by Mechanism of Action
I. Hormones that bind to intracellular receptors  Androgens  Calcitriol (1,25[OH]2-D3) Estrogens  Glucocorticoids  Mineralocorticoids  Progestins  Retinoic acid  Thyroid hormones (T3 and T4)

Classification of Hormones by Mechanism of Action
II. Hormones that bind to cell surface receptors A. The second messenger is cAMP
α 2-Adrenergic catecholamines β -Adrenergic catecholamines Adrenocorticotropic hormone (ACTH) Antidiuretic hormone (ADH,Vasopressin) Calcitonin Chorionic gonadotropin, human (hCG) Corticotropin-releasing hormone (CRH) Follicle-stimulating hormone (FSH) Glucagon Lipotropin Luteinizing hormone (LH) Melanocyte-stimulating hormone (MSH) Parathyroid hormone (PTH) Somatostatin Thyroid-stimulating hormone (TSH)

Classification of Hormones by Mechanism of Action
II. Hormones that bind to cell surface receptors B. The second messenger is cGMP

Atrial natriuretic factor (ANF) Nitric oxide (NO)

Classification of Hormones by Mechanism of Action
II. Hormones that bind to cell surface receptors C. The second messenger is calcium or phosphatidylinositols (or both)
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Acetylcholine (muscarinic) 1-Adrenergic catecholamines Angiotensin II Antidiuretic hormone(vasopressin) Cholecystokinin Gastrin Gonadotropin-releasing hormone (GnRH) Oxytocin Platelet-derived growth factor Substance P Thyrotropin-releasing hormone (TRH)

Classification of Hormones by Mechanism of Action
II. Hormones that bind to cell surface receptors D. The second messenger is a kinase or phosphatase cascade

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Adiponectin Chorionic somatomammotropin Epidermal growth factor Erythropoietin Fibroblast growth factor Growth hormone Insulin Insulin-like growth factors I and II Leptin Nerve growth factor Platelet-derived growth factor Prolactin

SPECIFICITY AND SELECTIVITY

A cell may have no hormone receptors (1), have one receptor (2+5+6), have receptors for several hormones (3), or have a receptor but no hormone in the vicinity (4).

SIGNAL TRANSDUCTION BY INTRACELLULAR RECEPTORS
Utilized by molecules such as steroid hormones, Vitamin D, retinoic acid, and thyroxine n Act through intracellular receptors located in the cytosol or the nucleus n Why do you think these classes of hormones can enter the cell?  Ans: They are all lipid-soluble
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Repressor removed

TRE- Thyroid response element HSP- heat shock protein

GRE- glucocorticoid response element - transcribed gene +

SIGNAL TRANSDUCTION BY INTRACELLULAR RECEPTORS
The effects of agonists acting through intracellular receptors are not immediate n For example, hours to days are required to achieve the therapeutic effects of steroids for the treatment of asthma n How do steroids help in the treatment of asthma?
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TRANSDUCTION BY CELLSURFACE RECEPTORS
Initiated by ligand binding to receptors located in the plasma membrane n In contrast to intracellular receptors, cell surface receptors do not regulate gene expression directly n Do they also need to be lipophilic to be effective?
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G-PROTEIN COMPLEX

E can be adenylyl cyclase, Ca2+, Na+, or Cl– channels, or it could be a K+ channel, phospholipase C, or cGMP phosphodiesterase

There is a large family of G proteins, and these are part of the superfamily of GTPases n The G protein family is classified according to sequence homology into four subfamilies (See table 43-3 of Harpers 26th ed.) n Some G proteins are also involved in olfaction and vision
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3 GENERAL CLASSES OF CELLSURFACE RECEPTORS

1. NEUROTRANSMITTER RECEPTORS LINKED TO ION CHANNELS
The receptor and ion channel are part of a single multimolecular complex n Seen in nerve and muscle (GABA, acetylcholine) n The binding of a neurotransmitter causes a rapid opening of ion channels that are selectively permeable to certain ions (remember your action potential in physiology?)
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2. CATALYTIC RECEPTORS
Have an inherent enzymatic activity as part of their structure n In most cases the enzyme activity is a tyrosine-specific protein kinase n For example, the binding of insulin to its receptor activates the intrinsic tyrosine kinase activity to initiate insulin’s effects
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3. RECEPTORS INVOLVING SECOND MESSENGERS
Many receptors signal their recognition of a bound hormone neurotransmitter by initiating a series of reactions that ultimately result in a specific intracellular response n These intracellular messengers serve to amplify signals to initiate its effects
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INTRACELLULAR MESSENGER SYSTEMS
“Second messenger” molecules n Intervene between the original message (the hormone) and the ultimate effect on the cell n Are the hormones that utilize second messengers usually lipophilic or not?  Ans: They are usually not lipophilic, so they use these 2nd messengers to initiate their effects on cell function
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ADENYLATE CYCLASE SYSTEM
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A membrane-bound enzyme that converts ATP to 3’, 5’-adenosine monophosphate (also calles cyclic AMP or cAMP)

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PKA exists in an inactive form as an R2C2 heterotetramer consisting of two regulatory and two catalytic subunits. cAMP generated by the action of adenylyl cyclase binds to the regulatory (R) subunit of PKA. This results in dissociation of the regulatory and catalytic subunits and activation of the latter.

