Endocrine, Paracrine, Autocrine Signaling

• Hormones, receptors, and signal transduction alter the psychological functions of the body

Cell Communications

• Gap junctions facilitate the passage of inorganic ions and small molecules from one cell to another
• Chemical signals include ions, hormones, neurotransmitters, and growth factors
• Chemical signals are transmitted via a secondary messenger, with the exception of steroids
• Steroids diffuse across the plasma membrane and interact with cytosolic or nuclear receptors

Cell Communications by Hormones

• Endocrine Communication: A specific cell type produces a hormonal response to another cell that needs an affinity
• Paracrine Communication: Cells are side-by-side
• Autocrine Communication: Cell has both chemical-producing and receptor functions

Endocrine System

• The endocrine system integrates organ function through hormones secreted from glands into the extracellular fluid
• Hormones are carried through the blood to distant target tissues
• Hormones are recognized by specific, high-affinity receptors
• A hormone is recognized by its target tissue, it can exert its biological action by signal transduction

Chemical Classification of Selected Hormones

• Hormones are peptides, metabolites of single amino acids, or metabolites of cholesterol
• Peptide hormones bind to cell-surface receptors and activate various signal transduction systems
• Amine hormones are made from tyrosine and tryptophan and act through surface receptors
• Thyroid hormones bind to intracellular receptors as steroids to regulate metabolic rate
• Steroid hormones are derived from cholesterol
• Steroid hormones bind to intracellular receptors that regulate gene transcription by activating a steroid response element

Hypothalamic and Anterior Pituitary Peptides

• The hypothalamus releases TRH, GnRH, CRH, Somatostatin, GHRH, and Dopamine
• The anterior pituitary releases Thyrotroph, Gonadotroph, Corticotroph, Somatotroph, and Lactotroph

Dopamine Inhibition of Prolactin

• Dopamine makes people happy; to produce milk by the mammary gland, dopamine must be suppressed
• Decrease dopamine for breastfeeding which may lead to postpartum depression
• Dopamine inhibits prolactin through the following:
  • Gai protein-mediated inhibition of cAMP production
  • Gi dimer-mediated activation of inward rectifier K+ channels and inhibition of voltage-gated Ca2+ channels
  • Activation of the g-protein leads to inhibition of cAMP
  • An activate Beta leads to K+ activation and inhibits Ca 2+

Activating Protein Kinase A (PKA)

• cAMP-dependent kinase (PKA) is composed of two regulatory (R) and two catalytic (C) subunits
• Binding of cAMP to the regulatory subunits induces a conformational change
• A reduction in affinity for the catalytic subunits is achieved
• Protein Kinase G (PKG) by cyclic guanosine monophosphate is similar

Peptide Hormones and Their Signal Transduction Pathways

• Hormone concentration is important for specifying selectivity

• Agonists and Linked Enzymes:

  • GHRH, CRH, ANG II, PTH/ Coupled to Gas/ Adenylyl cyclase
  • Somatostatin, ANG II, Dopamine/ Coupled to Gai/Adenylyl cyclase
  • TRH, GnRH, AVP, ANGII/ Coupled to Gag/ PLC
  • ANG II/ Coupled to G₁/G₀/ PLA2
  • ANP/ Guanylyl cyclase/Guanylyl cyclase
  • Insulin, IGF-1, IGF-2, EGF, PDGF/ Tyrosine kinase/ Tyrosine kinase
  • GH/ Associated with tyrosine kinase/ of tyrosine kinases

• Ang II acts at different places, which results in concentration differences

Receptors of Peptide Hormones

• Guanylyl cyclase receptors have an extracellular ligand-binding domain
• Ligand-binding leads to receptor dimerization and activation of guanylyl cyclase activity, converting GTP to cGMP

Receptors Serine/Threonine kinases

• Receptor serine/threonine kinases have two subunits, each with intrinsic serine/threonine kinase activity
• The ligand binds to the type-ll subunit, causing it to transphosphorylate the type-l subunit at serine and threonine
• This phosphorylation activates the type-l subunit, phosphorylating intracellular proteins at serine or threonine residues

Receptor Tyrosine Kinases

• There are two classes of RTKs
• Ligand binding to NGF receptors dimerizes and activates tyrosine kinase
• The monomers in the dimer phosphorylate each other and downstream effectors
• Ligand binding to the insulin receptor causes conformational changes in the pairs, activating tyrosine kinases.
• The activated B-subunits phosphorylate each other and downstream effectors

G-protein Via Adenylyl Cyclase (AC)

• G-protein coupled receptor activates a heterotrimeric G protein (as or ai).
• Adenylyl cyclase is activated (by as) or inhibited (by ai)
• Intracellular cAMP is formed from ATP catalyzed by adenylyl cyclase.
• cAMP binds to and activates the enzyme protein kinase A (PKA).
• The two catalytic subunits of PKA separate
• Serine and threonine residues are phosphorylated on various cellular enzymes and other proteins by the free catalytic subunits of PKA
• Modified phosphorylation leads to modified cellular function.
• The activation signal is terminated via:
  • Phosphodiesterases (PDE)
  • Serine/threonine-specific protein phosphatases

G-protein Via Phospholipase C (PLC)

• A ligand binds to a receptor coupled to alpha q thus activating phospholipase C (PLC).
• PLC converts PIP2 to IP3 and DAG.
• IP3 leads to the release of Ca2+ from intracellular stores, which activates Ca2+-dependent kinases and protein kinase C (PKC)
• DAG activates protein kinase C (PKC) to alter cellular functions.

