final Flashcards

Question

Activation and inactivation of hormones - half lives - ex. of deg enz

Answer 1

Activation – metabolism of the precursor or release from carrier protein activation 1. Prohormone – inactive form of hormone often present in the blood a. Common with peptide hormones – must undergo proteolytic activation 2. Released hormone has a half life in the blood – effects efficacy a. Affinity to carriers will be influenced by energy required to synthesize hormones • Steroids require lots of energy – will bind more tightly to carriers to prevent release and degradation in the blood • AA derived – require less energy & won’t bind to carriers as tightly b. General half lives • Singe AA derivatives – 1 minute • Peptide hormones – minutes to hours • Steroid hormones – hours 3. Free hormones bind to receptors of cells – either membrane bound or within cytosol or nucleus  response a. Response generally resets balance in response to change – often negative feedback Inactivation 1. Enzymatic degradation a. Endopeptidases – enzyme that degrades peptide bonds in the interior of an AA chain • Ex. trypsin – general endopeptidase b. Exopeptidases – enzymes that release single AA from peptides chains by removing from the ends 2. Hormone receptor complex endocytosis – complex is taken into cell and inactivated 3. Conjugation – chemical group is attached a. Sulfation – common for steroids • Improves water solubility – will be present in solution, filtered by the kidney, and excreted 4. Inactive proteins can be excreted when no longer required by the body

Answer 2

1. Neuroendocrine responses – combine neuronal and hormonal processes a. Activation of neuron causes release of neurotransmitters from axon terminal -> acts directly on target cells (does not enter bloodstream) -> endocrine response i. Ex. knee jerk response ii. Uses neurotransmitters – still a neuroendocrine response b. Activation of neuron causes release of neurohormones from axon terminal -> enters into bloodstream -> acts on target cells -> endocrine response 2. Hormone release with stimulation from neuron a. Neurotransmitter is released from axon terminal onto endocrine gland -> causes release of hormone -> enters bloodstream 3. Complex neuroendocrine a. Neurohormone released from axon terminal -> travels through bloodstream and stimulates endocrine gland -> causes release of hormone

Answer 3

Not the same as neuroendocrine Estrogen functions in neuromodulation 1. Diffuse modulatory systems – neurons diffused throughout the brain that regulate many physiological functions and behaviour a. Norepinephrine, Ach, serotonin, dopamine 2. Estrogens – reset the balance and receptivity of diffuse modulation systems a. Can govern mood, appetite, and are involved in mood disorders (ex. depression and bipolar and anxiety)

Answer 4

Levels of dysfunction o Primary dysfunction – site of lesion for the active non tropic hormone (ex. adrenal gland, thyroid gland) o Secondary dysfunction – dysfunction elsewhere in endocrine pathway o Tertiary dysfunction – dysfunction at site of action of the hormone (ex. end organ resistance) Ex. exogenous cortisol a. CRH is released from hypothalamus -> stimulates ACTH release from ant pit -> stimulates release of cortisol from adrenal cortex b. Primary dysfunction – occurs at adrenal cortex in release of cortisol • This is the hormone that actually causes the response Types of dysfunction 1. Hyposecretion – can be primary or secondary; too little hormones or response a. Usually the result of atrophy of the endocrine gland i. Normally treated through replacement therapy – supply of substance lacking in body b. Target cells may lack receptors or biochemical machinery at the target cell i. Ex. hyperinsulinemia – type II diabetes - There lots of insulin but response is malfunctioning 2. Hypersecretion – primary or secondary; too much hormone or response a. Usually the result of a benign tumor (adenoma) i. Normally treated through inhibition (antagonists) b. Target cell responsiveness is altered naturally (decreased response due to decreased hormones present)

Answer 5

1. Up and down regulation – receptors at the target cell are regulated in response to hormone levels which influence abundance and affinity of hormone a. Binding kinetics – how fast a compound binds to target and dissociates from it i. Types and effects - Competitive and allosteric - Agonistic and antagonistic ii. Reliant on abundance and affinity b. Law of mass action (pg 47-48) – determines concentration of [hormone] and [receptor] vs [hormone receptor complexes] - Equilibrium – association constant (Ka) drives the reaction both ways depending on the concentration of each - At equilibrium: [hormone] x [receptors] x Ka = [hormone receptor complex] x Kd i. Ka = association constant - High Ka = high binding affinity or high [hormone] ii. Kd = dissociation constant - High Kd = low binding affinity or low [hormone] c. Not all hormones complexes follow the law of mass action i. Non cooperative  law of mass action is upheld ii. Positively cooperative  ligand binding increases receptor affinity of vacant receptors iii. Negatively cooperative  ligand binding decreases receptor affinity of vacant receptors 2. Permissiveness – hormone cannot have full effect without another hormone being present a. Ex. T3 3. Synergism – the combined effect of multiple hormones is greater than the sum of the parts a. Ex. blood glucose levels are increased by the presence of cortisol and epinephrine 4. Antagonism – one hormone reduces the effectiveness of another hormone; can be direct or indirect a. Pharmaceutical applications – drugs able to bind to receptors to inhibit the actions of an endogenous hormone/signaling molecule b. Also occurs naturally

Answer 6

1. Membrane bound a. ligand gated; enzyme linked; guanylyl cyclase and GPCR i. most common is GPCR - 7 trans membrane domains (7 MSR) ii. enzyme linked - normally 1 MSR (single pass) - ex. insulin receptors iii. important in the NS and other excitable cells b. Second messenger systems i. Adenylate cyclase - Linked GPCR ii. Guanylate cyclase - Linked to guanylyl cyclase receptors (1 MSR) iii. Inositol phosphate and diacyl glycerol - Linked to GPCR 2. Nuclear receptors – most lipophilic hormones act through; often a genomic response a. Steroid hormone i. Bind in cytoplasm or nucleus – will form a ligand transcription factor - Affects transcription of genes and mRNA -> proteins ii. Initially thought that all steroid acted through nuclear receptors - More rapid response discovery in recent years indicates membrane bound receptors activation - There are membrane bound receptors for progesterone, estrogen, thyroid hormones (all lipophilic)

Answer 7

- Infundibulum – stalk that connects the pituitary to the brain/hypothalamus - Sphenoid bone – surrounds the pituitary gland Posterior pituitary – nervous tissue a. Extension of the neural tissue - Directly connected to hypothalamus - Neural embryonic origin b. Nomenclature - Pars nervosa - Neurohypophysis Anterior pituitary – glandular origin a. True endocrine gland of epithelial origin - Trophic hormones typically stimulate production of hormones within ant pit b. Nomenclature - Pars distalis - Adenohypophysis Intermediate pituitary – pars intermedia a. Disappear in humans by the time were born - Play a larger role in nonhuman animals - Mainly produces alpha melanocyte stimulating hormone (MSH)

Answer 8

Neuroendocrine system between the hypothalamus and posterior pituitary Cell bodies originate in the hypothalamus -> axons extend through infundibulum and terminate in post pit a. Hypothalamus synthesizes posterior pituitary hormones in 2 major nuclei • Paraventricular nucleus – mainly oxytocin • Supraoptic nucleus – mainly vasopressin b. Both nuclei can synthesis vasopressin and oxytocin incase of dysfunction in one Posterior pituitary releases hormones on demand – regulated - Regulated release – most hormones; only released when required - Constitutive release – more rare; constant release

Answer 9

Neurophysins – carrier proteins of OT and AVP synthesized in hypothalamus a. Neurophysins and proteolytic enzymes are packaged into vesicles and transported down through the axons of nuclei - Stored in secretory granules within axon terminals until stimulated to release Neurohypophysial peptides are released from post pit a. 2 types of nonapeptides (9 AA) – oxytocin (OT) and vasopressin (AVP) i. Similar structures • Ile and Phe differ • Leu and Arg differ ii. Different functions & release mechanisms OT and AVP are closely related but one can function without the other Ex. Brattleboro rats – genetically diabetic insipidus 1. Diabetes – “running through” a. Diabetes mellitus - glucose in urine causes increases in urine production due to osmotic mvmt of water - Mellitus – “honey”; sweet to the taste due to glucose b. Diabetes insipidus - lack of vasopressin (same as antidiuretic hormone) - AVP/ADH – allows the uptake of water back into the body in the kidney - Insipidus – sour to the taste

Answer 10

Nomenclature o Arginine vasopressin o Antidiuretic hormone (ADH) Release is stimulated by decrease in ECF volume – 2 sources 1. Due to water loss a. Reduced ECFV -> increased plasma osmolarity (more salts) -> fluid moves into ICF and triggers osmoreceptor activity (detect changes in osmotic pressure) -> increased AVP release from post pit • Ex. sweating – loss of water volume causes increase in plasma osmolarity -> water moves into cells to maintain concentration and triggers osmoreceptors 2. Due to blood loss a. Decreased left arterial volume in cardiac cycle -> decreased arterial BP -> trigger baroreceptors -> increased AVP release from post pit Action - targets kidney 1. Increases water resorption in renal tubules - Diaresis – increase in urine flow rate - Anti diaresis – reduction in urine flow rate (hence antidiuretic); retention of water in body 2. Causes vasoconstriction in vascular smooth muscle - Maintains blood pressure if there is blood loss

Answer 11

Release is stimulated by o Birth canal distension - increased OT o Infant suckling - increased OT Action - positive feedback o Increased uterine/myometrium contraction during birth o Increased milk ejection from mammary gland

Answer 12

Oxytocin 1. Rats a. Increases maternal behaviour – estrogens need to be present 2. Humans a. Plasma OT levels increase during sexual arousal in both sexes • May be linked in transport of sperm through reproductive tract due to increased levels in males and females 3. Acts as a strong neuromodulators in the brain – influence social recognition, memory and affiliative behaviours such as “pair bonding” (rodent research) a. Neuromodulators – oxytocin resets balance (similar to estrogen) b. Pair bonding may be related to OT release during let down reflex of mammary glands – pair bonding occurs during this process Vasopressin 1. Stimulates release of ACTH (adrenocorticotropic hormones) -> synergistic with CRH -> increases cortisol (due to stress) 2. Rodent research – seems to play a greater role in males than females in social recognition and consolidation of social memory (rodent research) a. Involved in aggression, courtship, scent marking, and learning • Research is done on tetrapods – related to link between AVP and fluid balance (water) o you need to protect your water resource as a land animals – links to aggression in rodents

Answer 13

Neurosecretory neurons release tropic hormones into median eminence – releases into hypophyseal portal blood supply 1. hypophysiotropic hormones – tropic hormones released from the hypothalamus into capillary bed that regulate the ant pit 2. portal capillary bed - capillary bed flows directly into another capillary bed a. first capillary bed at median eminence b. second capillary bed at anterior pit • blood vessels are surrounded by different cell types within ant pit that synthesize and release different hormones depending on trophic hormone in capillary bed 3. non portal supply: arteriole -> capillary -> venule adenohypophysial cells – cells surrounding blood vessels; release hormones into the capillary bed and blood stream 1. histological and cytological methods have provided definitive evidence on the cellular source for each hormone released from the adenohypophysis a. types of staining • basophil – basic staining • acidophil – acidic staining cell types and staining characteristics 1. Corticotroph cells - adrenocorticotropic hormone (ACTH) • Basophil 2. Thyrotroph cells - thyroid stimulating hormone (TSH) • Basophil 3. Gonadotroph cells - FSH & LH • There are cell types that release both and some that release only one or the other • Basophil 4. Lactotroph cells - prolactin (PRL) • Acidophil 5. Somatotroph cells - growth hormone (GH) • Acidophil

Answer 14

Hypothalamus o Release hypophysiotropic hormones into hypophyseal portal blood supply  can be stimulatory or inhibitory Endocrine axis – connects the hypophysiotropic hormones  anterior pit hormones  final hormone (often stimulates synthesis and release of other hormones) 1. Cortisol release axis a. High CNS has stressor b. Hypothalamus synthesizes and releases CRH -> released into medial eminence and hypophyseal blood supply -> stimulates ant pit c. Anterior pit releases ACTH -> released into bloodstream -> stimulates adrenal cortex d. Adrenal cortex releases cortisol i. Cortisol regulates its own release o Long loop -> cortisol inhibit release in hypothalamus, ant pit, and higher CNS o Short loop -> ACTH inhibits release from ant pit and hypothalamus 2. Thyroid hormone axis a. Hypophysiotropic hormone -> thyrotropin releasing hormone (TRH) b. Ant pit hormone -> thyroid stimulation hormone (TSH) c. Thyroid gland -> releases thyroid hormones (T3 and T4) 3. Androgen and estrogen axis a. Hypophysiotropic hormone -> gonadotropin releasing hormone (GnRH) b. Ant pit hormone -> FSH and LH c. Gonads (ovaries and testes) - androgens and estrogens 4. Growth hormone/IGF axis a. Hypophysiotropic hormone -> growth hormone releasing hormone (GHRH) b. Ant pit hormone -> growth hormone (GH) c. Target cells -> IGF’s • Liver and other tissues are targeted All axis have inhibitory and stimulatory factors – generally under control of one or the other 1. 4 main axis under stimulatory hypophysiotropic hormones – typically require stimulatory factors a. GnRH - stimulates release of LH and FSH in ant pit b. CRH - stimulates release of ACTH in ant pit c. TRH - stimulates release of TSH in ant pit 2. 2 main axis under inhibitory – dominant signal that regulates release is inhibitory -> require lack of inhibition in order to activate stimulatory regulators and release hormone a. Growth hormone • Somatostatin – prevents production of GHRH o Lack of somatostatin -> allows release of GHRH -> allows release of GH b. Prolactin • Dopamine – inhibits production of prolactin releasing hormone o Lack of dopamine -> allows production of prolactin Many hormones have metabolic actions in final effects -> regulation of energy