The active catalytic subunits phosphorylate a number of target proteins on serine and threonine residues. Phosphatases remove phosphate from these residues and thus terminate the physiologic response. A phosphodiesterase can also terminate the response by converting cAMP to 5'-AMP.

Subclassification of Group II.A Hormones.
Hormones That Stimulate Adenylyl Cyclase (HS) Hormones That Inhibit Adenylyl Cyclase (HI)

ACTH ADH β -Adrenergics Calcitonin CRH FSH

Glucagon hCG LH LPH MSH PTH TSH

Acetylcholine α 2-Adrenergics Angiotensin II Somatostatin

In prokaryotic cells, cAMP binds to a specific protein called catabolite regulatory protein (CRP) that binds directly to DNA and influences gene expression. n In eukaryotic cells, cAMP binds to a protein kinase called protein kinase A (PKA) that is a heterotetrameric molecule consisting of two regulatory subunits (R) and two catalytic subunits (C).
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Inhibitors of phosphodiesterase, most notably methylated xanthine derivatives such as caffeine, increase intracellular cAMP and mimic or prolong the actions of hormones through this signal

CALCIUM-PHOSPHATIDYLINOSITOL SYSTEM n Many receptors respond
to hormones by activating a membrane-bound phophodiesterase called Phospholipase C Activated Phospholipase C subsequently cleaves membranebound phophatidylinositol 1,4,5-trisphosphate, releasing two fragments (inositol

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Inositol 1,4,5trisphosphat e (IP3) binds to receptors on the endoplasmi c reticulum, causing a rapid release of calcium from intracellular stores

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Released calcium ions permits the formation of a calciumcalmodulin complex that mediates a wide variety of effects

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IP3 is a shortlived signal and is inactivated to inositol 1,4bisphosphat e and inositol 1phosphate

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Diacylglycerol n (DAG) activates n protein kinase C, an enzyme that phosphorylates proteins Protein kinase C requires calcium for maximum activity DAG and IP3 act synergistically to cause increased phosphorylation of proteins

WHAT IS CALMODULIN?
Calmodulin is a protein that acts as a mediator of calcium-linked effects in the cell n It is structurally and functionally related to troponin C, which mediates the role of calcium in skeletal and cardiac muscle contraction
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CYCLIC GUANOSINE MONOPHOSPHATE
Analogous to the cAMP pathway n Synthesized from GTP by a membranebound form of guanylate cyclase n Activates cGMP-dependent protein kinase or protein kinase G n Action also terminated by phophodiesterase
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CYCLIC GUANOSINE MONOPHOSPHATE
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Unlike cAMP which affects a wide variety of processes, cGMP functions as a specialized messenger, being involved in smooth muscle relaxation, platelet aggregation, and the visual system

CYCLIC GUANOSINE MONOPHOSPHATE
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Nitroprusside, nitroglycerin, nitric oxide, sodium nitrite, and sodium azide, all cause smooth muscle relaxation and are potent vasodilators. These agents increase cGMP by activating the soluble form of guanylyl cyclase, and inhibitors of cGMP phosphodiesterase (the drug sildenafil [Viagra], for example) enhance and prolong these responses

Insulin Transmits Signals by Several Kinase Cascades
Tyrosine (Y)

JAK-STAT signaling pathway
Takes part in the regulation of cellular responses to cytokines and growth factors n Cytokines are a group of proteinaceous signalling compounds that, like hormones and neurotransmitters, are used extensively for inter-cell communication.
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JAK-STAT signaling pathway
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Employing Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs), the pathway transduces the signal carried by extracellular polypeptides to the cell nucleus, where activated STAT proteins modify gene expression

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JAKs, which have tyrosine kinase activity, bind to some cell surface cytokine receptors The binding of the ligand to the receptor triggers activation of JAKs. Jak-P, an active kinase, phosphorylates the receptor on tyrosine residues The STAT proteins associate with the phosphorylated receptor and then are themselves phosphorylated by Jak-P STAT dimerizes, translocates to the nucleus, binds to specific DNA elements, and regulates transcription

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The transcription factor NF- κ B (Nuclear Factor kappa B) is a heterodimeric complex typically composed of two subunits termed p50 and p65

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Normally, NF- κ B is kept sequestered in the cytoplasm in a transcriptionally inactive form by members of the inhibitor of NF- κ B (Iκ B) family

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Extracellular stimuli such as proinflammatory cytokines, reactive oxygen species, and mitogens lead to activation of the Iκ B kinase complex, IKK, which is a heterohexameric structure consisting of α , β , and γ subunits.

