Finals Reviewer – LE 5 PHYSIOLOGY

Section C | March 20, 2018 LE 5

OUTLINE TYPES OF HORMONES

1. Steroid Hormones
5.01 Intro to Endocrine System
5.02 Hypothalamus, Pituitary, HPT Axis • Parent molecule: cholesterol
5.03 Thyroid Physiology • Lipid-soluble
5.04 Endocrine Pancreas • Pregnenolone – first step
5.05 Adrenal Glands • Not stored; only gets synthesized in demand from precursor
5.06 Calcium Homeostasis & Other Hormones • Released via simple diffusion ® bound to carrier proteins ®
5.07 Female Reproductive Physiology binds with receptor in the cytoplasm
5.08 Pregnancy and Lactation • General response: induction of new protein synthesis
5.09 Sex Differentiation • Response to receptor-ligand binding: Activation of genes for
5.10 Male Reproductive Physiology transcription and translation

2. Amino Acid Derivatives

5.01 Intro to Endocrine System • Deriving from tyrosine or tryptophan
• Tyrosine-derived: thyroid hormone, catecholamines
• Tryptophan-derived: melatonin, serotonin
ENDOCRINE SIGNALING
o Melatonin – from pineal gland associated with sleep
o Serotonin – happy hormone
• Involves the following:
1. Regulated secretion of the hormone to the ECF
3. Peptide Hormones
2. Diffusion of hormone into vasculature and its circulation
into the body • Synthesis & storage: made in advance as preprohormones ®
3. Diffusion of hormone out of vasculature into ECF and stored in secretory vesicles
binding to a specific receptor • Released from parent cell via exocytosis ® dissolved in the
plasma when transported in the blood vessels ® binds with
TYPES OF CELL SIGNALLING receptor in the cell membrane
• Response to receptor-ligand binding: activation of 2nd
Delivery via Target cell Example of messenger system and activate gene expression
bloodstream characteristics secretion • General response: modification of existing proteins and
Endocrine yes far from the insulin induction of protein synthesis
gland • Examples: insulin, PTH
Neurocrine yes at a distance norepinephrine
Paracrine no adjacent cells somatostatin 4. Fatty Acid Derivatives: Eicosanoids
Autocrine no the secreting IGF (insulin- • Arachidonic acid – most abundant precursor
cell itself growth factor) • Large group of molecules derived from PUFAs
Juxtacrine no must be in embryonic and • Arachidonic acid stores are present in membrane lipids and
contact with the regenerative released via lipase activation
secreting cell’s chemical • Typically only active for few seconds
surfaces with signals • The principal groups of hormones of this class are
the signaling prostaglandins, prostacyclins, leukotrienes, and
molecules thromboxanes.

HORMONES HORMONES & THEIR RECEPTORS

• Chemical messengers secreted into the blood by endocrine • Interaction of peptide or glycoprotein with the cell surface
cells and generally act on remote organ sites and alter rates receptor with second messenger effects will either:
of processes in target cells a) G-link receptor ® activation of second messenger
• Two forms of Hormones which are maintained in equilibrium: effects (calcium, cAMP, G proteins, IP3)
1. Free form: biologically active form of hormones, not b) Enzyme-linked receptor ® triggering of a cascade of
bound to any transport protein enzymatic reactions
2. Bound form: attached to transport protein, not free to c) Cytokine receptor ® activation of a nearby enzyme
act on target cells • In lipid-soluble hormones: there will be direct interaction with
nuclear receptors and/or DNA (DNA-binding domain of H-R
2 CLASSES OF HORMONES complex), triggering gene transcription.
o Steroid hormone receptor in the cytoplasm;
Table below: Two classes of hormones: water-soluble & lipid-soluble o Thyroid hormone receptor in the nucleus.
Water-soluble Lipid-soluble
receptor location: cell receptor location: intracellularly
membrane (e.g. cytoplasm, nuclear
membrane)
Catecholamines (epinephrine Thyroid hormone
and norepinephrine)
Peptide/protein hormones Steroid hormones
Vitamin D3

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 Receptors Hormones FEEDBACK CONTROL
Neurotransmitters amino
Ligand – gated ion Positive Feedback Negative Feedback
acids (acetylcholine,
channels
norepinephrine) Less common Most common
Neurotransmitter Hormone A acts on a target
(epinephrine in some Hormone X increases levels of
G – protein coupled organ to induce change in
cells), peptides, component Y which will
levels of component B which
prostaglandin stimulate secretion of hormone
will inhibit secretion of hormone
Cytokine, Growth X
A
Cytokine Hormone, Prolactin,
Erythropoietin, Leptin Examples: LH stimulation of Examples: High levels of T3
estrogen and oxytocin secretion and T4 will inhibit secretion of
Insulin, Growth Factors that causes uterine contraction TSH
Catalytic
(IGF-1)

Intracellular
Steroids, Thyroid 5.02 Hypothalamus, Pituitary, HPT Axis
Hormones
HYPOTHALAMUS
CONTROL OF ENDOCRINE ACTIVITY
• Part of the midbrain made up of different nuclei
• Physiologic effect of the hormones are largely dependent on • connected to the pituitary gland by the pituitary stalk –
concentration in blood and ECF infundibulum
• 3 factors determining concentration: • each region is responsible for different regulatory functions in
1) Rate of Production homeostasis
o Mediated by positive and negative feedback circuits. • central relay station that regulates pituitary gland secretion
2) Rate of Delivery
o Affected by blood flow if the hormone is mostly HYPOTHALAMIC HORMONES
free/unbound
§ High blood flow ® more hormones Source Secretion
§ Low blood flow ® less hormones Supraoptic Nucleus ADH
o Also affected by number of available carriers Paraventricular Nuclei Oxytocin
3) Rate of Degradation and Elimination Thyrotropin (TRH)
Paraventricular Nuclei
o Through the liver and/or kidney Corticotropin
o Shutting off secretion of a hormone that has a very Growth Hormone Releasing
Arcuate Nucleus
short half-life causes circulating hormone Hormone (GHRH)
concentration to plummet Periventricular Nucleus Somatostatin (GHIH)
o If one’s biological half-life is long, effective
concentrations persist for some time after secretion Anterior Hypothalamus, Gonadotropin-Releasing
Preoptic Area Hormone (GRH)
ceases
Prolactin Inhibiting Factor
Tuberoinfundibular Neurons
REGULATION OF HORMONE PRODUCTION (Dopamine)

HYPOTHALAMIC RELEASING HORMONES

A. Neural Control
o Neural input to hypothalamus: stimulates synthesis and
• Secretion is in pulses
secretion of releasing factors which stimulate pituitary
• All hypothalamic hormones: bind to GPCRs
hormone production and release
o Example: thyroid hormone from the signal of cold stress • Effects include the following:
to the hypothalamus o Stimulate synthesis of anterior pituitary hormones
o Stimulate hyperplasia and hypertrophy of target cells
B. Chronotropic Control o Regulates its own receptor via ultra-short loop
o Endogenous Neuronal Rhythmicity Table below: Hypothalamic releasing hormones and their effects
o Diurnal and circadian rhythms (e.g. GH and cortisol)
Hypothalamic Releasing Action on Anterior Pituitary
o Sleep/wake cycle influences release of hormones from
Hormone Hormone
neural input from the eye and stimuli from the
Corticotropin Releasing
environment
Hormone Stimulates ACTH secretion
(CRH)
C. Episodic Secretion of hormones
o Response-stimulus coupling enables the endocrine Thyrotropin Releasing Hormone Stimulates TSH + Prolactin
system to remain responsive to physiological demands (TRH) secretion
o Secretory episodes occur with different periodicity Growth hormone releasing
Stimulates GH secretion
hormone (GHRH)
D. Physiologic Importance of Pulsatile Hormone Release Gonadotropin releasing Stimulates LH and FSH
o Demonstrated by GnRH infusion hormone (GnRH) secretions
o Should be given once hourly to work Prolactin releasing hormone Stimulates prolactin (PRL)
o Slower frequency of pulsatile GnRH release will not (PRH) secretion
maintain gonad function