Answer 15

The anterior pituitary produces 10 polypeptide hormones (FLAT PG) o FSH, LH, ACTH, TSH, PRL, GnRH 2 families 1. GH and prolactin – similar structure family a. Growth hormone – well conserved in vertebrates • Any mutations throughout evolution have not been tolerated • AA sequence in humans will be similar to that of fish b. Prolactin – lots of variability • Same gene expresses different variants – normal (mammalian), cleaved, spliced 2. Glycoprotein family – similar structure a. Named due to the large % of carbohydrate moieties – up to 33% by weight are carbs b. Types • Follicle stimulating hormone (FSH) • Luteinizing hormone (LH) • Thyroid stimulating hormone (TSH) • Human chorionic gonadotropin hormone (hCG) c. Each has alpha and beta subunit i. Alpha unit - AA sequence is similar between hormones - Mutations have not been tolerated in evolution ii. Beta unit – varies between hormones - Functionally differentiates the types of hormones Ex. hCG – spikes early in pregnancy; pregnancy tests target these levels • Pregnancy tests would give pos tests to everyone if it targeted alpha subunit

Answer 16

Many animals have an anatomically separate pars intermedia 1. By the time humans are born – has disappeared a. During embryonic development - aMSH is produced by pars intermedia b. As adults - cells are not anatomically distinct but still synthesize and secrete aMSH (often considered part of anterior pituitary) Predominant endocrine product is αMSH – humans produce this in the ant pit 1. Precursor peptide -> pro-opiomelanocortin (POMC) a. POMC is also involved in regulating food intake b. POMC -> ACTH -> aMSH • aMSH is derived from AA sequence of ACTH which is an AA sequence of POMC • one POMC can’t synthesize and release ACTH and aMSH simultaneously 2. aMSH functions – pleotropic hormone (many functions) a. melanin synthesis • melanocytes regulation (skin pigmentation) – this is how it was first identified and named for b. anorexigenic – inhibit food intake; regulates energy balance c. immune responses 3. All occurs intracellularly in ant pit a. Different cell types will express proconvertase enzyme i. PC enzymes 1, 2, & 3 -> responsible for chopping up POMC depending on signal received o requiring reduction in food intake – will release aMSH o stress response – ACTH ii. higher signal dictate activity of proconvertase enzymes

Answer 17

Normal growth types 1. Anabolic processes – protein, fat and cartilage synthesis 2. Cell proliferation a. Hyperplasia – increase in numbers b. Hypertrophy – increase in size 3. Bone lengthening a. Increased extracellular matrix b. Occurs a lot during puberty to reach genetically resolved height - height achieved assuming adequate nutrients Normal growth is influenced by 1. Genetic resolve a. Reliant on proper nutrients – especially in fetal development and early life history (1-4yr old) 2. Diet and nutrient transfer a. If malnourished children increase nutrient intake as they grow – can correct; creates opportunity to address possible impacts on growth and reach genetic resolve 3. Disease and stress a. If it occurs in early life – will often result in not reaching genetic resolve 4. Multiple layers of hormonal control -> dictates individual tissue growth and whole body growth a. Ex. brain (individual), height (whole body)

Answer 18

Neonatal growth occurs under the influence of placental hormones After birth o Brain – fairly developed by age 10 o Height – a lot in early life and again in puberty Pubertal growth – GH levels increase dramatically 1. Associated with gonad development in males and female a. Androgen production i. Males – testicular androgens are very important and increase dramatically during puberty ii. Females – adrenal androgens increase - Adrenal gland is important for female development – lack testes - Adrenal androgens - dehydroepiandrosterone (DHEA) - Play large role in development of secondary sex characteristics in females b. Testosterone and estrogen both ultimately “put the brakes on” once genetic resolve has been achieved

Answer 19

Terms o Somatostatin  GHIH o Somatotrophin  GH o Somatomedins  IGF’s (insulin like growth factors) Hypophysiotropic hormones (hypothalamus/higher neural centers) a. Growth hormones releasing hormone (GHRH) -> stimulates production of GH b. Somatostatin (growth hormone inhibiting hormone) -> inhibits production of GH - Dominant regulatory hormone Anterior pituitary - secretes somatotrophin (GH) 1. GH is produced in somatotrophs (adenohypophysial cell) a. GH is a 191 amino acid long polypeptide (large) b. It is the most abundant adenohypophysial hormone • 4-10% of the wet weight of the gland (~ 5-10mg) 2. Functions in a. General anabolism b. Height and growth 3. Spontaneous secretion over a 24 h period a. Usually peaks in the first 90 minutes of sleep – many repair mechanisms regulated by GH while we sleep Triggers for release of GHRH and GHIH 1. GHIH - Exercise, stress and decrease in blood glucose a. GHIH (somatostatin) - Inhibits GH release from ant pit & downstream affects 2. GHRH - Increase blood AA or fatty acids a. GH (somatotropin) affects i. Liver – promotes somatomedins (IGF’s) o IGF’s - facilitates many actions of GH - Implicated in increased cell division, protein synthesis, and bone growth ii. Metabolic activities not related to growth - Energy balance - Increased fat breakdown and decreases glucose uptake by muscle cells - Increases concentration of glucose and FA in circulation to maintain homeostasis - Mobilizes energy resources GH is transported in plasma attached to one or more binding proteins o Hydrophilic – still requires and binds to proteins

Answer 20

“Growth hormone does not have a direct effect on growth of any given tissue but rather acts indirectly through somatomedins” - Doesn’t mean GH doesn’t influence growth - it does influence growth directly but is often facilitated by somatomedins Types of somatomedins (IGF’s) 1. 2 main somatomedins – both share many similarities with insulin a. IGF I -> 70 AA • Largely influenced by levels of GH b. IGF II -> 67 AA • Influenced less by GH 2. Mainly secreted and synthesized in the liver IGF’s were identified in early experiments – Influencing bone growth from blood samples 3 treatments in experiment 1 – serum from a hypex mouse a. Hypex = hypophysectomy -> connection between hypothalamus and pituitary is severed o No signals from HPH axis -> no GH or IGF hormones b. Saw no growth 2 – added GH + serum from hypex mouse a. Saw no growth with only GH 3 – injected hypex mouse with GH then added serum from mouse a. Saw growth o Indicated that GH stimulated something else that stimulated growth  IGF’s Affects of IGF’s 1. IGF I is associated with long bone growth a. Massive increase during puberty • GH levels increase much less by comparison • IGF I is primary driver of growth during puberty b. Tissue specific regulation of IGF I synthesis is evident in terms of bone growth 2. IGF II is important during fetal development a. Plays a role in adult growth – not as much as IGF I Insulin and IGF receptor similarities 1. Both single pass (1 MSR) a. linked to tyrosine kinase domains – enzyme of ICF triggered by binding of ligand to ECF side 2. Both dimers a. Monomers are attached by sulfate bridges

Answer 21

Bone is living tissue – surrounded by an extracellular organic matrix; have cell types with specific roles 1. Cells – important in the modulation and shaping of bone and in calcium balance a. Osteoblasts – bone builders b. Osteoclasts – bone breakers (crushers) Anatomy of bone 1. Diaphysis – the mature bone shaft 2. Epiphysis – at either end a. Epiphyseal plate – separates the epiphysis from the diaphysis during growth • Plate is Important in growth b. Epiphyseal line – separates epiphysis from diaphysis after maturation Compact vs spongy bone o Compact – outer surface of bone; dense and used for support o Spongy/trabecular – forms calcified lattice within compact bone Bone modelling requires constant formation (adding cells) and breaking down (removing cells)

Answer 22

Bone growth width – occurs throughout life 1. Osteoblasts – deposit new bone matrix on the outer edges of old bond to increase width a. Produce osteoid that provide a framework for hydroxyapatite crystals - Osteoid – mixture of collagen, enzymes and proteins - Hydroxyapatite crystal – inorganic components of bone tissue composed of calcium and phosphate - Within collagen matrix 2. Bone width formation is a dynamic process a. Osteoblasts - turn into mature bone cells (osteocytes) b. Osteoclasts - model the formation as bone grows - Bone degradation will slightly outpace construction throughout life - Bones become more brittle as we age Bone growth length – occurs during puberty 1. Largely governed by IGF’s o Growing pains – painful as bones lengthen 2. Process a. Chondrocytes – cartilage cells located in the epiphyseal plates - Lengthen bond by dividing and multiplying – proliferative cell layer - Older cartilage cells enlarging at the border of the diaphysis – hypertrophic layer b. Aspects of growth i. Hyperplasia - lots of cell division • Causes epiphysis to move apart from each other • Direction of growth is towards the epiphysis ii. Hypertrophia - increase in cell size • Occurs near diaphysis c. Ossification – chondrocytes disintegrate and osteoblasts lay bone on top of cartilage - Provides matric for hydroxyapatite crystals to aggregate on

Answer 23

GH and IGF I both direct proliferation and hypertrophia GH targets cells within germinal cell layer 1. Affects a. Increase in transcription and translation of IGF I – local production of IGF hormone • IGF production also occurs largely in the liver b. Increase in the development of IGF I responsiveness • increases receptor sensitivity and affinity – more efficient IGF I functions in proliferative cell layer and hypertrophic layer a. Functions as autocrine and paracrine factor b. Affects - Promotes cell division within proliferative layer – pushes epiphysis apart - Promotes cytoplasmic maturation and cell size increase in hypertrophic layer

Answer 24

influenced by the HPH axis Normal o GH targets liver cells - promote synthesis and release of IGF’s o IGF’s target somatic cells - stimulates growth Primary dysfunction - dysfunction in anterior pituitary 1. Hyperactivity – increase in activity and release of GH a. 2 phenotypes can result – dependent on when there is an increase • During infantry - results in gigantism • During puberty and adulthood - acromegaly b. People who suffer from: • Robert Wadlow – gigantism • Andre the giant – suffered from both gigantism and acromegaly; Very hyperactive pit gland throughout infant and lifetime 2. Hypoactivity – decrease in activity and release of GH a. Results in dwarfism – less GH being released  less action of GH targeting the liver  less IGF’s • Won’t grow to genetic resolve due to mutation Secondary dysfunction – dysfunction between pituitary gland and liver 1. Laron dwarfism - genetic mutation a. Village in Mexico (Loja) – everyone within that village is short in height • Due to genetic mutation • Doesn’t seem to affect men as much 2. Many forms - all affect IGF I a. Lack of GH receptors on liver - not as responsive • Leads to lack of IGF I production b. Reduced carrying capacity due to lack of binding proteins • Reduced affinity/abundance of GH binding protein • Reduced affinity/abundance of IGF binding protein Tertiary dysfunction – end organ resistance 1. IGF’s may not be able to impact the actions in long bone growth 2. Can be influenced directly by GH - If communication between GH and germinal cell layer is impacted - end organ resistance

Answer 25

1. Thyroid hormones – involved in energy homeostasis (balance and allocation) a. Hypothyroidism – reduced growth; due to inability to produce sufficient TH i. TH is largely permissive - Permissive – presence of TH is necessary for another hormone to have its affects - Critical for neuronal development 2. Insulin – involved in carbohydrate metabolism (glucose) a. Deficiency can block growth and excess can promote growth, potential cross reactivity with IGF receptors i. Deficient insulin – can block growth ii. Excess – can promotes 3. Androgens & estrogens – arrest “long-bone” length growth through ossification of the epiphyseal plate after puberty a. Different levels of hormones will cause different mechanisms i. Prepubescent boy - low levels of androgens ii. Puberty - increase in testosterone - Androgens can promote muscle growth - no one hormone acts alone; different combinations iii. Post puberty - causes ossification - It reaches a certain concentration at a certain age that triggers we need to stop growing 4. Prolactin – belongs to the GH family; influences mammary gland growth as well as aspects of the immune system (lymphocyte growth) a. Similar structure as GH 5. Placental lactogen – belongs to the GH family; influences neonatal development, maternal glucose and amino acid supply a. Peaks around mid pregnancy until full term b. Can play a role in gestational diabetes - there is a conflict between mother and fetus for nutrients i. The mother presents as type II diabetic – creates conflict between mother and fetus for glucose - Child is trying to rob mother of glucose ii. 90% of women – once the baby is born they’re fine

Answer 26

1. Neurotropic factors – nerve growth factors (NGF’s) a. Important for development and survival of neurons b. Often used in early treatment of neurodegenerative disorders i. Ex. Alzheimer’s 2. Erythropoietin – red blood cell growth factor a. Promotes growth of RBC b. Epo doping – athletes inject to promote RBC i. Have blood drawn and store blood ii. Use blood stores during training to promote o2 transfer and aerobic capacity iii. Banned 3. Platelet derived growth factors – vascular injury repair; also involved in the development of atherosclerosis (hardening of arteries caused by buildup of plaque in the inner lining of an artery) 4. Epidermal growth factors – enhanced proliferation of epidermis, gut lining, pulmonary lining a. Evolutionary connection in EGFs i. When herbivores graze  leave saliva on plant - There has been research that saliva promotes regrowth of plant - Epidermal GF within saliva is deposited on plant and plant uses for growth 5. Tumour derived growth factors – angiogenesis (growth of blood vessels) a. Tumors won’t grow without blood supply i. Research – understanding how cancer cells direct and promote angiogenesis b. Fibroblast growth factors c. Transforming growth factors i. Have different processes they target