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IKK phosphorylates Iκ B on two serine residues, and this targets Iκ B for ubiquitination and subsequent degradation by the proteasome

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Following Iκ B degradation, free NF- κ B can now translocate to the nucleus, where it binds to a number of gene promoters and activates transcription, particularly of genes involved in the inflammatory response

Glucocorticoid hormones are therapeutically useful agents for the treatment of a variety of inflammatory and immune diseases n Their anti-inflammatory and immunomodulatory actions are explained in part by the inhibition of NFκ B and its subsequent actions.
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Evidence for three mechanisms for the inhibition of NF- κ B by glucocorticoids has been presented:

(1)Glucocorticoids increase Iκ B mRNA, which leads to an increase of Iκ B protein and more efficient sequestration of NF-κ B in the cytoplasm (2)The glucocorticoid receptor competes with NFκ B for binding to coactivators (3)The glucocorticoid receptor directly binds to the p65 subunit of NF- κ B and inhibits its activation
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Incorrect regulation of NF-κ B has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development

HOW DO HORMONES AFFECT TRANSCRIPTION?
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(1)Hormones allow the access of transcription factors to DNA (2)Genes have regulatory regions, and transcription factors bind to these to modulate the frequency of transcription initiation (3)Hormone-receptor complexes bind to hormone response elements (HRE’s) to initiate transcription (4)Other hormone-generated signals can modify the location, amount, or activity of transcription factors and thereby influence binding to the regulatory or response element

WHAT IS A HORMONE RESPONSE ELEMENT?
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A hormone response element (HRE) is a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription The sequence is most commonly a pair of inverteD repeats separated by three nucleotides, which also indicates that the receptor binds as a dimer A gene may have many different response elements, allowing complex control to be exerted over the level and rate of transcription.

Hormone response elements resemble enhancer elements in that they are not strictly dependent on position and location n They generally are found within a few hundred nucleotides upstream (5') of the transcription initiation site, but they may be located within the coding region of the gene
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The DNA Sequences of Several Hormone Response Elements (HREs)
Hormone or Effector HRE DNA Sequence

Glucocorticoids Progestins Mineralocorticoids Androgens Estrogens Thyroid hormone Retinoic acid Vitamin D cAMP

GRE PRE MRE ARE ERE TRE RARE VDRE CRE

Members of the nuclear receptor family are divided into six structural domains (A–F) n Domain A/B is also called AF-1, or the modulator region, because it is involved in activating transcription
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The C domain consists of the DNA-binding domain (DBD) n The D region contains the hinge, which provides flexibility between the DBD and the ligand-binding domain (LBD,
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The LBD binds hormones or metabolites with selectivity and thus specifies a particular biologic response n The F region is poorly defined
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Functional Anatomy of the Hypothalamus and Pituitary Gland The hypothalamus is a region of the brain that controls an immense number of bodily functions n It is located in the middle of the base of the brain, and encapsulates the ventral portion of the third ventricle.
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Hypthalamus Optic chiasm

Pituitary Gland

HYPOTHALAMIC HORMONES
Controls the release of pituitary hormones n Hypothalamic hormones are released from the hypothalamic nerve fiber endings around the capillaries of the hypothalamic-hypophysial system in the pituitary stalk n Released in a pulsatile manner
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PITUITARY HORMONES

GROWTH HORMONE (GH)
Also called somatropin or somatotropin n Synthesized in somatotropes, a subclass of the pituitary acidophilic cells n The genes for human growth hormone are localized in the q22-24 region of chromosome 17
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Disulfide bonds

GROWTH HORMONE (GH)
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Peptides released by neurosecretory nuclei of the hypothalamus into the portal venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotropes.

GROWTH HORMONE (GH)
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Growth hormone releasing hormone (GHRH) from the arcuate nucleus of the hypothalamus and ghrelin* promote GH secretion, and somatostatin from the periventricular nucleus inhibits it.

Secretes GHRH

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Ghrelin is a hormone produced by P/D1 cells lining the fundus of the human stomach that stimulate appetite Ghrelin levels increase before meals and decrease after meals It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels.