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Table below: Hypothalamic inhibiting hormones and their effects o Negative Feedback
Hypothalamic Inhibiting Inhibition of hormone in § Stretch receptors in the atria due to overfilling ®
Hormone pituitary gland inhibition of ADH secretion
Inhibition of the following:
Growth Hormone Inhibiting o GH secretion Table below: Diabetes Insipidus vs Polydipsia – Lab test: water
Hormone (GHIH) aka o PRL secretion deprivation test
Somatostatin o ACTH secretions Neurogenic Nephrogenic
Diabetes Polydipsia
(pathological) Diabetes
Inhibition of the following: Plasma
o prolactin Synthesis ­ ­ ¯
Prolactin Inhibiting Factor Osmolality
o TSH secretion
Urine
o GSH secretion ¯ ¯ ¯
Osmolality
water
REGULATION OF HORMONE SECRETION deprivation ¯ ¯ ¯
(18 hours)
• Hypothalamic regulation through releasing and inhibiting Vasopressin
hormones only affects anterior pituitary injection – urine ­ no change no change
• Negative feedback control osmolality
a) Long loop: normal or high
Plasma ADH Low normal
o X hormone inhibits hypothalamus normal
o X hormone inhibits anterior pituitary
b) Short loop: ANTERIOR PITUITARY
o X stimulating hormone inhibits hypothalamus
c) Ultra short loop: • Connected to the hypothalamus by hypothalamo-anterior
o X releasing hormone inhibits hypothalamus pituitary portal vessels
• Produces 6 peptide hormones:
POSTERIOR PITUITARY 1) Follicle Stimulating Hormone (FSH)
2) Luteinizing Hormone (LH)
• AKA neurohypophysis, which is derived from neuroectoderm 3) Adrenocorticotropic Hormone (ACTH)
• Secretes ADH and oxytocin into the Hypophyseal arteries 4) Thyroid Stimulating Hormone (TSH)
• Pars nervosa: lowest portion of the posterior pituitary 5) Prolactin
6) Growth Hormone
• Infundibulum: the rest of the posterior pituitary that extends
from the median eminence down to the pars nervosa • Anterior pituitary secretions are influenced by releasing and
inhibiting hormones by the hypothalamus
OXYTOCIN AND ADH
ADRENOCORTICOTROPIC HORMONE (ACTH)
• Both oxytocin and antidiuretic hormone (ADH) are
synthesized as preprohormones in the Paraventricular Nuclei • Derived from proopiomelanocorti (POMC) as prohormone
in the hypothalamus • Binds to melanocortin-2 receptor in adrenal cortical cells
• As prohormones in secretory granules, they are conveyed (zona fasciculata)
through a fast ATP-dependent axonal transport mechanism • Pulsatile & diurnal secretion: peaks in AM before waking up
down in the infundibular stalk to the axonal terminal in the and a valley in the late afternoon
pars nervosa • Mechanism of action: ­ cAMP (via GPCR)
• Both hormones are made up of 9 amino acids, share 7 of • Effect: ­ glucocorticoid, mineralocorticoid, and androgenic
them in common and only differ in amino acids in positions 3 steroid synthesis and release from adrenal cortex
and 8
o Oxytocin: isoleucine at 3; leucine at 8 Figure below: Effects of ACTH on adrenal gland
o ADH: phenylalanine at 3; arginine at 8

• Oxytocin
o For parturition and lactation
o Positive Feedback regulation
o For labor & delivery: stretching of the cervical walls at the
beginning of parturition stimulates oxytocin to further
increase the contractions
o For lactation: nipple-sucking by the baby leads to
increased milk ejection by increased oxytocin secretion
• ADH
o Facilitates water reabsorption in the kidney
o Stimuli for secretion by hyperosmolarity
§ ­ plasma osmolality ® activation of ADH synthesis
by osmoreceptors in the hypothalamus ® ADH
secretion and circulation ® ­ H2O permeability in
the DCT and collecting duct ® ­ water reabsorption
thus ¯ plasma osmolarity ® restoration to normal
plasma osmolarity
o Stimuli for secretion by blood volume
§ ¯ circulating blood volume ® ¯ pressure from
baroreceptors in the carotid, aortic, and pulmonary
regions ® ­ ADH secretion ® water reabsorption ®
­ blood pressure
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 Table below: summary of ACTH regulation Feedback Regulation of LH and FSH
Stimulation Inhibition • Positive Feedback
• CRH • ­ cortisol o Happens prior to ovulation
• ¯ Cortisol • Enkephalins o ­ estrogen synthesis ® ­ GnRH receptors synthesis ®
• sleep-wake transition • Opioids ­ LH & FSH release ® LH & FSH surge midcycle prior to
• stress (surgery, trauma) • ACTH (negative feedback) ovulation
• exercise • Somatostatin o Progesterone amplifies the duration of LH and FSH
• hypoglycemia • GABA surge, augmenting estrogen’s effects
• norepinephrine • Endorphins • Negative Feedback
o Happens after midcycle of menstruation
• acetylcholine
o In females: estrogen & progesterone inhibit further
• serotonin
release of GnRH, FSH, LH
• α and ß adrenergic agonists o In males: inhibin, coming from Sertoli cells, selectively
• interleukin inhibits FSH release from gonadotrope
• gastrin-inhibitory peptide o Testosterone inhibits LH
(GIP)
GROWTH HORMONE
THYROID STIMULATING HORMONE
• Major target organ: Liver
• TSH acts on thyroid gland via its plasma membrane receptor • Stimulates production of Insulin-like Growth Factor I (IGF-1)
and ­ cAMP to stimulate synthesis of T3 and T4 • Excessive GH causes glucose intolerance
• Estrogen: ­ TSH sensitivity to TRH • Major site of degradation: Liver and Kidney
• Regulation • Effects in the liver:
o ­ TRH from cold stress (­ acetylcholine and • ­ amino acid uptake
norepinephrine) • ­ protein synthesis
o ¯ TRH (inhibition) by somatostatin and dopamine, which • ­ free fatty acid release from adipose cells
are in turn stimulated by T4/T3 produced (feedback loop)
• Regulators of GH
• Effects:
• Stimulator: GHRH from hypothalamus ® ­ cAMP
o ­ thyroid gland size and fasciculata
• Inhibitor: somatostatin by ¯ cAMP
o ­ iodide metabolism (uptake)
o ­ thyroidal peroxidase ® ­ incorporation of iodine to Table below: Indirect and direct actions of GH
MIT/DIT
Indirect Actions Direct Actions
o ­ lysosomal activity in thyroid gland
o ­ release of T3 & T4 from thyroglobulin • ­ skeletal, muscular, visceral • ­ protein synthesis
growth • ­ fat utilization
Figure below: Regulation of TSH secretion • chondrocyte proliferation
• ­ osteoblast activity by IGF-1 Diabetogenic effect on
• ­ organ size and function Carbohydrate metabolism
• ­ lean body mass • ¯ glucose uptake
• ¯ insulin resistance
• ­ gluconeogenesis