Answer 27

Linked to bone remodeling & Ca2+ in body Regulation is critical Highly regulated ion 1. 99% of Ca2+ is locked in bone within hydroxyapatite crystals 2. 0.9% in intracellular stores (vesicles and SER) a. Overall concentration is higher than ECF but majority is sequestered within cells • [free Ca2+]  ~0.001 mM o Requires active transport to move ICF to ECF (even through overall concentration is higher)  Ca2+ ATPase 3. 0.1% in ECF a. 0.05% is bound to proteins or negatively charged ions b. 0.05% is free floating Ca2+ • [free Ca2+]  ~2.5 mM Plays a role in excitability of cells and second messenger signaling a. Neuromuscular excitability – reduced calcium leads to tetanic muscle contraction and high levels lead to reduced muscular contraction - High levels would lead to reduced contraction - Reduced leads to tetanic muscle contraction b. Stimulus secretion coupling – many cells will require calcium to allow substance to enter the cell to stimulate the secretion of a given substance c. Cell to cell structure of tight junctions d. Cofactor for clotting blood e. Required for structural form of bone and teeth

Answer 28

Balance – input and output regulated by diet 1. Dietary ca2+ a. Must maintain balance - dietary intake should equal loss in urine and feces 2. Loss through urine a. if it is in the free form - passively filters into nephron (functional unit of kidney) i. may be voided or taken back up by cells o PTH - promotes reabsorption o Calcitonin - inhibits ca2+ reabsorption from urine b. if Ca2+ is bound to carrier - not freely filtered; benefit Homeostasis – internal regulation that feeds into balance 1. Hormones functions a. promote uptake of Ca2+ from small intestine  calcitriol (PTH and prolactin) b. promote deposition of ca2+ in the bone  calcitonin c. promote release of ca2+ from the bond into the ECF enviro • small amount of ca2+ is present here; half is bound to carrier proteins

Answer 29

very closely linked; make up hydroxyapatite crystals of bony tissue Bone – living tissue; hydroxyapatite crystals are between a collagen matrix o Hydroxyapatite crystals – composed of calcium & phosphate; regulation of calcium always impacts phosphate concentrations Precipitation of hydroxyapatite crystals – reversible reaction; calcium salts have low solubility 1. If concentration of ca2+ and phosphate exceed solubility product - precipitation a. Precipitation within bone - ca2+ and phosphate are shuttled toward spaces in bone; crystals precipitate out and provide strength of bond b. If this occurs in the wrong place - kidney stones 2. Below solubility product constant - ions stay in solution a. This is the goal in the ECF

Answer 30

2 sources of Ca2+ in bone – slow and fast component 1. Fast – taking Ca2+ phosphate from bone fluid space; fast homeostatic regulation (ATM) 2. Slow – taking from bony matrix; functions in balancing total body Ca2+ (teller) a. Bony matrix - ca2+ and phosphate have exceeded coefficient & hydroxyapatite crystals are formed b. In order to utilize  requires 3 main cells Remodeling (slow process) requires 3 cells that function deposition (formation of bone) and resorption (breakdown of bone) 1. Osteocytes – mature bone cells a. Derived from osteoblasts – will differentiate into mature bone cells • Osteoblasts – on peripheral bone; are actively building bone • Osteocytes – more inner; star shaped 2. Osteoblasts – bone builders; responsible for depositing the collagen matrix a. Derived from stromal cells – connective tissue b. Opposite function of osteoclasts 3. Osteoclasts – bone breakers; dissolve the hydroxyapatite crystals within bony matrix a. Derived from hematopoietic cells/macrophages in bone marrow – stem cell derivation • Stem cells also give rise to macrophages & blood cells (ex. platelets) b. Key characteristics – make them beneficial as bone breakers i. Jagged edges of the border – facing interface of cell/bone space o Increases the surface area – allows for more interaction of any chemicals released from osteoclasts onto the bone ii. Secrete 1. Hydrogen ions – decrease pH (more acidic) - increases the solubility coefficient – causes faster dissolution of crystals; frees ca2+ and P • H+ + PO43— HPO42— • Decrease in PO43— causes increased dissolution of hydroxyapatite crystals 2. Cathepsin – enzyme that degrades collagen and other proteins - Breaks down structure to free hydroxyapatite crystals 4. Osteoblasts and osteocytes – move free ca2+ and phosphate into the blood a. Requires specific Ca2+ ATPase transporters • Ca2+ ATPase are on surface of osteocytes and blasts – allows uptake of ca2+ into cell (active) from bone fluid space to release into blood o Influences the solubility coefficient within bone fluid space -> decreased concentration of ca2+ within space

Answer 31

- also regulates Ca2+ Communication between osteoblasts and osteoclasts: Osteoblasts & its precursor cells produce two main messengers 1. RANKL (receptor activator of NFκB ligand) – allows communication from osteoblasts to osteoclasts a. RANKL binds to osteoclasts and macrophages b. 2 effects - Promotes differentiation of immature osteoclasts from macrophages - Suppresses degradation of osteoclasts c. Promotes osteoclast action -> reduces bone mass 2. Osteoprotegerin – inhibits RANKL by decreasing RANKL concentration within ECF space • Causes decrease in osteoclast action - maintains bone mass • Estradiol - stimulates the production of Osteoprotegerin Bone resorption and deposition often balance a. Bone resorption tends to slightly outpace bond deposition – brittle bones as you age b. Most menopausal women – brittle bones are higher risk • Estradiol decreases – lack signal to stop clast activation and activity & bone resorption outpaces bone deposition

Answer 32

Reduced bone mineral density & hydroxyapatite crystals Onset of osteoporosis results ~1% of bone mass is lost every year after o Therapy efficacy depend on reason for osteoporosis presence in the first place Therapy includes: a. Exercise b. Ca2+supplements c. HRT d. Calcitonin e. SERMS and ANGELS - Serms – selective estrogen receptor modulator - Angels – activators of nongenomic estrogen like signaling Prevalence in men and women a. Lower prevalence in men – primary sex steroid is androgens; lower levels of estrogens - Testosterone is converted by aromatase to estrogens - Aromatase is expressed is cells that surround bone matrix and hydroxyapatite crystals -> convert androgens to estrogens so estrogen levels are more constant b. Prevalent in pre and post-menopausal women – due to decrease in estradiol concentrations

Answer 33

1. Parathyroid hormone 2. Vitamin D/calcitriol/cholicalciferol 3. Calcitonin

Answer 34

Strong negative relationship between plasma [PTH] concentration and plasma [Ca2+] Extremely sensitive 1. Ca2+ sensing receptors on parathyroid gland a. Decrease in [Ca2+]  causes increase in PTH secretion o PTH is hypercalcemic  causes increase in ca2+ concentration in blood Function of PTH 1. Stimulates osteoclast activity - promotes the dissolution of crystals within mineralized bone area (slow regulation of Ca2+) 2. Kidney - 2 effects (mass balance) a. Increases ca2+ resorption – more reuptake into body in renal tubes b. Decreases phosphate resorption • Ca2+ and P are regulated together - decrease in phosphate causes increase in dissolution of hydroxyapatite crystals to free both ca2+ and P 3. Intestine - Important in absorbing ca2+ from diet (mass balance) a. Actions are indirect through simulation of vitamin D3 production

Answer 35

calcitriol (cholecalciferol) Often considered a hormone - can be produced in the skin from 7-dehydrocholesterol 1. Needs to be converted to 1,25-dihydroxyvitamin D3 a. Cholesterol is one of the substrates 2. Structure a. 1,25 – (OH2) – vitamin D3 (calcitriol) 3. OH group addition -> steroid hormone becomes vitamin D3 a. Vitamin D is a seco steroid – similar structure to normal steroids that we synthesize (4 carbon rings) • Seco – one aromatic rings is broken 4. Two important enzymatic steps in sequential addition of hydroxyl groups to structure a. Activation of 1α hydroxylase -> enzyme is regulated by PTH; activating step • PTH promotes the activity of 1a hyd to promote the synthesis of vitamin D Regulation of vitamin D with PTH (make diagram**) 1. Vitamin D3 is hypercalcemic - causes increase in plasma Ca2+ 2. In hypocalcaemic event (low calcium) a. Vitamin D production i. Sunlight  UV radiation assists in conversion of cholesterol derivative to vitamin D in the skin o Moves to liver – additional OH group is added to position 25 o Moves to kidney – another OH group is attached in position 1 - Catalyzed by 1α hydroxylase -> stimulated by PTH (+) - Converts precursor to active vitamin D3 hormone ii. Active vitamin D3 targets o Gut – promote ca2+ uptake o Bone – promote ca2+ dissolution o Kidney – ca2+ reabsorption iii. Increased vitamin D3 -> increase in ca2+ in circulation -> decrease in PTH release from parathyroid gland o Reduction of PTH stops to promotion of vitamin D Target sites of NB vitamin D (make diagram**) 1. Steroids are hydrophobic – has a genomic effect (slow intracellular affect) a. Also has a rapid response – indicates binding to membrane receptors to illicit response 2. The gut – probably the best documented area of vitamin D3 action a. Vitamin D influences all components in enterocytes i. Rapid and slow components o Rapid – mainly facilitated by binding to cell membrane receptor o Slow – binding to nuclear receptors ii. Initiates transcription and translation of o TRPV-5 channels – allows influx of Ca2+ down gradient o Calbindin & calmodulin – sequestering of Ca2+ within cell o NCX pump and Ca2+ ATPase – active transport from ICF to ECF b. Many transport proteins involved in moving ca2+ i. Lumen = ~1mM ca2+ ii. ICF = ~100nm ca2+ (much smaller than ECF) o Apical membrane – passive movement of ca2+ - TRPV-5 – epithelial ca2+ channels (ECaC) allows passive movement from lumen to ICF o Sequestering of Ca2+ - Calbindin and calmodulin – bind ca2+ within cell to maintain low concentration - Ca2+ can also be taken up by organelles iii. ECF = ~1.2 mM ca2+ o Basolateral membrane – active transport - NCX pump – secondary active transport; Na+ Ca2+ exchanger • Relies on Na+ gradient initially established by Na+ K+ ATPase - Plasma membrane Ca+ ATPase – primary active transport Lack of vitamin D -> lack ability to bring Ca2+ into the blood - Ricket’s disease – brittle bones

Answer 36

Effects 1. Hypocalcaemic hormone – reduces plasma Ca2+ - The only hypocalcaemic hormone 2. Hypophosphatemic – reduces plasma phosphate Synthesis and secretion within the thyroid gland o Parafollicular cells – clear cells (c cells); between thyroid hormone follicles PTH and calcitonin – antagonistic effects 1. Increase in plasma ca2+ a. Reduces PTH b. Increases calcitonin 2. Decrease in plasma ca2+ a. Reduces calcitonin b. Increases PTH Not involved in constant regulation - may be involved during the absorptive state & pregnancy 1. Absorptive – post meal a. High influx of ca2+  will reduce if too much ca2+ is present in circulation 2. Pregnancy – milk is rich in ca2+ b. Newborn requires ca2+  prevent ca2+ levels getting too high • Satiety hormone – triggers stopping of feeding when infant is suckling

Answer 37

produces thyroid hormones - Well vascularized tissue – important in thyroid hormones, PTH, and calcitonin release o Carotid artery – running down either side o Sinusoidal capillaries – go through follicles - Parathyroid gland functions independently of thyroid gland but is right on top of the tissue

Answer 38

2 main hormones – tetraiodothyronine (T4) and triiodothyronine (T3) 1. Both are involved in the regulation of metabolic rate and are key during development 2. Both derived from thyroglobulin – precursor molecule a. Inefficient synthesis • Thyroglobulin is a very large precursor molecule (over 200 AA) – very few thyroid hormones (only 1 AA) are synthesized from these 3. Synthesized in follicles – fairly inefficient a. Follicular cells – surround colloid space b. Colloid – glycoproteins Synthesis of T3 and T4 1. Precursor is tyrosine – nonessential AA (can be made by the body) a. 2 tyrosine are linked together by ether link – oxygen bond i. Position of tyrosine carbon rings are important in function o Inner tyrosyl ring o Outer phenyl ring 2. Iodine/iodide (ion) – essential component of our diet a. Goiter – abnormally functioning thyroid gland; very prevalent 100 years ago i. Main causes – a lack of dietary iodine o Today – most table salt is supplemented with iodine ii. Main demographic – young to middle aged women o Not entirely understood Differentiation of hormones 1. T4 -> 4 iodine’s attached 2. T3 -> 3 iodine a. Most functionally relevant – primary biologically active component in pathway b. 2 types – dependent on placement of iodine i. Triiodothyronine T3 -> 2 iodine on inner tyrosyl ring • Loss of iodine on outer phenyl ring ii. Reverse T3 -> 2 iodine on outer phenyl ring • Loss of iodine on inner tyrosyl ring • Some function -> not as prevalent as T3 3. T2 -> 2 iodine’s attached to the backbone 4. T1 -> 1 iodine attached to the backbone