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Much of the growth hormone in the circulation is bound to a protein (growth hormone binding protein, GHBP) which is derived from the growth hormone receptor

Growth hormone receptor is a member of the cytokine receptor superfamily. n One growth hormone molecule binds to one receptor and then recruits a second receptor to form a dimer through which signalling occurs.
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The effects of growth hormone on the tissues of the body can generally be described as anabolic

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Height growth in childhood is the best known effect of GH action, and appears to be stimulated by at least two mechanisms: 1. GH directly stimulates division and multiplication of chondrocytes of cartilage. These are the primary cells in the growing ends (epiphyses) of children's long bones

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2. GH also stimulates production of insulin-like growth factor 1 (IGF1, formerly known as somatomedin C), a hormone homologous to proinsulin  The liver is a major target organ of GH for this process, and is the principal site of IGF-1 production  IGF-1 has growth-stimulating effects on a wide variety of tissues.  Additional IGF-1 is generated within target tissues, making it apparently both an endocrine and an autocrine/paracrine hormone.  IGF-1 will also have stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.

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GROWTH HORMONE (GH)
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GH secretion is also affected by negative feedback from circulating concentrations of GH and IGF-1

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EFFECTS OF GROWTH HORMONE
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Stimulators of GH secretion include exercise, hypoglycemia, dietary protein, and estradiol. Inhibitors of GH secretion include dietary carbohydrate and glucocorticoids. Increases the transport of amino acids into muscle cells and also increases protein synthesis Antagonizes the effects of insulin Decreases the peripheral utilization of glucose Increases hepatic glucose glucose production via gluconeogenesis

EFFECTS OF GROWTH HORMONE
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In liver, GH increases liver glycogen Promotes the release of free fatty acids and glycerol from adipose tissue Increases oxidation of free fatty acids in the liver Promotes a positive calcium, magnesium, and phosphate balance Causes retention of sodium, potassium and chloride ions Promotes the growth of long bones Stimulates lactogenesis

Genetic deficiencies associated with GH
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GH-deficient dwarfs lack the ability to synthesize or secrete GH, and these shortstatured individuals respond well to GH therapy Pygmies lack the IGF-1 response to GH but not its metabolic effects; thus in pygmies the deficiency is post-receptor in nature Laron dwarfs have normal or excess plasma GH, but lack liver GH receptors and have low levels of circulating IGF-1. The defect in these individuals is clearly related to an inability to respond to GH by the production of IGF-1

The production of excessive amounts of GH before epiphyseal closure of the long bones leads to gigantism n When GH becomes excessive after epiphyseal closure, acral bone growth leads to the characteristic features of acromegaly
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PROLACTIN
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Peptide hormone synthesized and secreted by lactotrope cells in the anterior pituitary gland Prolactin is a single chain polypeptide of 199 amino acids with a molecular weight of about 24,000 daltons The molecule is folded due to the activity of three disulfide bonds

The prolactin receptor - encoded by a gene on Chromosome 5 - interacts with the prolactin molecule as a transmembrane receptor n A specific second messenger has not yet been identified.
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Pituitary prolactin secretion is regulated by neuroendocrine neurons in the hypothalamus, most importantly by neurosecretory dopamine neurons of the arcuate nucleus, which inhibit prolactin secretion.

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Prolactin has many effects, the most important of which is to stimulate the mammary glands to produce milk (lactation). Increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands of the breasts and increases the production of milk. However, the high levels of progesterone during pregnancy act directly on the breasts to stop ejection of milk. It is only when the levels of this hormone fall after childbirth that milk ejection is possible.

Another effect, recently discovered by the University of Paisley and the Technische Hochschule Zürich, is to provide the body with sexual gratification after sexual acts n The hormone represses the effect of dopamine, which is responsible for sexual arousal, thus causing the male's refractory period. The amount of prolactin can be an indicator for the amount of sexual satisfaction and relaxation. Unusual high amounts are suspected to be responsible for impotence and loss of libido
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The prolactin receptor, a member of the hematopoietin/cytokine receptor superfamily, is ubiquitously expressed by cells in the immune system n Certain subpopulations of lymphocytes synthesize and secrete biologically active prolactin, which suggests that prolactin can act as an autocrine and/or paracrine factor to modulate the activities of cells of the immune system.
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Tumors of prolactin-secreting cells cause amenorrhea and galactorrhea in women n Excess PRL is associated with gynecomastia and impotence in men
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CHORIONIC SOMATOMAMMOTROPIN (CS; PLACENTAL LACTOGEN)
a polypeptide placental hormone n structure and function is similar to that of human growth hormone n modifies the metabolic state of the mother during pregnancy to facilitate the energy supply of the fetus n HPL is an anti-insulin.
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