Table below: Summary of stimulation and inhibition of GH

Stimulation Inhibition
• GHRH ® ­ cAMP • GHIH (somatostatin) ® ¯
• ¯ FAs cAMP
• Hypoglycemia • ­ Free FAs
• Ghrelin • Hyperglycemia
• Sleep (stages 3 & 4) • Sex steroid hormones
• Exercise • Immune system activity
• Physical stress (cytokines)
• Postprandial • Stress
LUTEINIZING HORMONE hyperaminoacidemia • Postprandial hyperglycemia

Table below: Target and Action of LH Clinical Correlation with Growth Hormones
Target Action
Leydig Cells (Males) ­ Testosterone Table below: Summary of Gigantism vs Acromegaly
Synthesis of estrogen and Gigantism Acromegaly
Follicular Cells (Females)
progesterone • Affects children • affects adults
Corpus Luteum (Females) Progesterone secretion • ­ GH before epiphyseal • direct effects of tumor
closure • enlargement of hands and
FOLLICLE STIMULATING HORMONE • ­ IGF-1 feet
• coarsening of facial features
Table below: Target and Action of FSH • hyperglycemia
Target Action
Sertoli Cells (Males) Testicular growth
estrogen synthesis
Follicular Cells (Females) early growth and maturation of
ovarian follicle

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 Table below: Different Types of Dwarfism • IRST SUBTOPICFIRST SUBTOPICFIRSSUBTOPI
Type Deficiency STEP 2: Iodide Pump/Trapping
Pituitary Dwarfism Isolated GH deficiency • Iodide from circulation is actively transported into the
end organ insensitivity leading basolateral membrane of thyroid epithelial cells via
to: Sodium-Iodide Symporter (NIS)
Laron Dwarf
- ¯ IGF-1 o NIS is a secondary active transporter that uses
- ¯ GH ® ¯ linear growth Na+/K+ ATPase as driving force to its function
¯ GH before puberty with o 1 iodide per 2 Na+ enter the cell
Cretin Dwarf
mental retardation
• Inside the cell, iodide is converted into nascent iodine I0 or
PROLACTIN I3 – capable of combining directly with tyrosine
• Iodine is then transported across the apical membrane via
• Released by lactotrophs pendrin into the follicle lumen
• Site of degradation: liver
• Effects: STEP 3: Oxidation of Iodide Ion
o Development of mammary gland
• I- ® I2 via thyroid peroxidase (TPO) and H2O2
o Lactogenesis (milk production)
o Regulates prolactin-inducible protein (milk protein gene) • This step can only be done in thyroid gland
in breasts
o PRL receptor Figure Below: Summary of thyroid hormone synthesis and
o Regulation of PRL secretion
o Under inhibitory control of hypothalamus
o Disruption of pituitary stalk and
Hypothalamohypophyseal portal vessels ® ­PRL

Table below: Summary of prolactin regulation

Stimulation Inhibition
• Pregnancy • Dopamine
• Sleep • GABA
• Nursing • Somatostatin
• Serotonin • TSH
• TRH • GH
• VIP • Prolactin (autoregulation)
• Dopamine antagonists • Dopamine agonists
(methyldopa) (levodopa)
• Opioids
• MAO inhibitors

Clinical Correlation: Hyperprolactinemia

• Hypogonadism (¯ GnRH secretion) ® ¯ FSH / LH pulses and
absence of LH surge STEP 4: Iodination / Organification
• This explains lack of menstrual cycles of most of lactating • Organification of the thyroglobulin is the binding of iodine
mothers initially after childbirth with the tyrosine residues in thyroglobulin
• In women: o I2 will bind directly but slowly with tyrosine
o Anovulation (no oocyte released) • The following products are produced:
o Shortened luteal phase 1. Monoiodotyrosine (MIT)
o Oligomenorrhea (infrequent menstruation) 2. Diiodotyrosine (DIT)
o Infertility
• In men: STEP 5: Coupling / Conjugation of MIT and DIT
o ¯ testosterone synthesis • Formation of the following:
o ¯ sexual libido • T3: MIT + DIT (active)
o infertility • T4: DIT + DIT (inactive)
• rT3: reverse T3
5.03 Thyroid Physiology • Product concentration: rT3 < T3 < T4

**Note: Steps 3 – 5 require TPO to occur**

THYROID HORMONE SYNTHESIS
STEP 6: Uptake & Thyroid Hormone Release
STEP 1: Thyroglobulin Synthesis
• Thyroglobulin: derived from tyrosine and is synthesized in • Colloid Droplets (T3 + T4 within thyroglobulin) are taken up
along with megalin (endocytic receptor) by thyroid epithelial
RER cells via phagocytosis
o Excreted from vesicles via exocytosis into the colloid in • In the cytoplasm, the colloid droplets fuse with lysosomes ®
the follicular lumen hydrolysis of thyroglobulin’s peptide bonds with T3 & T4 ®
o It is a protein that gets iodinated by thyroid epithelial cells release of T3 & T4 into the blood stream via MCT8
(to be discussed further)
• Thyroid Peroxidase (TPO) STEP 7: Deiodination & Recycling
o Enzyme complex spanning the apical membrane that is • This lysosome-thyroglobulin leads to the formation digestive
responsible for thyroid hormone synthesis vesicle containing digestive enzymes from the lysosomes
mixed with the colloid
o Inhibited by propylthiouracil (PTU)

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• Digestion of the thyroglobulin molecules by the proteases will - Has an action on protein kinases, 2nd messengers,
release T3 and T4, as well as remaining MIT and DIT and ion channels
• Iodotyrosine deiodinase deionidates MIT and DIT ® iodine
and tyrosine residues are recycled THYROID HORMONE ACTIONS
• Iodine is the rate-limiting factor in thyroid hormone synthesis
Peripheral Actions:
BINDING OF THYROID HORMONES TO PLASMA PROTEIN • Bone/Tissue: linear growth and maturation
• CVS: ­ contractility, HR and cardiac output
• Circulating T3 and T4 (99%) will bind to plasma proteins:
• Liver: ↑ gluconeogenesis & glycolysis
o thyroxine-binding globulin (TBG) -70%
§ 10x more affinity to T4 than T3 • Kidney: ↑ EPO synthesis
o Transthyretin – 15% • Respiration: ↑ central stimulation of respiration
o Albumin – 15% • Energy Metabolism:
• Free, circulating T3 are greater than T4 o ↑ BMR, O2 consumption
• Bound thyroid hormones are released to the tissue cells o ­ heat production
slowly o Stimulation of Na+/K+ ATPase
• Half the thyroxine in the blood, due to its higher affinity, is • Heart:
released to tissue cells about every 6 days, while half of T3 is o ­ α and ß adrenergic receptors
released in about 1 day due to its lower affinity o ­ vasodilation due to high head and CO2