Answer 39

Hypothalamus – secretes TRH -> stimulates anterior pituitary Pituitary gland – secretes TSH -> stimulates follicular cells of thyroid gland a. TSH binds to GPCR -> initiates adenylyl cyclase pathway - TSH stimulates many varieties of factors within thyroid follicular cell Within follicles of thyroid gland -> TH are synthesized (make diagram**) 1. Iodide must enter the follicular cell from ECF a. Iodine concentration is typically higher in ICF - Na+ I- symporter – secondary active transport - Iodine moves into cell up concentration gradient - Na+ moves into cell down concentration gradient - Initially established by Na+ K+ ATPase b. Iodide is moved from basolateral to apical membrane • Pendrin – ionic transporter; moves iodine from ICF to lumen of follicle 2. Peroxide generating system – within follicular lumen a. Thyroid peroxidase converts I- to free radical iodide – high energy emitting; causes damage to neighboring molecules • Must be created within follicular lumen/colloid space in ECF – could otherwise damage cell b. Free radical is required to couple to ring structures of tyrosine molecule via oxidative coupling – binds tyrosine residue on thyroglobulin molecule 3. Thyroglobulin – synthesized in follicular cells and secreted into colloid/lumen a. Precursor to TH i. Very large molecule o Has 2 identical subunits – both 330 kilodaltons ii. Only about 4-6 tyrosine residues per thyroglobulin o Iodine radicals must bind to tyrosine residues – limits the number of TH synthesized b. Thyroid peroxidase – catalyzes oxidative coupling of iodine free radicals to tyrosine residues on thyroglobulin i. MIT and DIT o monoiodotyrosine – 1 iodine o diiodotyrosine – 2 iodine ii. MIT and DIT -> further oxidative coupling to T3 or T4 o Still attached to thyroglobulin molecule at this stage o MIT + DIT = T3 o DIT + DIT = T4 4. Endocytosis of colloid droplet into follicle – thyroglobulin with T3 and T4 attached a. Fuses with secondary lysosome • Releases T3 and T4  enter into circulation 5. Deiodination a. Thyroglobulin’s iodotyrosines are recycled – iodine is expensive • Shuttled back to processing area for TH synthesis • Deiodinase – enzyme recycles iodotyrosines to iodine & Also converts T4 to T3 or reverse T3 – will be located in tissues that T3 and T4 are moved to b. Deiodinases can have a strong preference for specific TH’s i. Type I -> preference for reverse T3 ii. Type II -> deiodinates only the outer ring o coverts T4 to T3 iii. Type III -> deiodinates only the inner ring o converts T4 to reverse T3 c. Can be tissue specific i. Type II is highly expressed in the liver o Outer ring deiodination  coverts T4 to T3 IRD – inner ring deiodination ORD – outer ring deiodination

Answer 40

Calorigenic – TH is the most important regulator of basal metabolic rate 1. Balancing energy input and output a. Input – allows storage of energy as lipids or use immediately i. Internal and external work o Internal – general cell function o External – movement b. Output – all generate thermal energy 2. Promotes the consumption of energy  generates processes withing cell a. Futile cycles – important in generating heat • Ex. promotes the insertion of Na K ATPase into cell membranes – forces change in membrane potential - Energy used by ATPase – heat is a byproduct b. Brown adipose tissue – generates heat through futile cycles stimulated by thyroid hormone production • Common in infants o Initially thought we could not produce heat through adipose tissue past infancy – we’ve learned that we can through similar mechanisms Sympathomimetic effect – action similar to the sympathetic nervous system 1. Ex. in cardiovascular regulation a. Promotes increases in catecholamine receptors and their effects b. In heart – epinephrine and NE can increase • heart rate – chronotropic effect (time/rate) • stroke volume – inotropic effect (increasing force of contraction of the ventricle in a single cardiac cycle) Cardiovascular – largely a result of the increase in catecholamine receptors and calorigenic effects Growth – synergistic actions with both GH and IGF’s. TH is essential for normal growth and neural development o Critical role of TH during development – neural development

Answer 41

common endocrine disorder (close to type II diabetes); prevalent in young women 2 types – hypothyroidism & hyperthyroidism 1. Both are characterized by Goiter – enlargement of the thyroid gland due to overstimulation a. Overstimulation of thyroid gland is not necessarily related to the capacity of the gland to synthesize and release TH • Can be linked to autoimmune disorders 2. Exophthalmos – bulging eyes a. Common feature of Graves disease – an autoimmune disease • Link between overactive thyroid gland is not well understood b. Caused by buildup of fluid and carbohydrates behind the eye – forces the eyeball outwards Hypothalamic pituitary thyroid axis a. TRH -> TSH -> T3 and T4 - Components can negatively feedback and stop stimulus from previous steps b. Primary dysfunction – at thyroid gland c. Secondary dysfunction – at anterior pituitary or hypothalamus When medicating – can overshoot and cause symptoms of both when trying to balance medication Removal of thyroid gland – it can be much easier to maintain medicated levels

Answer 42

lacking TH ``` Causes 1. Primary dysfunction – dysfunction in the thyroid gland; not making enough T3 and T4 a. ↓T3& T4, ↑TSH i. TSH wants to increase T3 and T4 o Hypothalamus – produces more TRH o Pituitary – produces more TSH ii. TSH target thyroid and promotes hypoplasia and hypertropia of follicular cells o Causes goiter b. Goiter present ``` 2. Secondary dysfunction – hypothalamic or anterior pituitary failure; unable to produce sufficient TRH or TSH a. ↓T3& T4, ↓TRH and/or ↓TSH • Reduced signaling mechanism – doesn’t promote thyroid synthesis b. No goiter 3. Lack of dietary iodine – similar to primary failure; can’t make enough T3 and t4 (not enough iodine) a. ↓T3& T4, ↑TSH b. Goiter present ``` Symptoms o Low BMR o Decreased perspiration o Slow pulse o Lowered body temperature o Cold intolerance o Lethargy, tiredness o Weight gain o Loss of hair o Edema of face and eyelids o Menstrual irregularities o Goiter (may or may not be present) ```

Answer 43

increase in T3 and t4 production Causes 1. Abnormal presence of long acting thyroid stimulator (LATS) – Grave’s disease a. Signaling mechanisms from hypothalamus and pituitary is still working b. Antibody (part of autoimmune disorder) – acts in place of TSH and promotes thyroid hormone synthesis and release and enlargement of glands i. ↑T3& T4, ↓TSH o Presence of T3 and T4 inhibits TSH c. Goiter present 2. Secondary dysfunction – excess hypothalamic or anterior pituitary secretion a. ↑T3& T4, ↑TRH and/or ↑TSH • Overstimulation of thyroid gland and increase in T3 and T4 b. Goiter present 3. Hypersecreting thyroid tumour – increasing T3 and T4 production (primary dysfunction?**) a. ↑T3& T4, ↓TSH • Inhibits TSH production b. Goiter is often not present • You would expect there would be due to presence of tumour -> not often the case ``` Symptoms o Elevated BMR o Increased perspiration o Rapid pulse o Increased body temp o Heat intolerance o Nervousness and anxiety o Weight loss o Muscle wasting o Increase appetite o Exophthalmos (sometimes) o Goiter (primary or secondary in origin) ```

Answer 44

Released from the pineal gland Synthesized from the amino acid tryptophan ``` Synthesized and released rhythmically 1. Closely related to circadian rhythms a. Regulated by light • Scotophase (dark) – stimulates synthesis and release • Photophase (light) – inhibits release b. Universal for humans • Polar regions can be light or dark for 24 hours a day – rhythm of melatonin synthesis is still maintained through optic tract o it fluctuates in different seasons c. Peaks in the middle of the night ``` Enzymes involved in synthesis of melatonin also follow a daily rhythm Reproduction follows cycles – there is a link between melatonin-sex hormones and reproduction 1. Hypothalamic pituitary gonadotropin axis (HPG) 2. Research on the antigonadotrophic actions of melatonin in long day breeders – animals that breed in spring after winter • Longer days - total amount of melatonin released becomes less because the nights shorten • Longer night - less breeding Pleotropic effects – many processes (similar to TH) o Aids in sleep o Antigonadotrophic actions (lessen reproductive hormones) – affects humans as well Rhythm is regulated by the link between suprachiasmatic nucleus and pineal gland 1. Suprachiasmatic Nucleus (SCN) – major biological clock a. PER genes are expressed into CLOCK proteins – cycles at a constant rate that shifts depending on light cues i. 3 families of PER genes - PER I – expression is continuous in darkness ii. Expression of genes and translation to clock proteins runs at 24 hours + 11 min (+ or – 16 min) - Slightly offset from 24 hour clock 2. Resets daily to 24 hour cycle based on the earths rotation a. Lower light levels in nocturnal species and humans that are exposed to longer nighttime – still allows clock to reset - Linked between optic tract and pineal gland – important in regulating daily rhythms 2 pathways 1. Inferior accessory optic tract 2. Retino hypothalamic pathway a. Sunlight in daytime – retina receives photo info i. Melanopsin – released from the back of eyeball -> activates retino-hypothalamic pathway - Stimulation of SCN -> brainstem -> spinal cord -> preganglionic fibres -> synapse onto superior cervical ganglions (post ganglionic fibres) -> synapse onto pineal gland -> decreased secretion of NE ii. Sunlight = less NE b. Nighttime – no stimulus of retino pathway o NE increases -> acts as nt to promote pineal gland activity -> promotes melatonin synthesis and release

Answer 45

1. Adrenal medulla – release catecholamines a. Often considered an extension of the sympathetic NS i. Preganglionic neurons release Ach onto adrenal medulla – acts as a modified post ganglionic neuron b. Primary products i. Epinephrine ~ 80% ii. Norepinephrine ~ 20% 2. Adrenal cortex – there are primary steroid hormones released from each (adrenal steroids) a. Zona glomerulosa – aldosterone i. Mineralocorticoids – balances minerals b. Zona fasciculata – cortisol i. Glucocorticoids – balance glucose and energy c. Zona reticularis – DHEA (adrenal androgens & some estrogens) i. Adrenal sex steroids play larger role in females and development of secondary sex characteristics – lack other types of androgen synthesis ii. Sex hormones - Dehydroepiandrosterone & androstenedione – androgens - Estrogens Hypothalamic pituitary adrenal axis (HPA axis) 1. Hypothalamus  CRH 2. Anterior pituitary  ACTH 3. Adrenal cortex a. Cortisol b. Aldosterone – life essential hormone - Proximity to kidney – hormones are involved in adrenal function - Not many hormones are absolutely life essential – there are usually backup systems that will maintain function

Answer 46

Precursors for hormones – most reactions are reversible (steroids are expensive to make and you want to be able to utilize that energy if you need it) 1. Adrenocorticosteroids a. Corticosterone – precursor for • Cortisol – major glucocorticoid in humans • Aldosterone – major mineralocorticoid in humans 2. Sex steroids a. Androgens i. DHEA -> androstenedione -> testosterone -> DHT (terminal steroid) ii. DHEA - dehydroepiandrosterone iii. DHT - dihydrotestosterone - Terminal steroid – cannot be reversed (many other can be reversed) b. Estrogens i. DHEA -> androstenedione -> aromatase -> estrone ii. Aromatase – key enzyme in conversion of androgens to estrone; creates an aromatic ring structure in the first ring that forms androgens - Allows conversion of androgens to estriols within the bony tissue iii. Testosterone -> aromatase -> estradiol -> estriol o ex. within bony tissue – makes men less prone to osteoporosis Synthesis of adrenal hormones 1. Cholesterol is a precursor to hormones of adrenal gland – required for steroid synthesis a. Side chain (after 20 carbon) – important in steroid synthesis i. P450 sidechain cleavage enzyme (P450SCC) – key enzyme required to synthesize steroids (steroidogenesis) - Removes sidechain carbon – different amounts depending on parent molecule being synthesized - First step in steroidogenesis 2. 3 main parent molecules a. C = number of carbon atoms in a molecule b. Functionally • Pregnane – pregnenolone (C21) • Androstane – androgens (C19) • Estrange – estrogens (C18)

Answer 47

1. Secretion of aldosterone a. Largely independent of pituitary gland b. Regulated by i. Renin angiotensin system - Angiotensin II especially ii. Circulating K+ concentrations – direct affects 2. Aldosterone – acts on the distal and collecting tubules of the nephron in the kidney; promotes Na+ resorption and K+ excretion in kidney a. Regulates body fluid volume -> implications on the renal and cardiovascular systems i. Increased Na+ uptake = increased volume within body ii. Increased K+ secretion = decreased volume within body b. The steroid is essential for life -> cells cannot number if concentrations of K+ and Na+ are affected i. All vertebrates have – cells cannot function without correct concentrations of Na+ and K+ ii. Body has evolved to have “backup systems” – aldosterone does not have a backup system 3. Hyperaldosteronism a. Levels of dysfunction i. Primary -> Conn’s syndrome - At adrenal gland ii. Secondary b. Symptoms i. Hypernatremia – too much Na+ ii. Hypokalemia – too little K+ iii. Usually hypertension - Especially common with hypernatremia – increased Na+ in ECF will cause movement of water out of cells -> increased volume in vessels and increased pressure

Answer 48

1. Adrenal gland produces small amounts of androgens and estrogens from DHEA a. DHEA – an adrenal androgen -> can be converted by aromatase 2. Sex differences a. Males -> testosterone overpowers the actions of DHEA i. Gonads produce androgens b. Females -> lack other sources of androgens; DHEA plays a role in the pubertal growth spurt, hair growth and the female sex drive i. Gonads produce estrogen 3. Adrenogenital syndrome – too much DHEA; symptoms are dependent on sex and age of hyperactivity onset a. Adult females – masculinization, facial hair, deepening of voice etc b. Newborn females – psuedohermaphrodism  born with male genitalia phenotype i. Can reverse during puberty – does not always c. Adult males – no effect (testosterone overpowers anyway) d. Pubertal males – precocious pseudopuberty  adult male phenotype (secondary sex characteristics) is expressed but they are infertile 4. Adrenarche – unique to humans and old world monkeys a. In females i. Stead increase in fetal development of DHEA – peaks at birth - May be related to triggering parturition ii. Post birth - Declines & stays low in early years - Increase during onset of puberty -> increase in sexual development - Peaks and declines slowly throughout life