G-protein Via Phospholipase A (PLA2)

• Binding of a ligand to activates Ga₁ or Ga11
• Membrane-bound PLA₂ is stimulated by activated Ga.
• Membrane phospholipids are cleaved by PLA₂ to produce lysophospholipid and arachidonic acid.
• Arachidonic acid is converted to prostaglandins, prostacyclins, thromboxanes, and leukotrienes.

Chromosomes

• Chromosomes are nuclear structures contain a linear thread of DNA that transmit genetic information

Human Karyotypes

• A full set of chromosomes in a cell is a karyotype
• Humans have 2 types of chromosomes:
  • A single pair of sex chromosomes
  • 22 pairs of autosomal chromosomes (autosomes)
• Females have two X chromosomes
• Males have one X and one Y chromosome

Types of Cell Division in Reproduction

• Mitosis occurs in somatic cells for growth
• Meiosis occurs only in germ cells for the production of male and female gametes
• Mitosis forms two identical daughter cells with the same number of chromosomes as the original cell
• Mitosis consists of five phases: prophase, prometaphase, metaphase, anaphase, and telophase
• Reasons for genetic identity in mitosis
  • No exchange of genetic material occurs between homologous chromosomes
  • Sister chromatids of each chromosome split, one going to each daughter cell during anaphase

Meiosis

• Occurs in germ cells (spermatogonia in males, and oogonia in females), yielding four haploid daughter cells
• Involves two divisions: homologous chromosomes separate during meiosis-1, and chromatids separate during meiosis-2
• Division-1 involves recombination and reduction to the haploid number of chromosomes
• Division-2 separates the sister chromatids, similar to mitosis
• A zygote's genetic sex is established at fertilization, when an X- or Y-bearing sperm fertilizes an oocyte
• Gonadal dysgenesis starts at puberty

Meiosis in Male (spermatogenesis) and Female (oogenesis)

• A major difference between male and female gametogenesis is that 1 spermatogonium yields 4 spermatids, whereas 1 oogonium yields 1 mature oocyte and 2 polar bodies

Genetic Aspects of Sexual Differentiation

• A zygote's genetic sex is established by an X- or Y-bearing sperm fertilizing an oocyte
• Parent sex chromosomes determine the offspring's genotypic sex
• Genotypic sex determines the gonadal sex
• Gonadal sex determines the phenotypic sex that becomes fully established at puberty

Epigenetics

• An epigenetic modification is a change in phenotype, but it does not change the genotype and can be inherited
• Epigenetics indicates cellular characteristics that are heritable by daughter cells without changing the underlying DNA sequence
• Epigenetic changes involve many changes in DNA methylation and histone modification
• Histones are major protein components of chromatin. They are important for gene regulation
• Epigenetic changes are caused by modifications of DNA/histone complexes
• Epigenetic changes fundamentally dictate gene activity modifying chromatin accessibility
• Epigenetic changes are influenced by environmental factors, lifestyle, age and disease state
• In a fetus, epigenomes direct stem cell development
• DNA methylation is where methyl groups attach directly to DNA strands
• An equilibrium between methylation and de-methylation directs healthy cell growth and differentiation
• Traditional genetics determine sex

Determination of Gonadal Sex

• Gonadal sex is determined by an outer cortex and an inner medulla
• The testis medulla develops into the medulla
• The cortex regresses and becomes a testis
• The ovary cortex develops into the cortex
• The medulla regresses and becomes an ovary
• Chromosomes exert a testis-determining effect
• When the primary sex cords differentiate, male sex is established and seminiferous tubules form

Factors Influencing Gonadal Sex

• The Y chromosome exerts a testis-determining effect
• The male sex is established and the primary sex cords differentiate into seminiferous tubules.
• In the absence of a Y chromosome, the indifferent gonad develops into an ovary
  • In embryos with XX chromosomes, the cortex develops into ovaries, and the medulla degenerates.
• In embryos with XY chromosomes, the medulla differentiates into a testis, and the cortex regresses.