THYROID HORMONE REGULATION OF HYPOTHALAMIC PITUITARY AXIS

Table below: Comparisons between T4, T3, rT3 A. Stimulation, Release and Negative Feedback
T4 T3 rT3 Figure below: Negative Feedback Control
Daily production µ 90 35 35
From 100 25 35
thyroid(%)
From t4(%) 75 95
Extracellular pool 40 40
Plasma
concentration
Total 8.0 .12 .04
free 2.0 .28 .20
Half-life days 7 1 .8
Metabolic 1 26 77
clearance
Fractional 10 75 90
turnover per day
Secretion 30µg/day 80 µg/day 35
µg/day
Source 20-25% by Solely by %age • Long loop negative feedback: excess T3 and T4 inhibit
gland gland from anterior pituitary’s TSH secretion
75-85% by thyroid:5 • TSH also has an inhibitory effect on TRH (hypothalamus), which
conversion t4: 95 is a short loop negative feedback (not shown in figure above)
Potency 3-4 x more Potent • TRH on hypothalamus is an ultra short loop (autocrine)
potent than
T4 B. Factors Affecting Thyroid Hormone Function
Binding .2% .02%unbound
unbound Figure below: Illustration of factors affecting thyroid hormone
function
• Majority of the hormone produced by thyroid follicles is T4
(90%)
o Meanwhile T3 (10%); and rT3 is the least
• T3 is more potent than T4 due to the following:
1. There are more T3 in free from compared than T4
2. There is a peripheral conversion of T4 to T3 through the
action of deiodinase
3. There are more receptors for T3 than T4

THYROID HORMONE: MECHANISMS OF ACTIONS

1. Act through nuclear receptors in the target tissue ®

modulation of gene expression

2. Non-genomic pathways:
- Cellular effects are independent of their effects on gene
transcription
- Found in the heart, pituitary, adipose tissues
- Enhances mitochondrial oxidative phosphorylation

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 CLINICAL CORRELATIONS • 2nd Phase of Insulin Release
o Represents newly synthesized insulin
Table below: Levels of thyroid hormones in different disease states o Levels of insulin are seen as a gradual rise and fall
o Consists of preformed insulin + newly synthesized insulin

Table below: factors affecting the insulin release

Regulating Factors
¯ Decreased Insulin ¯ ­ Increased Insulin ­
Exercise Fed state

Sympathetic Nervous System Parasympathetic Nervous System

Incretin
Somatostatin
­ cAMP

α2-Adrenergic Receptors
β-Adrenergic Receptors
↓ intracellular Ca2+ by ¯ in
↑ intracellular Ca2+
cAMP and PKA

5.04 Endocrine Pancreas Galanin

FFAs through GPR40
↑ intracellular Ca2+
ISLET OF LANGERHANS
Cholecystokinin (CCK)
↑ intracellular Ca2+
• Make up the endocrine part of the pancreas
• Majority are β cells (75% of the islets) Acetylcholine
• Blood flow: from Center ® Periphery ↑ intracellular Ca2+ by increasing
PLC and IP3 as it binds to muscarinic
receptors
Cell Type Product/s Location %Mass
Alpha (α) Glucagon Periphery 10%
Cells INSULIN SIGNAL TRANSDUCTION
Beta (β) Insulin, Proinsulin, Predominant 75%
Cells C peptide, Amylin 1. Insulin binds to its receptor
in the center
o Receptor Tyrosine Kinase (RTK) family
Delta (δ) Somatostatin Interspersed ~5%
Cells o Insulin Binds to the α-subunit ® ß-subunit undergoes
between β
F Cells Pancreatic ~5% conformational change ® autophosphorylation ® triggers the
and α cells
Polypeptide signaling cascade

INSULIN 2. Activation of receptor

o Receptor’s conformational change signals its activation
• Anabolic hormone that maintains the upper limit of glucose o This results to the phosphorylation of the Insulin Receptor
and free fatty acid blood levels Substrate (IRS), triggering a signaling cascade

• Synthesis 3. Three Major Signaling Pathway

o Preproinsulin (contains Leader Peptide) ® Proinsulin o All of the three pathways translocate GLUT 4 from vesicles
(contains C-peptide) ® stored in secretory granules in onto the membrane leading to ↑ availability of GLUT4
zinc-bound crystals ® Mature / preformed insulin o ↑ availability of GLUT4 leads to:
§ ↑ mitogenic growth factors
• Secretion § ↑ glucose storage and oxidation
o Triggered by high blood glucose, AA’s, and FA’s § ↑ protein synthesis; ↓ proteolysis
o STEPS § ↑ TAG synthesis; ↓ lipolysis
1. Entry of glucose in β –cell via GLUT 2
2. Phosphorylation of glucose into G6P by glucokinase 1. PI3K Pathway
3. G6P continues into glycolysis/TCA cycle o PI3K is activated upon binding to the phosphorylated IRS
4. Closing of ATP-sensitive K+ channels due to ­ ATP from o PI3K phosphorylates PIP2 (a membrane lipid) ® PIP3
step 3 o ↑ PIP3 leads to major changes in glucose and protein
5. Opened voltage-gated Ca2+ channels in plasma metabolism
membrane
2. SHC or GRB2 Pathway
6. ­ intracellular Ca2+
o SHC or GRB2 are phosphorylated and activated upon
7. Activates Ca2+ dependent proteins ® release of
binding to IRS
preformed Insulin from secretory granules along with C-
o Either of which can trigger the Ras signaling pathway,
peptide (equimolar released, 1:1)
leading through MEK and MAP kinases
o Effect: ↑ gene expression and growth
• C-peptide
o No established function 3. SH2-containing Proteins Pathway
o Used as marker for ß-cell identification o SH2-containing Proteins are activated upon binding to
specific phosphotyrosine groups on either the insulin
Two Phases of Insulin Secretion receptor or IRS proteins
• 1st Phase of Insulin Release
o release of preformed Insulin stored in the β –cells
o lasts for about 2-5 minutes
o lost in Type I DM due to ß-cell destruction
DOWNREGULATION OF INSULIN RECEPTORS

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 ® mature glucagon by proteolytic cleavage in pancreatic α-cells
• Decrease sensitivity of target tissue without diminishing only
the maximal effect of insulin
• Chronic high levels of insulin ® downregulation of Insulin **only the other amino acid sequences in proglucagon are utilized
receptors (IR) ® ­ degradation and ¯ synthesis here (e.g. glicentin, GLP-1, IP-1)
• Number of insulin receptors is determined by:
o ­ Receptor synthesis = ­ IR number Table below: factors affecting glucagon secretion
o ­ Recycling of receptors = ­ IR number ¯ Decreased glucagon ¯ ­ Increased glucagon ­
o ­ Degradation of receptors = ¯ IR number Ingestion of glucose Drop in blood glucose level /
Hypoglycemia
Table below: metabolic effects of insulin Somatostatin Ingestion of proteins
Metabolic Effect Target Enzyme Free fatty acids Catecholamines
­ Glycolysis Hexokinase/Glucokinase keto acids Insulin
Phosphofructokinase
Mechanism of Action
Pyruvate kinase 1. Glucagon binds to GPCR
­ Glycogenesis Glycogen synthase 2. GDP is exchanged for GTP
3. G-protein is activated
­ Lipogenesis Acetyl CoA carboxylase
4. Conformational change
Fatty acid synthase 5. Activation of membrane-bound adenylate cyclase
¯ Gluconeogenesis PEPCK 6. Conversion of ATP ® cAMP
Fructose Bisphophatase 7. ↑ cAMP activates PKA
Glucose-6-phosphatase 8. PKA phosphorylates and deactivates key enzymes in
¯ Glycogenolysis glucose-1-phosphatase glycolysis and glycogenesis