Answer 49

Release a. HPA axis (hypo pit adrenal) i. CRH/CRF (f = factor)  stimulates ACTH  cortisol in adrenal cortex - ACTH precursor is POMC = pro-opiomelanocortin - POMC produces multiple complexes -> ACTH, endorphins and MSH - Cortisol has a steroid base ii. Cortisol release is continuous – normally peaks in the morning and decreases at night Direct actions a. Catabolic effects – breakdown of macromolecules to be used for energy b. Increases blood glucose (hyperglycemic) – linked to stress response (mobilizing energy reserves) i. Stimulates gluconeogenesis – generation of glucose from non-carbohydrate substrates (amino acids, pyruvates, glycerol) ii. Inhibits glucose uptake by many peripheral tissues (ex. muscle cells) - Makes more available to nervous system to maintain brain function c. Increase in blood amino acids i. Stimulates protein degradation in muscle d. Increase in blood fatty acids i. Stimulates lipolysis – alternative energy source Permissive actions a. Enables glucagon activity – also hyperglycemic b. Enables catecholamine activity – modifies within synaptic clefts through the regulation of enzymes involved in degradation of NE and E i. Vascular collapse can occur during stressful events if glucocorticoids are absent - Very rare – speaks to how important presence of cortisol is in a stressful event - NE and E regulate blood vessels – especially required during acute stressful events Anti-inflammatory and immunosuppressive a. Prevention of leucocyte infiltration into the wound site b. Atrophy of lymphatic system i. More chronic stress – inhibit ability to fight infection - Ex. during exams – getting colds c. Anti-inflammatory effects are seen in supra physiologic (far above physiological levels) or pharmacologically induced states i. Cortisol injection in site of inflammation – injection site is critical to have proper effects ii. NSAIDS – nonsteroidal anti-inflammatory agents - Ex. ibuprofen & advil & Tylenol

Answer 50

Cushings syndrome – hypersecretion a. Causes i. Increased CRH or ACTH - Excessive activity in hypothalamus or anterior pituitary – secondary or tertiary ii. Adrenal tumours at adrenal gland – primary iii. Ectopic ACTH release – atypical tissue releasing ACTH - Many reasons this occurs b. Symptoms include: i. Excess glucose – cortisol promotes energy liberation - Adrenal diabetes – elevated levels of glucose in blood ii. Fat deposition in the face and abdomen, thin legs and arms iii. Facial hair excess Addisons disease – hyposecretion a. General name for bilateral damage to the adrenals – there are many forms of addisons disease with varying severity b. Can also be primary or secondary in nature i. Damage to adrenal – primary ii. Pituitary or hypothalamus – secondary or tertiary c. Symptoms include: i. Increased integument pigmentation - HPA axis – CRH release in hypothal -> ACTH in pit -> cortisol from adrenal gland a. Reduction in cortisol due to bilateral damage negatively feeds back and increases CRH and ACTH i. Increase in ACTH -> requires increase in POMC - POMC – precursor to multiple hormones - MSH - promotes skin pigmentation ii. Weakness, weight loss, hypotension, salt craving and hypoglycemia - Hypotension & salt craving – linked to lack of aldosterone (losing too much Na+) - Hypoglycemia – lack of cortisol - Weakness and weight loss – burning more energy to try and promote glucose production a. Linked to lack of cortisol and epinephrine i. Lessened ability to access glucose -> leads to weakness and lethargy ii. You still have energy but it’s not as efficient

Answer 51

Developed from Canon’s ideas on “Fight or flight” and Hans Seyle’s “General adaptation syndrome” o General adaption syndrome – general alarm response they would display regardless of stimuli they were faced with 3 stages 1. Primary alarm response – during acute response a. catecholamine surge into the system – lots of NE and E b. ↑ in basal metabolic rate (BMR) – mobilize energy reserves c. ↑in blood flow to required organs – the brain and muscles i. Away from intestine d. hepatic glycogenolysis – breakdown of glycogen into glucose 2. Secondary resistance response a. Effects of cortisol -> increases blood glucose, FA, AA i. mobilization of glucose for central organs – the brain ii. breakdown of alternative energy stores – lipids and proteins - gluconeogenesis – forming glucose from other sources 3. Tertiary exhaustion response – maladaptive a. muscle wasting, hyperglycemia (diabetes mellitus) b. atrophy of the immune system, gastric ulcers c. vascular derangements d. impacts on cardiac functions i. chronic stress -> prone to heart attacks

Answer 52

Extension of sympathetic NS – preganglionic fibres synapse onto medulla and release Ach Acts in primary alarm response Catecholamine release is largely under the control of the SNS o Chromaffin granules – stores NE and E o 80% epinephrine and 20% nor-epinephrine NE and E are active ligands in the adrenergic system – bind to adrenergic receptors: α1, α2, β1, β2, β3 1. Large area of research a. Effects of ligands on different isoforms of receptors 2. Receptors are promiscuous?? (double check) a. Both NE and E bind to all isoforms – there are isoforms of the 5 listed (ex. alpha 1A and B) b. Will have different effects depending on receptor bound – receptor that is expressed at target site is just as important as what hormone is released Epinephrine effects 1. Rapid mobilization of the bodies energy reserves 2. Increase cardiac output and total peripheral resistance a. Increase in cardiac output – caused by both chronotropic and inotropic effects • Chronotropic – increased HR • Inotropic – increased contraction force 3. Increase coronary and skeletal muscle arteriolar dilation – powers fight or flight 4. Reduce gut motility – non essential 5. Increases glycogenolysis in liver and muscle 6. Increased CNS alertness 7. Dilates pupils and flattens the lens 8. Increases sweating

Answer 53

Opposing effects of ligand depending on what receptor the ligand is bound to α1 - Most sympathetic target cells a. Not all sympathetic target cells i. ex. B2 is expressed in some b. ligand affinity -> NE > E c. 2nd messenger -> activates PLC d. Generalized arteriolar vasoconstriction α2 - Digestive system a. ligand affinity -> NE > E b. 2 mess -> ↓ cAMP c. Decreased motility in digestive tract during acute stressful event β1 - Heart & kidney a. ligand affinity -> NE = E (equivalent) b. 2nd mess -> ↑ cAMP c. Inotropic and chronotropic actions i. Betablockers – targets this receptors within the heart - Pharmacological treatment to reduce impacts of NE and E β2 - Skeletal and smooth muscle in some blood vessels and organs a. ligand affinity -> E > NE b. 2nd mess -> ↑ cAMP c. Glycogen breakdown in skeletal muscle, bronchiolar dilation, and smooth muscle dilation in blood vessels in the heart i. Heart blood vessel dilation – facilitate blood flow ii. Bronchiolar – increased oxygen uptake β3 - Adipose tissue a. ligand affinity -> NE > E b. 2nd mess -> ↑ cAMP c. Mobilizes lipids for subsequent catabolism – energy reserves are mobilized

Answer 54

Antagonistic effects due to the differing effects depending on which receptor is activated a. Multiple receptors with different responses – can reverse the response o Both can be expressed in blood vessels – regulation of vascular tone where E can dilate and constrict the same blood vessel b. Numerous agonists/antagonists for adrenoreceptors have been developed o Betablockers o Phenylephrine is an antagonist specific for α adrenoceptors – used to regulate hypertensive effects

Answer 55

Hypothalamus activates SNS -> release of E from adrenal medulla a. E stimulates pancreas & arteriolar smooth muscle i. Pancreas - Increase in glucagon and decrease insulin • Insulin is hypoglycemic – will remove glucose from circulation • Glucagon is hyperglycemic – will increase glucose in circulation ii. Vasoconstriction in blood vessels - decreases renal blood flow • Increase in renin -> increases angiotensin -> increases aldosterone Hypothalamus releases CRH -> releases ACTH -> releases cortisol

Answer 56

Exocrine – acinar cells; secrete juice into duodenum a. In response to acidic chyme entering from the stomach - Entering of chyme causes release of secretin from the endothelial cells lining the duodenum - Stimulates the acinar cells of the pancreas to release enzymes and alkaline juice to neutralize and digest Endocrine – islets of Langerhans; secrete into blood vessels o Release many hormones

Answer 57

All hormones are involved in regulating fuel metabolism and all act at multiple levels Insulin & amylin - released from B or β cells a. 10:1 ratio of insulin to amylin b. Insulin – hypoglycemic hormone c. Amylin – released with insulin following a meal i. Slows down the absorbance of glucose in intestine to prevent dramatic spike in blood glucose - Assists insulin to prevent hyperglycemia Glucagon - released from α cells a. Acts antagonistically to insulin b. Hyperglycemic Somatostatin - released from D or δ cells a. Released in response to increased glucose and amino acid levels i. Acts as paracrine and autocrine signal to regulate release of hormones from alpha, beta cells and F cells - D cells are always close to a and B cells – local regulation of insulin and glucagon ii. Inhibits digestion, absorption, and mobilization of energy reserves – your blood levels are already high b. Plays a role in inhibiting GH i. In the pancreas – largely independent of GH axis Pancreatic polypeptide (PP) - released from PP or F cells a. Increase in plasma PP postprandial (after meal) b. Antagonistic to somatostatin i. PP levels suppress SST levels and vice versa Complex integration and regulation between 4 cells types a. D and F cells may be regulating each other (as well as αand βcells)

Answer 58

Increase in blood glucose -> glucose enters b cells -> converted through glycolysis to produce ATP -> increase in ICF ATP -> inhibit ATP gated K+ channels -> changes RMP -> allows L type Ca2+ to open -> ca2+ moves into cell -> increase in ICF Ca2+ causes release of insulin into circulation -> insulin secretion from B cells into circulation

Answer 59

Energy sources – Carbohydrates, Fats and Proteins o Carbs – primary (glucose) Metabolism – a generalist term for the chemical reactions that occur in the body a. Anabolism – energy requiring (ATP); synthesis of larger macromolecules either for function or energy storage b. Catabolism – energy releasing; breakdown of macromolecules - hydrolysis: glycogen →glucose - oxidation: glucose →ATP (cellular respiration) Balance between anabolism and catabolism a. Not always completely balanced i. Growth periods ii. Short and long term “gaps” in food intake • We’ve evolved to deal with food shortages iii. Absorptive (fed) and post-absorptive (fasted) states • Fluctuations in hormones due to presence of food or lack of food in the body

Answer 60

balancing energy demands of the body To increase blood glucose 1. absorption from GI tract 2. hepatic glucose productions a. glycogenolysis – glycogen into glucose b. gluconeogenesis – carbs and fats into carbs then glucose decrease blood glucose 1. transport into cells a. energy production – cellular work b. energy storage – storage as glycogen 2. excrete excess a. glucose is osmotically active – high concentration will cause movement of water into urine to balance • key symptom of diabetes – high urine flow rate due to concentration of glucose

Answer 61

Synthesis 1. proinsulin – a chain and b chain connected by c peptide a. this is packaged in secretory vesicles in beta cells prior to release b. proinsulin can be released into circulation – not as common 2. more often released as mature peptide into blood a. c peptide is cleaved – releases mature peptide b. 3 disulfide bonds between a and b chain – cystine residues Release 1. High glucose and amino acid concentrations -> insulin secretion (positive relationship) 2. Feed forward regulation by glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) a. Signaling rom gut -> pancreas to promote insulin secretion to prepare for influx of glucose into blood stream b. Peptides studied by Bayliss and Starling – determining anticipatory response in dogs

Answer 62

Carbohydrate transport 1. Facilitates movement of glucose through GLUT or SGLT (sodium glucose) transporters a. Many types of GLUT – 1, 2, 3, 4 2. Within skeletal muscle and adipose tissue a. GLUT 4 -> transports most of the circulating glucose during the absorptive state into skeletal muscle and adipose tissue i. housed in intracellular vesicles in the absence of insulin - inserted into the cell membrane in response to insulin concentration increase ii. Insulin binds to receptors -> signal transduction -> exocytosis and insertion of GLUT 4 into membrane b. Diabetes type II – arises through lifestyle & more prevalent in older people i. Exercise can alleviate symptoms – 2 reasons - Insulin independent pathway – may increase GLUT 4 insertion into cell membrane - Insulin dependent pathway – may increase insulin receptors; this increases insulin sensitivity at target sites – not as much insulin is required to obtain the same effects 3. Within liver a. GLUT 2  transports glucose in and out of hepatocytes; always present in membrane i. Post absorptive state (low blood glucose) -> glucose is transported out ii. Absorptive state (high blood glucose)  glucose is transported into hepatocytes b. Insulin also facilitates conversion of glucose into glucose 6-phosphate to keep intracellular concentrations low during absorptive state i. Maintains sufficient gradient to keep movement passive ii. Enzyme hexokinase transforms glucose  glucose 6-phosphate c. Inhibits glycogenolysis – breakdown of glycogen to glucose 4. Within brain a. Glucose uptake in the brain is by GLUT-1 & 3  largely independent of insulin i. Glucose is the main fuel for neurons – does not need hormone to control energy transfer - The body regulates energy balance within ECF of neurons to ensure glucose is always present 5. Inhibits gluconeogenesis – transformation of other substances to glucose a. Reduces circulating amino acids & maintains AA concentrations intracellularly Actions on fat – removal of fatty acids and glucose from the blood and storage in adipose tissue a. Inhibits lipolysis b. Stimulates fatty acid uptake in adipose tissue – promotes storage of energy c. Stimulates glucose uptake and conversion to triglycerides Actions on protein a. Promotes amino acid uptake b. Stimulates protein synthesis c. Inhibits protein degradation