Testis-determining Gene

• The testis-determining factor (TDF) is a single gene on the Y chromosome's short arm, also known as SRY (Sex-determining Region Y)
• TDF is necessary for normal testicular development
• The TDF may be found translocated on other chromosomes
• An XX male is an individual whose sex chromosome is XX but is phenotypically male.
• There is a presence of an abnormal exchange of genetic material between X and Y chromosomes
• If the sperm that fertilizes an ovum contains the defective X chromosome with a the TDF, the individual develops into a male
• XX males are sterile, have small testes and may display feminine characteristics

Gonadal Dysgenesis

• A term used when the sex chromosomes are abnormal
• Loss of one of the X chromosomes of the XX pair results in ovarian dysgenesis
  • In an XO individual, the gonads appear as lines in the adult
  • Turner syndrome is gonodal dysgenesis
  • Disorder of the female sex characterized by short stature, primary amenorrhea, sexual infantilism, and other congenital abnormalities
  • Karyotype of individuals with Turner syndrome is 45,XO

SRY Gene-Related Anomalies

• There are two genes which are associated to be linked to development
• Discordance between genotype and gonadal phenotype

Transformations of the Genital Ducts

• Before 9 weeks of pregnancy there are important parts used to form male
  • If those important parts are not present or working, then this is not possible
  • 1. an adequate amounts of steroid
  • 2. ant-mullerian hormone to suppress feminine gender
• In the indifferent duct system, the mesonephric and paramesonephric ducts are distinguished
• Bilateral removal of the testes results in female ducts and genitalia in the genetically male fetus
  • Female duct develops if the removal of ovaries (during early castration)
  • Müllerian development continues along normal female lines. Ovary is not required for female duct development

Differentiation of the Internal Genital Ducts

• 8-9 weeks gestation
• Embryos have double sets of genital ducts
• Males: mesonephric or wolffian ducts develops into vas deferens, seminiferous tubules, and ejaculatory duct Females: paramesonephric or mullerian ducts develops into oviducts, uterus, and upper third of vagina Wolffian ducts require testosterone
• In a normal male: wolffian ducts develop (females mullerian ducts degenerate)
• In a normal female: paramesnephric develops (males wolffian ducts degenerate)

Factors affecting differentation of internal genital ducts

• Bilateral removal of the testes deprives the embryo of testosterone and anti-mullerian hormone
• If the removal of ovaries occurs, then it is not required for female duct development
• Unilateral removal of the testis leads to female ducts on the side of the castration, duct develops on the remaining testes
• If there is an absence of testes, then the wolffian ducts can develop, and müllerian regression can occur

Absence of Testes

• In the absence of the testes and both testes a - administering testosterone wolffian ducted can develope
• In the pesence of both ovaries- the testoterone promote development of the wolffian ducts, without testes
• Both mullerlian ducted is created by an ovarian system which has not amh
• In unilateral - remial both a femae duct system will be created

Male pattern of sexual differentiation

• The testis and the containted andogen is used to create males
• This pattern requires the following in the male:
  • Testosterone
  • dihydrotestosterone
  • anti-müllerian (AMH)
• The tesit produces testosterone and AMH
• If the product tdf occurs after 9 weeks, then an ovary will develop

Factors Involved

• The male pattern allows differentiation
• The androgens allows testosterioene

  • will trigger conversion of the Wolffian duct which equals the male ejaculatory, this requires DHT

    Phases of Male Sexual Differentiation

  • wolffian phase regulated by testosterone

  • Virilization requires DHT

• DHT: steroid reception compared to the testosterone

Factors That Influence Differentation Systems

• Sertili cells creates antifertility which allow ducts to regression
• The leydig cells began to produce the testosterone - leydig has testosterone - sertili cells release amh

Sertoli Cells

• Sertili cells also produces a androgen binding potein to maintain a concentration and differention - wolffian system remains un-formed

Testosterone

• Cells lack5aloh so reduce (williot) and not converted to DHT for se development prostate

Differentiation External Genitalia

• The 5oh is going is used to create and are capble in converting the exterior
  • The converse 5oh, the 5oh is associated with the normal for creation

Female Pattern of Sexual Differentiation

• Female Pattern: - Is directy of enocrine and paracrine control - There is NO TESTERONE in the wolffian ducts

Imp Hormones and sex determination

• Sex differentaion

Congenital Adreanal Hyperplasma

• ambiginous is known to is know to create

There has to be 21- hydroxylze deficiency of to accounts of 95

• All adrenal steriod causes a sign to make the andgenital system
• In is difficult which creates a normal female by is a rare genetic condition called CAH

Functions of Androgen

• Play 2 major roles

2 Types that are presented

• Is when the Testosterione deficenent states
• Is when are defects leads to when in male
• Activity of that is created by the andgeron
• Testoterioene leads to

DHT

• This is an area to has 2 receptors
• Androgyn is a member of family and is bound has to be a good
• Congenta absence- leads to what the leads to

AMH

• Glycoprotein and the test produces amm and mis
  • This what the androgens that are needed
  • Testosterone is need for all sex

Steroid and hormoses

• THeres GR , MR and is used in receptor

Sterroid homeros - the steroid is on the cell which allos steroid to create

• Homroes and by that is is used
• The cel activated by is used stimulate the genea

Endo and paracrin

• By a ceel in the tissue which does auto

Explore cell signaling methods, including endocrine, paracrine, and autocrine. Learn about hormone transport, steroid hormone mechanisms, and cell communication. Investigate growth factors and hormone classes.