Effects of Glucagon
Table below: Insulin’s metabolic effect on target organs
Target Organs Effects • ↑ blood glucose level and free fatty acids for energy via lipid
and carbohydrate metabolism
Ó Glycolysis
• Glucagon phosphorylates enzymes, causing deactivation
Ó Glycogenesis
• Insulin dephosphorylates enzymes
Ó Lipogenesis
• In general:
Ô β-Oxidation
Liver (Hepatocytes) - anabolic hormones – active when dephosphorylated
Ó Protein synthesis
- catabolic hormones – active when phosphorylated
¯ Gluconeogenesis
¯ Glycogenolysis Table below: metabolic effects of glucagon
¯ Degradation of proteins Metabolic Effects Target Enzyme
­ GLUT 4
Muscles glycogen phosphorylase
Same as liver except NO GLUCONEOGENESIS
­ Lipogenesis ↑ Glycogenolysis
glucose-6-phosphatase
­ GLUT 4
Adipocytes pyruvate carboxylase
­ Glycolysis
­ Lipoprotein lipase (LPL) PEPCK
↑ Gluconeogenesis fructose-1,6-bisphosphatase
GLUCOSE TRANSPORTERS glucose-6-phosphatase
↑ TAG degradation hormone sensitive lipase
• GLUT 2: β-cells and liver
↑ β-oxidation acetyl CoA carboxylase (inhibits)
• GLUT 4: heart, striated muscles, and adipose tissues
↑ Ketogenesis HMG CoA synthase
AMYLIN ↓ Glycolysis PFK-1
glucokinase
↓ Glycogenesis
• Peptide hormone co-secreted with Insulin (100:1) ratio glycogen synthase
• Assists insulin to slow glucose “spikes” through:
o Inhibiting glucagon secretion EFFECTS OF NUTRITIONAL STATES
o Slows down gastric emptying
o Promotes satiety • Dictated by an interplay of both Insulin and Glucagon
o Inhibits secretions from GIT
• Insulin-Glucagon Ratio
GLUCAGON o Better marker for the Fed and Fasted states
o fed state: high ratio ; fasted state: low ratio
• Primary counter-regulatory hormone (to insulin) o High catecholamine-insulin ratio ® stimulates
• Catabolic and diabetogenic (causes ­ blood glucose) phosphorylation of HSL ® ­ free fatty acids to be used
peptide hormone by skeletal muscle as alternative energy ® formation of
• Primary target organ: liver ketone bodies used by brain to produce ATP
• Receptor: GPCR
• Fed State
Synthesis o ↑ Blood glucose ® ↑ Insulin, ↓ Glucagon
o ↑ Insulin- Glucagon ratio
Preproglucagon w/ signal sequence ® removal of signal o Net effect: Storage of Energy ® ↑ Glucose uptake by
sequence by peptidases in RER ® Proglucagon ® proglucagon Peripheral cells
processing in (1) intestinal L-cells** and (2) pancreatic α-cells o Expected predominant hormone: Insulin

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 • Fasted State 3 LAYERS OF ADRENAL CORTEX
o ↓ Blood glucose, very ↓ Insulin, relatively ↑ Glucagon
o ↓ Insulin- Glucagon ratio Table below: 3 layers of adrenal cortex: superficial ® deep
o Net effect: Effects of Glucagon Zona Glomerulosa Zona Zona
§ Glycogen stores are used up to maintain blood Fasciculata Reticularis
glucose level • 15% of the cortex • 75% of the • 10% of the cortex
• secrete cortex • secrete
SOMATOSTATIN mineralocorticoid • secrete androstenedione +
s (aldosterone) glucocorticoids dehydroepiandroste
• Inhibits secretion of almost all hormones (GH, insulin, • aldosterone (cortisol + rone
glucagon, gastrin, VIP, and TSH) via inhibiting adenylyl synthase – can corticosterone)
cyclase ® ¯ cAMP ® ¯ intracellular Ca2+ only be found
o Used in treatment of endocrine tumors here
• No CYP17 –
PANCREATIC POLYPEPTIDE reason why this
layer does not
synthesize
• Secreted by F-cells
cortisol
• No known biologic activity as of now
STEROID HORMONE SYNTHESIS
DIABETES
1. LDL enters the cell ® free cholesterol (FC) from LDL enter
• Persistently elevated blood glucose level due to two main mitochondria via StAR (steroidogenic acute regulatory
causes:
protein) – rate-limiting step
1. Insufficient insulin secretion
2. FC ® pregnenolone catalyzed by CYP11A1 / Cytochrome
2. Decreased responsiveness of tissues to insulin
P11A1 ® smooth ER for lipid soluble hormone synthesis
• Common symptoms are: 3P’s (polyphagia, polydipsia,
®®® final products: aldosterone, cortisol, androstenedione
polyuria) and nocturia
• There are two types: Type 1 and Type 2
STEROIDOGENIC PATHWAYS
A. Type 1 Diabetes
Figure below: Summary of biosynthetic pathways for steroid hormones
• Insulin-Dependent (Berne & Levy, 7th Ed. Pg 773)
o Need for exogenous insulin to prevent ketosis and to
maintain life
• Autoimmune Selective Destruction of β cells
• Most cases begin in childhood ® formerly known as Juvenile
Diabetes
• More prone to ketosis

B. Type 2 Diabetes
• Associated with obesity, lack of exercise, hypertension
• Insulin Resistance ® Muscles and adipocytes become
insensitive to insulin
• 3 major causes:
1. ↓ GLUT4 mediated uptake of glucose in skeletal muscles
2. ↓ Repression of hepatic glucose production
3. Inability to repress hormone-sensitive lipase or ↑
lipoprotein lipase in adipose tissue
o Insulin resistance ® Reactive Hyperinsulinemia ®
Relative Insulinemia ® β cell failure

Diabetic Ketoacidosis
• Characterized by hyperglycemia, ketoacidosis, and
ketonuria
• Main problem: Imbalance of insulin and glucagon
o Insulin <<< Glucagon (low insulin : glucagon ratio)
o Enhanced hepatic gluconeogenesis, glycogenolysis,
lipolysis

Note: where the reactions take place (sER = smooth ER)