Answer 63

Diabetes mellitus – likely the most common endocrine disorder in the western world 1. “honey running through” – comes from initial identification when physicians would taste urine a. Diabetes - urine running through b. Mellitus - sweet/”honey” 2. Urine output a. Non diabetic – almost 100% of glucose is reabsorbed in kidney b. Diabetic – high concentration of excess glucose in urine saturates transporters in renal tubules; transport maximum for glucose • Osmotically active – pulls water into primary urine & increases urine flow rate ``` Other types of diabetes 1. Diabetes insipidus a. Dysfunction of AVP/ADH b. Reduction in capacity to synthesize ADH from post pit – a lot of water lost by kidney • Cannot reabsorb water in renal tubes c. Not sweet because of lack of glucose 2. Adrenal diabetes a. Dysfunction of cortisol ```

Answer 64

Type I or insulin-dependent diabetes -> lack of insulin secretion a. Normally seen in children and represents a small proportion of diabetics – usually genetically based - Insulin medication required for their whole life Type II or non-insulin-dependent diabetes -> lack of insulin sensitivity a. The most common form and invariably seen alongside obesity (80-90%) b. Lacks ability to insert GLUT transporters into membrane – glucose stays in circulation - High glucose levels following a meal due to inability of cells to absorb

Answer 65

Primarily from perspective of type I diabetes (insulin deficient); some aspects are also applicable to type II - Starvation in the midst of plenty – there is lots of glucose available but it’s unable to be taken up by cells Carbohydrates – purple 1. Increase in hepatic glucose output a. GLUT 2 move glucose out of liver when insulin is not present i. Other cells are requiring glucose ii. it’s not being converted to glucose 6 phosphate 2. Decreased uptake by cells a. Through GLUT 2 in liver and GLUT 4 in skeletal muscle b. Intracellular glucose deficiency i. Polyphagia – excessive hunger due to inability of cells to take up glucose; cells still won’t be able to take it up 3. Hyperglycemia – too much glucose a. Increased urine production due to high concentrations of glucose in urine i. Polyuria – osmotic flow and increase in urine flow rate b. Dehydration i. Polydipsia – excessive drinking (person is always thirsty) ii. Cellular shrinkage – moving from ICF to ECF due to decreased volume in ECF - NS malfunction -> death iii. Decrease in blood volume – decrease in BP - Peripheral circulatory failure -> renal failure -> death Lipids – yellow 1. Lessened ability to store energy a. Decrease triglyceride synthesis b. Increase lipolysis – to create glucose to feed cells i. Causes Increase in blood FA 2. Ketosis – alternative energy source utilization; body burns fat and forms ketones a. Ketoacidosis/metabolic acidosis i. Causes increased ventilation - Heavy breathing with sweet smelling breath due to burning of fats -> produces acetate that gives sweet smell ii. Diabetic coma -> death - Can also result from overdose 3. Insulin shock can occur in type I – too much insulin causes glucose levels to plummet in ECF & forces cells to use alternate energy sources a. Ketosis – utilized by cells in emergency when glucose is lacking (ex. neurons) i. Increased ventilation ii. Diabetic coma and dealth b. More common early on in trying to learn levels of medication required Proteins – pink 1. Decrease in AA uptake by cells and increase in protein degradation a. Muscle wasting and weight loss (in muscle mass) b. Increase in blood AA i. Increase in gluconeogenesis – utilizing AA for glucose Hyperglycemia – same effects as what occurs in purple carb box

Answer 66

antagonistic to insulin Secretion - Negative relationship between blood glucose levels and glucagon – increase in blood glucose causes decrease in glucagon Effects – glucose liberation; large effects in liver 1. Carbohydrates a. Stimulates hepatic glycogenolysis and gluconeogenesis – largely through phosphorylase i. Glucagon – activates phosphorylase o Glycogen -> glucose (glycogenolysis) ii. Insulin – activates glycogen synthetase o Glucose -> glycogen 2. Fats a. Increases lipolysis – release of triglycerides, diglycerides, monoglycerides from fats b. Inhibits hepatic ketogenesis – conversion of free fatty acids (FFA) to ketone bodies. • Working to liberate glucose 3. Proteins a. Promotes hepatic protein catabolism – breakdown

Answer 67

Pancreatic α and β cells response Sugars and fats – a and B cells work in opposite directions to regulate levels 1. Production of ATP a. inhibits K+ ATP gated pumps in b cells – stimulates release of insulin b. stimulates K+ ATP gated pumps in a cells – inhibits release of glucagon increase in AA – works in the same direction 1. stimulates b and a cells to secrete both insulin and glucagon a. increase in glucagon – hyperglycemic • increases hepatic glucose output b. increase in inulin – hypoglycemic • increased uptake of AA and protein synthesis • increased uptake of glucose • decreased hepatic glucose output 2. balances blood glucose

Answer 68

1. gonads – paired organs a. males – testes b. females – ovaries 2. gametes – formed via gametogenesis & have endocrine role a. males – sperm i. androgens b. females – ova i. estrogens and progesterone 3. reproductive tracts a. males – vas deferens b. females – fallopian tubes 4. accessory glands a. Male i. Seminal vesicles – major site of seminal fluid 1. Capacitation – sperm are not fully viable until they hit female tract ii. Prostate – produces fluids that aid in survival of gametes and movement of sperm iii. Bulbourethral (Cowper’s) glands – same function as prostate b. Female i. Bartholin’s glands – assist in sexual act ii. Clitoris iii. Breasts

Answer 69

Testes – leads into penis for ejaculation via vas deferens a. Seminiferous tubules – production of gametes Cell types 1. Leydig cells – outside of blood testes barrier in interstitial area; important in communicating gamete development in cells 2. Sertoli cells – within seminiferous tubule; support and aid in development a. Tight junctions between cells separate developing gametes b. Basal lamina – creates blood testes barrier (similar to BBB) - Prevents immune system from attacking gamete c. Myoid cells – found within basal lamina - Critical for communicating between Leydig and Sertoli cells - Assist in movement of fluid across cell layer Gametes develop as they move through the seminiferous tubule into the lumen 1. Gamete ECF has high K+ and steroids (testosterone) in lumen a. Androgens binding proteins – released into lumen to bind to testosterone (lipid soluble) to keep concentration high (makes water soluble) b. Higher K+ slows metabolism to save energy for when they’re released into female – lowers motility Theoretically – males can continue testosterone and sperm production throughout life 1. Process slows with age due to blood vessel degradation – results in androgen deficiency in aging males (ADAM) a. Degradation in blood vessels supplying testes – results in poor communication between Leydig and Sertoli cells b. Lower fertility Testicular development – develop from gonadal ridge 1. Descend through the inguinal canal – usually complete before 7 months of gestation within mother a. Cryptorchidism occurs in 1-3% of newborn males – testes have failed to descend and are trapped within the body i. Trapped testes – male tends to be infertile 2. Testes lie external to reduce temp – 3° lower than core body temp a. Important for development and increased mitochondria (for energy) for sperm i. Increased energy increases ability to fertilize egg Epididymis – gathering of seminiferous tubules 1. Storage area for gametes a. Not yet fertile – must be capacitated i. Low pH due to production of H+ by infertile sperm b. Produce defensins – protects sperm & helps to become motile i. Partial capacitation – completed in the female reproductive tract c. Unejaculated sperm is reabsorbed via phagocytosis d. 80% of ** 2. Enters into ductus/vas deferens  penis during ejaculation a. Semi motile sperm are stored here for a few days Accessory glands – empty into ejaculatory duct 1. Prostate a. Releases alkaline fluid, prostaglandins, clotting enzymes and fibrinolysin b. Cancer of prostate is common 2. Seminal vesicle a. Fluid contains – fructose, prostaglandins (PG’s), fibrinogen i. ~ 50% of the seminal fluid is produced by seminal vesicles b. Deposition into females i. Fibrinogen – clotting enzymes promote clotting & aids in retention of sperm within females ii. Fibrinolysin – works on fibrinogen to break clot and release sperm within female 3. Bulbourethral gland a. mucus like substance – aids in sexual act as lubricant Within penis a. Dorsal vein and dorsal artery – deep arteries within i. Well vascularized to allow for erection to occur – imbalance of blood flow (more in than out) b. Corpora cavernosa – spongy tissue Prostaglandins – hormones a. Production i. First identified in prostate gland ii. Seminal vesicles produce as much if not more into sperm and fluid around sperm b. Aid in reproductive act – promote ejaculation and contractile forces within the female tract to promote mvmt of sperm

Answer 70

1. Hypothalamus – produces GnRH -> positively stimulates ant pit 2. Ant pit – FSH and LH a. 2 main target sites – they can both act on both but have a dominant pathway LH – targets Leydig cells for testosterone production 1. 2 avenues for testosterone a. Goes into blood and circulates b. Negatively feedback to inhibit LH and GnRH i. Indirect inhibition of FSH through GnRH FSH – targets Sertoli cells and increases actions 1. Effects a. Gamete development b. Production of androgen binding protein c. Production of inhibin  negatively feedbacks on FSH 2. Testosterone is key for function of Sertoli and viability of sperm a. There are no androgen receptors on male gametes – must be converted to estrogens (sperm have receptors for estrogen) i. Issues that society has in developing male contraception’s

Answer 71

Linked to HPG axis o Hypothalamus secretes GnRH -> pit secretes LH -> Leydig cells produce testosterone Functions of testosterone a. Before birth – Influence the reproductive system i. Development of accessory glands - Wolffian duct differentiation and growth – sex determination ii. External genitalia - Growth and differentiation of scrotum and penis during fetal development b. Pubertal – surge in testosterone i. Development of libido – is not essential for maintenance of libido - Vasectomy – many males are hesitant because they believe it will decrease sex drive; it won’t ii. Development of secondary sex characteristics - Skeleton & muscle – masculine physique, epiphyseal closure - Vocal cords – voice deepening - Skin – facial hair growth and/or cranial hair loss iii. Reproductive development - Testis – sertoli cell maturation and androgen binding protein synthesis - External genitalia – penile and scrotal growth - Accessory sex glands – prostate, seminal vescile and bulbourethral growth iv. Non-reproductive actions - Bone growth - Males don’t produce many estrogens – have aromatase to assist in bone growth - Aggression – increased testosterone has increased aggressive phenotype v. Increase in testosterone – negatively feedbacks & inhibits LH in HPG axis - Development of negative feedback regulation

Answer 72

1. Protect sperm cells – as they mature and move through tubules into lumen 2. Feed sperm cells a. Sperm are stored in epididymis prior to release 3. Remove unwanted material a. Dead cells from meiotic division – resorbed and processed 4. Secrete seminiferous tubule fluid a. Aid in supporting cell viability and life b. Creates positive pressure – buildup of fluid pushes sperm down tubule into epididymis i. They are otherwise non motile due to concentration of K+ 5. ABP secretion a. Androgen binding protein – binds to testosterone and allows high concentration within lumen of seminiferous tubule i. May assist in concentration gradient as well 6. Endocrine feedback regulation a. Inhibin is synthesized – selectively inhibits FSH

Answer 73

3 stages a. Mitotic proliferation i. Spermatogonium – undifferentiated germ cells; diploid - Undergo mitosis – produce more spermatogonia - Undergo meiosis b. Meiosis i. Primary spermatocyte – undergo first meiotic division; diploid - Crossover occurs to produce genetic variation ii. Secondary spermatocyte – undergo second meiotic division; haploid iii. Spermatids – underdeveloped sperm - Each will have either X or Y chromosome 2. Y chromosome contains SRY gene – critical for sex determination c. Development i. Spermatids – move through seminiferous tubules into lumen - Daughter cells stay connected until this point – there are genes on the X chromosome that are needed for development ii. Spermatozoa – fully differentiated sperm cells; haploid - Head – contains nucleus - Acrosome – tip of the head & Contains enzymes for breaking through egg and fertilizing - Mid piece – between head and tail - Lower temp of testes promotes generation of mitochondria and allows swimming of sperm - Tail – flagella Approx. 64 days a. Ongoing and constant within seminiferous tubules i. Produced throughout lifetime ii. 200 million sperm available on a daily basis - Massive production and energy required b. 16 sperms from singe spermatocyte in theory i. Not often the case – 40-60% die in the process of development - Sertoli cells – clean up cells that have divided and gone wrong

Answer 74

1. Excitement – arousal and erection a. This is largely due to imbalance between blood inflow and outflow i. Penile arteriole dilation – vasocongestion - Inhibition of vasoconstriction neurons and sympathetic neurons that synapse with endothelial cells ii. Blood can’t flow out and erection results b. Similar responses through i. Tactile stimulation – sensory neurons ii. Mental arousal c. Erection reflex i. Higher brain center are activated - Stimulation of mechanoreceptors  sensory pathway - Arousing thoughts Descending autonomic pathway 1. SNS – inhibited to decrease vasoconstriction - Plays a role in ejaculation 2. PSNS – stimulated a. Penile arteriole vasodilation  erection - Erection compresses veins and decreases outflow of blood b. Bulbourethral and urethral glands  increased mucus and lubrication 2. Plateau phase a. Continued arousal includes increase in i. heart rate ii. mean arterial blood pressure iii. respiration rate iv. muscle tension 3. Orgasmic phase – ejaculation and muscle contraction combined with intense physical pleasure a. Ejaculation i. Emission – preparatory phase a few seconds prior followed by expulsion of seminal fluid and sperm from the penis ii. Average volume – 3mL (considerable range) - Average concentration = ~66 million sperm per mL - Clinically infertile is < 20 million sperm per mL 4. Resolution phase – return to pre-arousal state