5.05 Adrenal Gland
ALDOSTERONE
FUNCTIONAL ANATOMY
Metabolism & Transport
• Paired, endocrine glands • 90% cleared by liver and excreted in urine
• Derived from neuronal and epithelial tissue • Excreted by the kidneys as tetrahydroaldosterone
• Has 2 Layers: • half-life: 20 minutes
1. Adrenal Cortex (mesodermal Cells) • Transport
§ Zona Glomerulosa o 35 – 70% Free
§ Zona Fasciculata o Rest is bound in
§ Zona Reticularis - Aldosterone-binding globulin
2. Adrenal Medulla (neural crest-derived cells) - Albumin
§ Secretes 80% epinephrine and 20% norepinephrine - Transcortin/CBG
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Function • Neurogenic stimuli: fear, emotions, anxiety
• Regulates salt and volume homeostasis • Systemic stimuli: illness, fever, hemorrhage
• Secretion is stimulated by ACTH • Diurnal Rhythm
• Mineralocorticoid receptor: Intracellular receptor for o Peak: 8:00 AM
aldosterone o Lowest: ~ 12:00 midnight
o Also express 11ß-HSD2 which converts cortisol ® o Can ­ cortisol secretion during stressful times
inactive steroid cortisone • Hormones that stimulate hypothalamic CRH production
§ This prevents cortisol from binding to the o Norepinephrine
mineralocorticoid receptor o Acetylcholine
Regulation o Serotonin
• Hormones that inhibit hypothalamic CRH production
Stimulation o Endorphins
1. ¯ Na+ / ­ K+ in blood or ¯ blood volume / ¯ blood pressure o GABA
o kidney secretes renin ® RAAS ® aldosterone ® ­ Na+ • ADH: stimulates pituitary ACTH production
reabsorption + blood volume • BNP: inhibits pituitary ACTH production
2. Stress
o Hypothalamus secretes CRH ® ­ ACTH by EFFECTS OF CORTISOL
adenohypophysis ® minimal stimulation of aldosterone
secretion Stimulates Inhibits
3. Others Liver Skeletal Muscles
- Serotonin - VIP • glycogenolysis • Protein Synthesis
- Acetylcholine - PACAP • gluconeogenesis • GLUT4-mediated glucose
uptake
Inhibition Skeletal Muscles
1. ­ blood pressure / ­ blood volume • proteolysis Adipose Tissue
o heart secretes ANP ® inhibition of aldosterone in 2 • glycogenolysis • GLUT4-mediated glucose
ways: (1) inhibition of RAAS and (2) direct inhibition to uptake
the glomerulosa cells Adipose Tissue • lipogenesis
2. Others • lipolysis
o Dopamine Other
o ANP • fibroblast
o Hypokalemia • collagen proliferation
o Angiotensin II (negative feedback) • ADH synthesis
• cell-mediated immune
EFFECTS OF ALDOSTERONE response (except for B-cell
production)
• Other effects: • inflammation
o Elevated aldosterone ® hypokalemia
o ­ K+ uptake into the cells
o ­ urinary K+ excretion ADRENAL ANDROGENS
o ­ Na+ reabsorption in the intestinal wall
• Androgens: exert masculinizing effects along with protein
CORTISOL anabolism and growth
• 3 kinds:
Metabolism 1. DHEA (Dehydroepiandrosterone)
• half-life in circulation: 70 minutes 2. DHEAS (Dehydroepiandrosterone sulfate)
• Glucocorticoid receptor: intracellular receptor o Most abundant hormone circulating in young
• gets inactivated by 11ß-HDS2 into cortisone in cells with adults
3. Androstenedione
mineralocorticoid receptor ® travel in the bloodstream to
o Can be converted into testosterone and estrogens in
glucocorticoid target cell ® cortisone is converted back to
adipose and other peripheral tissues
cortisol by 11ß-HDS1
• liver: uses glucoronide and sulphate to inactivate Metabolism
cholesterol and active conjugates
• Active androgens peripherally in both sexes:
• Excretion
o Androstenedione
o 25% - feces
o DHEA
o 75% - urine
• Active androgens peripherally in males:
Transport o Testosterone
o Dihydrotestosterone
• only unbound hormones can diffuse into the target cell
• Half-life
• 90% - corticosteroid-binding globulin (CBG) / Transcortin o DHEA: 15 – 30 minutes
• 5-7% - albumin o DHEAS: 7 – 10 hours
• 3-5% - free & unbound
Circulation
Regulation & Secretion
• Androgens are bound to:
• Positive feedback o Albumin (with low affinity)
o Stress ® ­ CRH ® ­ ACTH ® ­ cortisol synthesis o Sex hormone binding globulin (SHBG) – where
• Negative Feedback testosterones are tightly bounded
o cortisol ® ¯ hypothalamic CRH production ® ¯ ACTH
o cortisol ® (directly) ¯ anterior pituitary ACTH production

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• Diurnal Rhythm o Acetylcholine: signals secretion by doing the following:
o DHEA and androstenedione have the same rhythm as o ­ tyrosine hydroxylase
cortisol o ­ dopamine ß-hydroxylase
• Stimuli for synthesis and secretion: stress, exercise,
CATECHOLAMINES hypoglycemia, trauma, anxiety, hypovolemia
• Do not need transporters in circulation
• Tyrosine-derived Metabolism
• Receptors: G-Protein Coupled Receptors • 2 primary enzymes involved in degradation:
• Effects: 1) monoamide oxidase (MAO)
• ­ glucagon secretion and ¯ insulin secretion 2) catechol-O-methyltransferase (COMT)
• ¯ energy demand by signaling more ATP producing • Predominant fate of adrenal catecholamines:
• more effects discussed in the table below o Methylation by COMPT in non-neuronal tissues e.g.
liver and kidney
Table below: adrenal receptors and actions • Final product before excretion in the urine:
Receptor Type 2nd Messenger Examples of Action o Vanillymandelic acid (VMA)
α1 ­ IP3, Ca2+, DAG ­ vascular smooth muscle

α2 ¯ cAMP
contraction
inhibit norepinephrine,
5.06 Calcium Homeostasis & Other
insulin release Hormones
ß1 ­ cAMP ­ cardiac output
ß2 ­ cAMP ­hepatic glucose output CALCIUM AND PHOSPHATE
¯ vascular, bronchioles, • Both are major components of hydroxyapatite crystals in
uterine, contractions bones
ß3 ­ cAMP ­ hepatic glucose output • Regulated by same set of hormones
­ lipolysis
Table below: functions of Calcium and Phosphate
Synthesis Calcium Phosphate
Figure below: illustration of catecholamine synthesis. Note the • Bone formation • Important organic molecule
location where reactions take place. (Berne & Levy, 7th Ed pg 770) • Cell division • Intermediates of metabolic
• Growth pathways
• Blood coagulation • Major constituent in bone
• Hormone response • 45% free ionized
• Electrical stimulus response • Urinary Phosphate
– muscle contraction and - buffer in acid-base balance
nerve conduction • Cellular energy, and
• Exocytosis, and activation activation and inactivation of
and inactivation of many many enzymes
enzymes

Table below: comparison between calcium and phosphate distribution

Calcium Characteristics Phosphate
99% deposited in Deposition 85% in bone and teeth
bone and teeth
1% ICF 14% (major
intracellular anion)
0.1% ECF 1%
45% free ionized 45% free ionized
(physiologically
active form)
Plasma/Serum
45% bound to 25% bound to plasma
Composition
plasma proteins proteins
10% complexed with 30% complexed
LMW* anions
8.5 – 10.2 mg/dL Normal Serum 3-4 mg/dL
Values

Table below: Effects of Albumin and pH on calcium where both show

indirect relationships
Albumin pH
• Low albumin ® higher • Low pH ® higher ionized
ionized calcium calcium
• High albumin ® lower • High pH ® lower ionized
ionized calcium calcium

PARATHYROID HORMONE
Regulation • Produced by the principal cells / chief cells of the
• Androgens secreted by zona reticularis - exert NO Parathyroid gland
FEEDABCK on CRH and ACTH • Main hormone which protects from hypocalcemia
• Secretion is regulated by sympathetic signals • Primary targets: bone & kidneys

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 • ­ plasma [Pi] stimulates PTH secretion
• ­ Ca2+ and ­ Vitamin D inhibit gene expression of PTH Table Below: Calcitonin vs PTH vs Vitamin D
• Half-life: 2 minutes Calcitonin PTH Vitamin D
• Synthesis: Stimulus ↑ Serum Ca2+ ¯ Serum Ca2+ ↓ Serum Ca2+
for ↑ PTH
o Pre-proPTH ® proPTH at ER ® PTH at golgi apparatus
Secretion ↓ Serum Pi
® packed in secretory granules for secretion via Action on
exocytosis Bone ↓ Resorption ­ Resorption ­ Resorption
• ¯ Pi • ↑ P reabsorption
VITAMIN D
reabsorption • ↑ Ca2+
• Active forms are made in the liver: with ­ urinary reabsorption
o 1,25-hydroxycholecalciferol Kidney N/A
cAMP • ↑ Ca2+ absorption
o 1,25-hydroxyvitamin D • ­ Ca2+ • (Calbindin D-
o Calcitriol reabsorption 28K)
• Sources: (1) dietary intake & (2) de novo synthesis
• How inactive vitamin D reach the liver: ­ Ca2+
1) Via portal circulation absorption via
↑ phosphate
2) Via chylomicrons in lymphatic vessels (lacteals) activation of
N/A absorption
• Vitamin D Deficiency Intestines Vitamin D
o ¯ Ca2+ and Pi absorption in the GIT ® ­ PTH to restore
normal Ca2+ and Pi values
Overall effect on
Synthesis & Metabolism Serum
¯ ­ ­
Ca2+
Figure below: synthesis and metabolism of Vitamin D
Serum Pi ¯ ­
(Berne & Levy, 7th Ed. Pg 726)
FIBROBLAST GROWTH FACTOR 23

• peptide hormone produced by osteocytes

• acts similarly like PTH in ¯ Phosphate reabsorption at PCT
• inhibits NPT2 → increase renal excretion of phosphates

Table below: Actions of PTH and 1,25-Dihydroxyvitamin D on Ca2+/Pi

Homeostasis
PTH 1,25-Dihydroxy Vit. D
• no direct action • ­ Ca2+ absorption by
Small ­ TRPV, calbindin,
Intestines PMCA expression
• ­ Pi absorption
• osteoblastic bone • Regulates osteoclast
formation differentiation via
• regulates M-CSF, RANKL expression in
RANKL, OPG in osteoblasts
Bone osteoblasts • Maintains Ca2+ and Pi
• Chronic high levels to support bone
promote mineralization
osteoclastic bone
resorption
• Stimulates 1α- • ­ Ca2+ reabsorption
hydroxylase activity through ­ calbindin
• Stimulates Ca2+ expression
Kidneys
• ­ Pi reabsorption in
• Renal 1α-hydroxylase is tightly regulated by: PCT via ­ NPT2a
o PTH and hypophosphatemia ® ­ a-hydroxylase expression
activity ® ­ vitamin D synthesis • No direct action • Direct inhibition of PTH
o Fibroblast growth factor 23 (FGF-23) ® ­a- gene expression
hydroxylase activity ® ¯ vitamin D synthesis Parathyroid ([-] feedback)
• Receptor: nuclear Vit. D receptor (VDR) Gland • Directly stimulates
o VDR: ligand-dependent transcription factor CASR gene
• Primary action of 1,25-dihydroxyvitamin D: regulate gene expression
expression in target tissues: small intestines, bone, kidneys,
parathyroid gland CALCIUM & PHOSPHATE IN SMALL INTESTINES

IV. CALCITONIN Calcium Absorption

• takes place mostly in duodenum and jejunum
• 32-AA peptide hormone secreted by thyroid gland’s • Stimulated by 1,25-Vitamin D ® absorption is more efficient
parafollicular cells when dietary Ca2+ is low
• Main stimuli: ­ plasma [Ca2+] • Transcellular Route
• Primary effect: ¯ plasma [Ca2+] o Apically: via TRPV5 and TRPV6 channels
• Important during bone remodeling for growing children o Inside the cell: Ca2+ binds to calbindin-D9k
• Clinically important for patients with hypercalcemia o Basolaterally: via plasma membrane calcium ATPase
(PMCA)

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 § Na+/Ca2+ exchanger (NCX) – contributes to 2) Distribution of Ca2+ between bone and ECF
transport of Ca2+ out of the enterocyte on the o PTH and Calcitriol: regulate the distribution of Ca2+
basolateral side between bone and ECF, together with the kidneys,
regulate plasma Ca2+.
Phosphorus Absorption o PTH: ­ bone resorption ® ­ Ca2+ reabsorption by DCT
• Dietary phosphates absorbed by the jejunum remains ® ­ calcitriol ® ­ plasma Ca2+
relatively constant at about 70% § Production of calcitriol in the kidney is stimulated
• Has both active/transcellular and passive/paracellular routes by low Ca2+ and Pi
• Limiting process in the transcellular route is transport across o Hypercalcemia: ­ CaSR (Calcium Sensing Receptor) in
the apical border, which is mediated by Na/Pi cotransporter the TAL of Henle’s loop ® ¯ Ca2+ reabsorption ® ¯
(NPT2) plasma Ca2+

BONE PHYSIOLOGY Phosphate Homeostasis

• Bone remodeling occurs continually by basic multicellular • FGF-23: ­ renal Pi excretion ® ¯ plasma Pi concentration
units (BMU) • Dependent on two factors:
• Bone remodeling involves: 1) Distribution of Pi in the body
o Destruction of fatigued or microdamaged bone ® release § Intake: 800 – 1500 mg/day
of Ca2+ Pi, hydrolyzed bone matrix § Kidneys maintain total body Pi by excreting an
o Synthesis of osteoid, at the site of resorption ® amount of Pi in urine = amount absorbed by the GIT
mineralization by Ca2+ and Pi 2) Distribution of Pi between the ICF and the ECF
• Ca2+ and Pi balance: stimulation of bone remodeling produces § Kidneys maintain plasma Pi within 1 - 1.5 mmols.
more calcium and phosphate § PTH: ­ Pi excretion ® ¯ PCT Pi reabsorption
§ Calcitriol: ¯ Pi excretion
Bone Remodeling Mechanism § Hyperphosphatemia: ¯ calcitriol production by the
1. Osteoblasts produce monocyte colony-stimulating factor PCT ® ¯ intestinal Pi absorption
(M-CSF) ® produces monocyte/ macrophage lineage • Summary- factors that ¯ plasma Pi:
preosteoclasts (AKA CFU-GM) o ­ FGF-23
2. CFU-GM ® preosteoclasts, which has a surface receptor o ­ PTH
called receptor activator of nuclear factor k-B (RANK) o ¯ calcitriol
3. RANK ligand (RANKL) displayed by osteoblast-lineage cells
binds to RANK ® fusion and activation of osteoclast
INTEGRATED PHYSIOLOGICAL REGULATION OF CA2+ AND PI
precursors ® osteoclast
§ Osteoblast-lineage cells also produce Osteoprotegerin Serum Ca2+
(OPG), which acts as a decoy for RANKL and thus
inhibits osteoclast differentiation and function • ¯ serum Ca2+ detected by the CaSR on parathyroid chief
4. Osteoclast has a ruffled border, a highly invaginated cells stimulates secretion of PTH.
membrane that secretes HCl and hydrolytic enzymes that • Direct effect on Kidneys
cause bone resorption o PTH: ­ Ca2+ reabsorption in the distal tubule and to a
5. Bone resorption releases Ca2+ and Pi into the blood lesser extent in the distal thick ascending limb of the loop
6. Holes left will be filled by osteoblasts. It will produce bone of Henle
matrix, and later on will be mineralized o PTH inhibits NPT2 (Na/Pi cotransporter) in the
proximal tubule to ¯ Pi reabsorption and ­ Pi clearance,
Hormonal Regulation thereby counterbalancing Pi mobilized from the bone and
• PTH and Vitamin D: ­ bone resorption ® ­ serum calcium gut.
and phosphate • ­ serum Ca2+ inhibits PTH ® prevention of hypercalcemia
• PTH has two effects to mobilize Ca and Pi from bone
o Slow phase: PTH induces osteolysis. Only Ca is Serum Pi
released to extracellular fluid • Under low serum Pi :
o Rapid phase: PTH increase bone resorption, which o ­ Vitamin D production ® ­ RANKL expression ® ­
releases both Ca and Pi bone resorption
o ¯ PTH ® ­ Pi reabsorption in PCT to help ­ serum Pi
Table below: hormones and effects in the bone o ¯ FGF-23 production ® Pi reabsorption in PCT
Hormone Effect
PTH ­M-CSF and RANKL expression EICOSANOIDS
Vitamin D ­ RANKL expression • Contain 20-C atom coming from the oxygenation of poly-
Estrogen ¯ bone resorption unsaturated long fatty acid (Arachidonic Acid)
Testosterone anabolic effects • Synthesis is stimulated by physical stress, chemical,
inflammatory and mitogenic stimuli
Glucocorticoids ­ bone resorption
Biosynthesis of Eicosanoids
CA2+ AND Pi REGULATION BY THE KIDNEYS
1. Presence of either physical stress, chemical, inflammatory, or
Calcium Homeostasis mitogenic stimuli ® activation of Phospholipase A2 which
then releases esterified Arachidonic Acid from the membrane
• PTH and Vit. D: inhibit Ca2+ excretion by promoting Ca2+
phospholipid to the interior of the cell *Rate-limiting step*
reabsorption
2. Arachidonic Acid will undergo tissue specific metabolism to
• Dependent of Two Factors form various eicosanoids
1) Total Amount of Ca2+ in the body
o Net absorption by the intestine: 200 mg/day
o Ca2+ ingested in the diet: 1000 mg/day
o Ca2+ excretion: 200 mg/day (urine); 800 mg/day (feces)