Answer 75

Aspect of infertility without medication – incapable of sexual act a. About 50% between 40 and 70 Failing to produce sufficient NO 1. Common with atherosclerosis and diabetes mellitus 2. Nitric oxide is synthesized by NO synthase in response to PSNS stimulation a. Causes vasodilation through enzyme linked receptor pathway – uses cGMP as a second messenger i. cGMP activates PKG pathway – cGMP dependant protein kinase G - results in phosphorylation of SR Ca2+ ATPase (SERCA) – activates & lowers cytoplasmic concentration of ca2+ - results in muscle relaxation – vasodilation Viagra – cannot cause an erection but it can sustain it - Sildenafil – active ingredient in Viagra - Prolongs effects of nitric oxide by inhibiting phosphodiesterase-5  breaks down cGMP

Answer 76

Much more complex than male reproductive physiology – require fetal development, parturition and nurturing o Much greater energy investment Two critical differences in gametogenesis from males 1. The number of available gametes is set at birth (conventional view) a. Suggestion of embryonic stem cells in mice – have not been replicated • Ovarian stem cells – may be there; ability to form functional oocytes has not been proven 2. Reproductive potential ceases in middle age – menopause a. Plays role in bone degradation b. Decrease in estrogen causes decrease in reproductive potential c. Males – can be reproductively active until they die • ADAM – can limit in aging males; blood vessel degradation o Lessens motile sperm production

Answer 77

External structure 1. Embryonic origins a. Clit – same as penile head b. Labia minora – penile shaft c. Labia majora – scrotum 2. Bipotential phase – where embryonic development could go either way a. Dependant on presence of SRY Internal structures 1. Fallopian tubes/oviduct – connect ovaries (gonads) to the uterine cavity a. Fimbriae – “fingers” that hold onto ovaries • Not a very tight connection – egg can occasionally enter into body cavity instead b. Ectopic pregnancy – egg is fertilized outside of uterus; very rare - usually fatal to infant and dangerous to mother without medical intervention - implantation of fertilized egg in oviduct is damaging to mother – space does not facilitate development 2. Uterus a. Uterine artery – delivers energy and nutrients to fetus • Venous – removes waste b. Outer connective tissue c. Myometrium – very interconnected smooth muscle of uterus d. Endometrial lining – blastocyst implants during proliferation

Answer 78

All available gametes usually produced by the fifth month of gestation 1. During embryonic development – approx. 6-7 million available gametes a. Oogonium – only present pre birth; diploid • Undergo mitosis (proliferation) and meiosis (form oocytes) 2. At birth – approx. 1-2 million primary oocytes survive a. Primary oocytes – are arrested in prophase I; diploid 3. By puberty – about 300-400 thousand primary oocytes remaining 4. Menstruation – approx. 400 oocytes are ovulated in lifetime Meiosis 1. First division occurs just before birth but is not completed – primary oocytes are arrested in prophase I 2. One primary oocytes completes meiosis every month after puberty a. Meiosis I is completed just prior to ovulation – arrested in prophase II • Produces – secondary oocyte & 1 polar body b. Meiosis II is completed after fertilization • Polar body – produces 2 daughter polar bodies • Secondary oocyte – produces 1 egg and 1 polar body

Answer 79

lasts ~28 days 3 phases 1. Follicular phase – preparation of oocyte a. Primordial follicles – most will never develop & die from atresia (hormone regulated death) b. Primary follicles – contain primary oocytes i. Primary oocytes - Surrounded by zona pellucida – single cell layer; increases in width throughout development ii. Primary follicle – single layer of granulosa and theca cells, separated by basal lamina (basement membrane) - No antral space - Granulosa cells – protect follicle from atresia (degradation) and absorption - Basal lamina – analogous to BBB & Prevent immune system from attacking oocyte iii. Follicle that is ovulated is dependant on - Size – larger will be ovulated - Smaller – can aid in development of follicle that is ovulated c. Secondary follicle i. Proliferation of granulosa and theca cells – direct development - Analogous to Leydig and Sertoli cells in males - Synthesis of steroids ii. Granulosa & theca cells – secrete estrogens - Estrogen levels increase – all estrogens are present a. Estrones b. Estradiol – highest concentration c. Estriol - Granulosa cells secrete fluid – forms antral cavities (rich in estrogens) d. Tertiary/graafian/mature follicle – increases in diameter to ~12-16mm i. Antrum – fusion of antral cavities ii. Ruptured follicle – is ovulated - Only dominant mature follicle will release egg and be ovulated - Controlled by surge in LH 2. Ovulation/menstruation – release of secondary oocyte (meiosis I is completed just prior) a. Typically very short b. Collagenases – secreted by the follicle; allows the mature follicle to break free i. Secondary oocyte is expelled into the abdominal cavity – quickly drawn into the oviduct ii. Occasionally 2 secondary oocytes are expelled – fraternal twins - 1 egg and embryo develops twice – maternal twins 3. Luteal/post ovulatory phase a. Granulosa and theca cells differentiate into corpus luteum i. Secretes hormones to prepare reproductive tract for fertilization and implantation - Mostly progesterone – some estrogen ii. Luteum is full of lipids - Provide precursor molecules for steroids – progesterone and estrogen b. Corpus luteum is fully functional within 4 days and functions for 5 days whether or not its fertilized i. Fertilized – further development into mature corpus luteum - Continues to make steroids to support embryo ii. No fertilization – degradation of luteum to albicans (white) - Atresia – facilitated degradation

Answer 80

lasts ~28 days 3 phases 1. Menstrual phase a. Beginning of follicular phase in ovaries 2. Proliferate – additional endometrial lining being laid down a. Latter part of follicular phase 3. Secretory – secretion of endometrial lining to prepare for blastocyte implantation a. Post ovulation – in luteal phase i. Prepares uterus for implantation Interruptions 1. Pregnancy 2. Menopause 3. Nutritional balance – training a. Amenorrhea – lack of menstruation in women i. Female athletes – gymnasts and ballerinas in early teen years (prepubescent); menstrual cycles were abnormal or didn’t exist ii. Evolutionary – lack of resources for regular cycling and resources to maintain pregnancy iii. Can be reversed – takes time to develop normally

Answer 81

period of enhanced sexual receptivity a. Area of study for women trying to get pregnant b. Core body temp increases just after ovulation o Period of most likelihood chance of pregnancy o Males have evolved to be more attracted to females during ovulation c. Was initially thought this didn’t occur in human females Lap dancer study – done by Miller 1. Studied correlation between menstrual cycles and tip earning in women who were not on contraception (experimental group) and women on contraception (control group) a. Control group o Women on contraction have abnormal levels of estrogen and progesterone – prevents pregnancy b. Experimental group o More honest signalling during periods of oestrous increased tip earning 2. Suggested presence of oestrous phase in human women

Answer 82

1. Excitement – arousal and erection increase in PSNS and decrease in SNS a. Arousal of tissue – clit will be engorged with blood (similar to penile head) 2. Plateau phase a. Continued arousal includes increased i. heart rate ii. mean arterial blood pressure iii. respiration rate iv. muscle tension There can be an increase in circulating levels of oxytocin - Can also occur in males - 2 effects 1. Promotes pair bonding between couples a. Same sex couples – unsure of whether this occurs 2. Promotes transport of sperm within female tract a. Promotes contraction**? of vascular tissue that lines cervical canal and the uterus b. Promotes movement of sperm up through female tract and fertilization 3. Orgasmic phase – not essential for successful fertilisation (unlike males); it does aid in sperm transport a. Females can have multiple orgasms – there may be an increase in OT and vasoactive hormones i. Can further promote movement of sperm through tract and fertilization of egg 4. Resolution phase – if stimulation is sufficient arousal decreases but females do not have a period of latency as in males

Answer 83

Conception can only take place in a limited window a. Sperm can reach the oocyte within 30min following intercourse - Can survive in the female reproductive tract for up to 5 days – lengthens window b. If egg is not fertilized it will disintegrate and be absorbed

Answer 84

Usually occurs in the distal portion of the fallopian tube a. Favourable environment – quick access to nutrients & hormones i. Fairly close to ovaries b. Ectopic pregnancy – occurs outside uterus i. Can be fetal to female and child ii. Ectopic tubule pregnancy – occurs within oviduct & gets stuck in oviduct - Can be fatal as well for female and child Sperm actions a. First appear within cervical canal within 1-3 minutes after ejaculation b. A lot is lost i. 97% is lost in vagina and won’t enter cervix ii. Some is also lost in uterus and won’t enter oviduct c. Not very many actually reach egg – this is why so many sperms need to be released Aid of female reproductive in moving sperm – cervix  oviduct a. Compete capacitation of sperm once they’re in females i. Dead sperm may make it to egg – shows assistance of female b. Estrogens i. “thinning” cervical mucous – allow fluid to form channels within cervical canal - Canals are ideal dimensions and create forward movement of sperm - Fibres resonate at similar frequencies as the beating of flagella of sperm - If flagella is beating irregularly – won’t be propelled though & these will be more inhibited (they may still make it) ii. Stimulate cervical and oviduct contraction - oxytocin is also released during sex – may assist in contraction and motility of sperm c. chemotaxis – cells follow chemical gradient; not a lot of chemical is required i. humans – may only apply within oviduct itself ii. frogs eggs releases allurim – sperm follows this concentration of chemical (allures) d. thermotaxis – sperm follow temp gradient between vagina and cervical canal and oviduct i. may facilitate the movement of sperm towards egg ii. low to high gradient – marginally warmer in oviduct to promote direction Acrosomal reaction – enzymes on sperm head that allow fertilization a. Contact dependant – binding molecule on sperm binds to receptor on zona pellucida i. Outer acrosomal membrane allows release of acrosome enzymes b. Proteins involved are very species specific – prevents cross species fertilization i. Acrosomal enzymes allow sperm to “drill” through cell layers surrounding oocyte - Zona pellucida – protective glycoprotein - Corona radiata – appears on egg at ovulation; loosely connected granulosa cells Inner acrosomal membrane protein binds to receptor on egg plasma membrane 1. Fertilin – binding molecules on the sperm membrane; binds to integrin on the oocyte surface 2. Fusion of inner acrosomal membrane and egg plasma membrane allows deposition of: a. Nucleus b. And other molecules i. Prostaglandins ii. Nitric oxide – induces release of stored Ca2+ - Believed to initiate the final meiotic division of oocyte (arrested in prophase II up to this point) iii. Calcium iv. RNA – assists in early stages of developments v. Mitochondrial DNA – debate - Paternal mitochondrial deposition does occur – debate is whether it’s incorporated into developing oocyte - Most suggest paternal mitochondrial DNA is not – majority is definitely maternal - Suggested that paternal is tagged by ubiquinone and degraded Cortical reaction – Induces change in oocyte membrane which block polyspermy; keeps more than 1 sperm from fertilizing - Cortical granules in peripheral of cytoplasm of egg release their contents into the space just outside egg

Answer 85

1. Syngamy – merging of 2 haploid genomes a. Normally occurs in oviduct – small and nutrient rich i. Blastocyst – proliferation; usually formed within oviduct before entering uterus b. Occasionally 1 in 80-90 result in twins i. Dizygotic/fraternal twins – fertilisation of two oocytes - 2 placenta develop for dizygotic ii. Monozygotic/maternal twins – early embryo dividing in two iii. Conjoined or Siamese twins - First identified by siam - Highly publicized separation 2. Morula to blastocyst a. Morula – approx. 32 cells i. Day 3 after fertilization ii. Inner cell mass will develop into the embryo b. Blastocyst – supports the cells dividing at the pole during intrauterine life i. Day 4-5 after fertilization – moves to uterus ii. Day 5-9 after fertilization – can implant iii. Surrounded by trophoblast – protects inner cell mass iv. Inner cell mass continues to divide and multiply into fetus - Full of embryonic stem cells – will differentiate into other cell types - Pluripotent cells – divide and develop into 3 primary germ cells layers of embryo 3. Implantation – blastocyst adheres to the endometrium a. Trophoblast – extend and digests the surrounding endometrium i. The only embryonic tissue that come into direct contact with mother – forms placental barrier & create favourable environment for development ii. Cell types - Cytotrophoblast – inner layer of trophoblast - Syncytiotrophoblast – outer (purple) cells > Release proteases that degrade lining of endometrium – will continue to digest until the placenta develops > Endometrial decidua – degraded endometrial lining where the blastocyst is submerged iii. Stimulates prostaglandin release within endometrial decidua - Angiogenesis – creation of new blood vessels - Oedema – collection/gathering of fluid - Improved storage – for nutrient transport to embryo and removal of waste

Answer 86

~12 days after fertilization o Embryo is completely embedded o Trophoblast is 2 cell layers thick – forming chorion Chorion – continues to degrade endometrial decidua 1. Chorionic villi – project into endometrial space with maternal blood; provides nutrients and removes waste a. Within 5 weeks – should be a developing heart within embryo b. Villi contain embryonic capillaries – creates interlocking maternal (decidual) and fetal (chorionic) tissue = placenta • Decidual derived – material • Chorionic derived – fetus Placenta 1. During early development – acts as lungs, kidney, digestive system a. Only later in fetal development can the fetus support its own life 2. Transfer of a. Gas, nutrients b. No blood mixing – chemicals and molecules transfer in between 3. Placenta can’t prevent movement of everything a. Fetal alcohol syndrome – usually results in impaired brain development b. HIV can also cross

Answer 87

46 chromosomes in cells 1. 23 pairs a. 22 pairs of autosomes b. 1 pair of sex chromosomes –X and Y 2. Chromosomes determine sex a. SRY on Y chromosome – vital b. X is bigger than Y – there are many unmatched genes from X on Y; X genes become dominant alleles i. Often result in maternally derived conditions – X linked mutations/conditions o Red green colour blindness o Hemophilia o Muscle dystrophy ii. Many populations have operant sex ratios • Often 1:1 males to females – can be skewed iii. In humans o At fertilization: 120 male:100 female o At birth: 105 male:100 females - Males have a greater increased potential of not reaching term Karyotype – chromosomal type 1. XXY – viable a. Klinefelter’s syndrome – infertile adult males 2. XYY – viable a. No real side effects (super males – taller) 3. YO – not viable a. X chromosome is vital – will otherwise not reach term 4. X0 – viable a. Turners syndrome – usually infertile females Genotypic sex potential – sex determined by genes 1. Some organisms – sex can be determined by environment 2. Bipotential period – 6-7 weeks where XY embryos have the potential to develop either way a. Sex is undetermined b. Sex determining region on Y – expresses SRY gene in cells on the urogenital ridge - Stimulates the production of the protein H-Y antigen – directs the development of the male gonads - Females lack Y and therefore the SRY gene

Answer 88

will develop from the same undifferentiated tissue of urogenital ridge - 5-6 week period will see development of different ducts - Reproductive tract develops from 1. Mullerian ducts –females a. Will ultimately be expressed as female 2. Wolffian ducts -Males a. Will ultimately be expressed as male Hormones are important 1. Ovum fertilized with Y  XY chromosome a. SRY stimulates production of H-Y antigen in plasma membrane of undifferentiated gonads • H-Y antigens directs differentiation of gonads to testes b. Testes secrete Mullerian inhibiting factor & testosterone i. Degeneration of Mullerian ducts ii. Testosterone o Wolffian ducts develop into male reproductive tract iii. 5 alpha reductase – key enzyme that converts testosterone to DHT - DHT – promotes development of undifferentiated external genitalia - Insufficient 5 alpha reductase – insufficient DHT; retardation in male genitalia until puberty • Female genitalia may be expressed at birth • Spike in testosterone at puberty may lead to the growth of male genitalia 2. Ovum fertilized with X  XX chromosome a. No Y and no SRY  no H-Y antigen • Lack of H-Y antigen causes undifferentiated gonads to develop into ovaries b. No testosterone or Mullerian inhibiting factor i. No testosterone o Degeneration of Wolffian ducts o Promotes development of undifferentiated external genitalia ii. No Mullerian inhibiting factor o Mullerian ducts develop into female reproductive tract

Answer 89

rats & mice have bicornate uterus – uterus is split in 2 with developing fetuses that neighbour each other a. developing fetuses arranged sequentially in uterine horns – compartments i. each in its own amniotic sac with its own placental connection b. secretions of fetal endocrine glands alter the morphology, physiology & behaviour of neighbouring compartments i. well described in rats and mice 3 types of females a. 0M, 1M, 2M i. 1M – neighboured by single male ii. 2M – neighboured by 2 males iii. 0M – neighboured by females By day 17 in gestation – males have 3x the testosterone of females 1. there can be spillover from males to female compartments a. female fetuses are “contaminated” by testosterone from male neighbours – hormones pass via uterine blood vessels to neighbouring fetuses i. can masculinise females – changes in behaviour - 2M>1M>0M - 2M exhibit more male type behaivours – more aggressive

Answer 90

each male developing in utero increases the probability of subsequent male being gay 1. A result of “contamination” effect in rat research 2. Not attributable to environmental effect a. stepbrothers in home don’t produce effect b. biological brothers raised apart still produce effect 3. Potentially explained by “maternal immunization hypothesis” a. mother carrying first son has little exposure to male proteins due to placental barrier – particularly Y-coded i. mixing of fetal and maternal blood at birth causes female immune response to male proteins – antibodies produced against Y coded proteins b. subsequent sons are exposed to these antibodies which attack male-specific proteins – alters development and increasing probability of male being gay i. each previous male increases probability of next male by 1/3 - ex. 5th male – almost certain they’ll be gay Only applies to right handed males

Answer 91

1. Hypothalamus – releases GnRH a. Arcuate nucleus of hypothalamus – releases into median eminence & move through portal blood supply i. Kisspeptin – neuropeptide regulated by estradiol; important and promotion of GnRH release b. master sex hormone i. absence  no LH and FSH  no sex steroid production in gonads in males and females ii. initially thought to be 2 hormones – FSHRH and LHRH c. concentrations i. very low blood circulation – almost undetectable ii. very high concentration within portal blood supply d. preproGnRH – precursor peptide i. mature peptide is bioactive e. Tonic pulses in both sexes every 1-3h i. Critical to normal function and release of LH and FSH - Tests on different invertebrates – elevated levels caused inhibition of LH and FSH - Caused by down regulation of GnRH signalling pathway GnRH pulse generator influences – different mechanisms have been proposed 1. Threshold of release a. Autocrine regulation – self regulating feedback control i. Higher levels inhibit b. Creates pulses of GnRH release 2. Stimulation via NE 3. Local inhibition via dopamine or GABA (universal inhibitor for neural function) 2. Anterior pituitary – FSH and LH a. gonadotrophs – release and synthesize LH and FSH 3. Gonads – sex steroids Concentrations are important in type of feedback regulation – especially in females 1. High plasma estrogen in females – positive feedback on production of GnRH a. Increase GnRH i. Increase in kisspeptin causes increase in GnRH b. Increase FSH and LH c. Targets ovary – ovulation i. Prior to ovulation – high levels of FSH and LH  cause increase in estradiol 2. Moderate plasma estrogen/androgen levels in males or females – negative feedback on GnRH a. Less GnRH i. Less kisspeptin and GnRH b. Decrease FSH and LH c. Gonads – decreased estrogens and androgens produced i. in males – you never have very high levels of androgens in males (unlike estrogen in females) 3. Lower levels – more classic endocrine feedback a. No feedback on GnRH – causes increase in GnRH b. Increase in FSH and LH Gonads – increases

Answer 92

Classic endocrine feedback – more commonly seen in males a. You never have excessively high levels of androgens in males like you do estrogen in females b. GnRH secretion begins slowly at the onset of puberty - Prepubertal period – LH and FSH are not secreted ``` HPG axis 1. Arcuate nucleus – GnRH 2. Gonadotrophs – LH and FSH a. Sertoli cells – FSH stimulates i. Increased o Spermatogenesis – gamete synthesis o Inhibin – selectively inhibits FSH o ABP – binds testosterone to allow high concentration within seminiferous tubules > Also released into blood b. Leydig cells – LH stimulates i. Testosterone production – negative feedback on GnRH  inhibits FSH and LH o Can also target anterior pituitary production – mainly targets hypothalamus ``` Onset of axis – many factors a. Energy balance b. Genetic basis in timing c. Melatonin may play a role - Linked to regulation of HPG axis – long day breeders ex. - Varies depending on season

Answer 93

1. Key roles of LH and FSH a. LH – promotion of androgen production in thecal cells i. Conversion of cholesterol to pregnenolone 1. Initiates delta 4 & 5 pathway ii. Increase results in increased androgen production b. FSH – conversion of androgens to estrogens in granulosa cells i. Primary target – aromatase activity ii. You only need a small amount of FSH to promote aromatase activity 2. Theca & granulosa cells a. Delta 5 pathway – occurs in theca cells i. Cholesterol  pregnenolone (C21)  17-hydroxygregnenolone  DHEA  androstenedione b. Diffuses to granulosa cells i. Androstenedione  testosterone  estradiol - FSH – targets aromatase activity 3. Luteal cells a. Delta 4 – cells undergo shift i. Cholesterol  pregnenolone (C21)  progesterone  17-hydroxyprogesterone  androstenedione ii. Alternate pathways - 17-hydroxypregnenolone  17-hydroxyprogesterone - DHEA  androstenedione b. Products of androstenedione i. Testosterone (reversible)  (all terminal?) - DHT - Estradiol 17B - Estriol ii. Estrone  estradiol 17B (reversible) 4. Estradiol – major product & enters bloodstream 5. LH targets P450SCC enzyme  cleavage of cholesterol to pregnenolone to progesterone??** a. Does this occur only in luteal cells??

Answer 94

Unlike males - Cyclical in nature – increases and decreases of sex steroids that occur in predicable and timely fashion - FSH and LH do not specifically target gametogenesis or gonadal hormones respectively – play a role in both - There are both positive and negative feedback controls ``` Similar to males - GnRH secretion begins slowly at onset of puberty - Onset determined by o Energy balance o Genetics o Melatonin ```

Answer 95

1. Early follicular phase – timed with menses in uterus a. FSH – promotes follicular development in ovary i. Typically high in first 7 days – during menstration ii. Antral space – formation causes slow and steady increase in estrogen production from growing follicles b. LH – drives increase in estrogen through promotion of androgen production in theca cells i. Conversion to estrogens in granulosa cells – low levels of FSH can maintain aromatase activity c. Estrogens exhibit negative feedback 2. Late follicular phase a. Granulosa cells of dominant follicle secrete i. Estrogens – now positive feedback on GnRH - Kisspeptin protein increase - Increased GnRH  LH surge ii. Inhibin – selectively inhibits FSH - Prevents additional follicular development - Decline in FSH leads to atresia of all but leading follicle - Anti Mullerian hormone (AMH) – secreted by larger follicle & plays a role in determining while follicle will become dominant & may also inhibit maturation of neighbouring follicles b. LH surge – causes ovulation i. Granulosa cells - Small amounts of progesterone positively stimulate GnRH during ovulation - primarily inhibitory at any other time - Decrease in estrogens following ovulation -> Causes decrease in GnRH  decreased FSH and LH ii. Increase in prostaglandins - Aids in rupturing follicle and release of egg iii. Resumes meiotic division within oocyte past prophase II iv. Promotion of differentiation from follicle to luteal cells - Causes increase in progesterone (delta 4 pathway) 3. Luteal phase – follicular cells have differentiated a. LH – increased progesterone and estrogen levels through P450SCC enzyme i. Surge is critical for - Hyperplasia of endometrial lining - Hyperemia of blood vessels b. Corpus luteum – secretes estrogen and progesterone through delta 4 pathway i. Increased progesterone – occurs fairly quickly - Inhibits FSH and LH - Stimulates exocrine activity to increase embryotroph – nutrient rich fluid; uterine milk to support early development of blastocyst and embryogenesis ii. Increased estrogens also occurs once mature corpus luteal - Negative feedback of GnRH iii. Increased inhibin of FSH – don’t want another follicle developing if it does get fertilized 4. If fertilization does not occur a. Corpus luteum dies – decrease in estrogen and progesterone b. Increase in GnRH  increased FSH and LH i. Causes development of new follicles

Answer 96

used to pinpoint timing of parturition fairly accurately 1. Human Chorionic gonadotropin (hCG): a. Glycoprotein – FSH and LH family - Beta subunit – less conserved; targeted by pregnancy test b. Early pregnancy – produced by the blastocyst to preserve the corpus luteum - Promotes estrogen and progesterone - hCG declines overtime as estrogens and progesterone increase c. At delivery – decline in all 3 hormones (estrogen, progesterone, hCG) - Delivery determination is indicated by ratio of 3 hormones 2. Human Placental Lactogen (chorionic sommatomammotropin): a. Mammary gland development – although not essential b. Regulating maternal metabolism – linked with gestational diabetes - Females suffer from diabetes – 90% go back to non diabetic after birth

Answer 97

Placenta  increased CRH & ACTH Stimulates fetal adrenal cortex 1. Increase cortisol  stimulates development of fetal lungs a. Increased pulmonary surfactant fluid in amniotic fluid  increased macrophages in utero  Increased interleukin 1B i. Increased uterine stretching & IL 1B  increased activated NF-kB which causes (nerve factor capa beta) - increased interleukin 8 - increased prostaglandin production ii. Causes lung maturation & readiness for breathing air 2. Increase DHEA  targets placenta  converted to estrogen in placenta a. Increase in prostaglandin production o cervical stretching o contraction of myometrium b. Increased gap junction in myometrium o coordinated contraction of muscle c. Increased oxytocin receptors in myometrium o uterine responsiveness to low levels of oxytocin o oxytocin stimulates oxytocin effects 1. neuroendocrine reflex a. increased uterine contraction  pushes fetus against cervix  increased oxytocin secretion 2. increased prostaglandin secretion If female is under chronic stress  increased cortisol o Tend to deliver before term o Normal levels – easy predicted o Low levels – gestation is prolonged

Answer 98

Stimulus – crying baby 1. Inhibition of PIH – prolactin inhibiting hormone (aka. Dopamine) - Increased milk production by PRL 2. Release of oxytocin - Increase in smooth muscle contraction

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