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Table below: 3 pathways of eicosanoid synthesis & their final products o Precursor of ET-1 is preproendothelin; its activation is
Pathway Final Products promoted and inhibited by the following factors listed on
Cyclooxygenase pathway prostacyclins the table below
prostaglandins
thromboxanes Table below: Inducers and Inhibitors of PreproET-1.
Lipooxygenase pathway leukotrienes Inducers Inhibitors
lipoxins • Low Shear Stress • High Shear Stress
Cytochrome P450 epoxides, HETEs, diHETEs • ANG II • NO
• Cytokines • PGI2
Cyclooxygenase Pathway • Thrombin • ANP
• Stimulus: Tissue Injury ® oxidation of phospholipids ®
produces Arachidonic acid ® converted into PGG2 via the o Endothelial cells convert preproendothelin to PR
enzyme Cyclooxygenase (COX) which exists in 2 forms: endothelin and then to mature endothelin
COX1 and COX2 o Prepro ET → Big ET → Mature ET (by FT converting
• PGG2 ® PGH2 ® prostaglandin, prostacyclin, and enzyme) → receptors → ET 1 (vascular smooth muscle,
thromboxanes – collectively called prostanoids vasoconstriction) → ET 2 (endothelial cells release of
NO)
Table below: Differences between COX1 and COX2. o Upon receiving endothelin, there is an initial vasodilation
COX 1 COX 2 due to the pathway’s activation of nitric oxide. However,
Constitutively produced Inducible; expression varies the persistent effect of endothelin is vasoconstriction
depending on stimulus
Protective for gastric mucosal Recruits inflammatory white FEEDING BEHAVIOR HORMONES
lining cells
Aid in platelet aggregation Sensitize skin pain receptors; • Leptin
stimulate hypothalamic fever o Produced from adipose tissues, gives sense of fullness
response o Brain control actions, vascular function, reproduction,
controls the deposition of white adipose tissue, bone and
Generates prostanoids for Major source of prostanoids in
cartilages and immune system modulation and activation
housekeeping functions inflammation and cancer
o Other targets: kidney, bowel, pancreas, muscle
Table below: Inducers and Inhibitors of COX. • Ghrelin
Inducers Inhibitors o Increases ERCP, stimulates hunger
o Released by enteroendocrine cells in the mucosal layer
• Cytokines • NSAIDs
of the stomach in response to fasting; highest ghrelin
• Growth Factors • Aspirin
concentrations in stomach’s fundus
• TNF-a • Cortisol
o Infusion into bloodstream or cerebral vesicles ® ­
Table below: Effects of Prostaglandin, Prostacyclin, & Thromboxane.
growth hormone (GH) secretion
Prostaglandin Prostacyclin Thromboxane
Table below: Factors affecting Ghrelin secretion.
• Vasodilation • Vasodilation • Vasoconstriction ­ Ghrelin ¯ Ghrelin
• ↑ Vascular • ↓ Platelet • ↑ Platelet • Leptin • Food Intake
Permeability Aggregation Aggregation
• Fasting • Glucose/Lipid
Lipooxygenase Pathway • GnRH, Thyroid Hormone • Insulin
• Sleep deprivation • Somatostatin
• Synthesizes the following leukotrienes:
• Low BMI • High BMI
o Leukotriene B4 (LTB4)
• Anorexia nervosa • PYY/PP
o Leukotriene C4 (LTC4)
o Leukotriene D4 (LTD4
Fasted State
o Leukotriene E4 (LTE4)
• Effects of leukotrienes are symptoms of asthma: • ­ Ghrelin; ¯ Leptin ® ­ argouti-related protein (Argp), ­
vasoconstriction, bronchospasms, and increased neuropeptide Y (NYP), ¯ POMC ® hunger
vascular permeability
• LTC4 and LTD4 are potent bronchoconstrictors and are Fed state
primary components of SRS-A secreted in asthma • (Pathway is a direct opposite of fasted state)
• LTB4 causes chemotaxis and inflammatory response • ­ Leptin; ¯ Ghrelin ® ¯ Argp, ¯ NYP, ­ POMC ® satiety

VASOACTIVE SUBSTANCES TRYPTOPHAN DERIVED SUBSTANCES

Nitric Oxide Serotonin

• Endothelium-derived relaxing factor • Also known as 5-hydroxytryptamine
• Gaseous signaling molecule; Readily diffuses across the cell • Secreted by neurons of raphe nuclei; also synthesized by
membrane neuroendocrine cells
• Synthesized from arginine via Nitric Oxide Synthase • Higher during day-time
• Potent vasodilator and platelet aggregation inhibitor • Circulating serotonin is generally not involved in normal
systemic control of the circulation but rather in local control
Endothelin • Has multiple functions due to its numerous receptors
• A 21-AA peptide found in endothelial cells
• Potent vasoconstrictor Melatonin
• Exists as 3 isopeptides: ET-1, ET-2, and ET-3 • Synthesized from serotonin
o ET-1 being the most predominant form • Rate limiting enzyme is N-acetyltransferase
• Binding of an endothelin to any endothelin receptor subtype • Tells that nighttime has arrived; induces sleep
® ­ Ca2+
• Synthesis

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• Feedback to suprachiasmatic nucleus at dawn or dusk also • Pre-antral: the stage before the appearance of antrum
helps evoke day-night entrainment of the SCN 24- to 25-hour • Primary oocytes: gametes
clock • Divided into 2: Primary & Secondary Preantral
• Peak in the middle of the night, opposite to cortisol which follicles
peaks in the morning
Table below: Comparison Between Primary and Secondary Follicles
ERYTHROPOIETIN Primary Follicles Secondary Follicles
• Hypoxia stimulates kidneys to produce erythropoietin which Increased numbers of
will produce progenitor cells (including RBC) single layer of cuboidal granulosa cells that form
• Secreted by the renal tubular cell granulosa cells multiple layers (3-6) around the
oocyte
Once it acquires the 3-6 layers,
5.07 Female Reproductive Physiology Granulosa cells begin to it secretes paracrine factors that
express FSH receptors induce nearby stromal cells to
OOGENESIS differentiate into epithelioid
theca cells
Oogenesis – development of oocyte to mature egg Referred to as a mature
1. At 6 weeks – primordial germ cells migrate to the outer preantral follicle once a thecal
Stimulators of FSH receptor
surface of the ovary layer forms
expression include FSH
2. 12-24 weeks – proliferation of oogonia with 6-7 million cells; itself, activin, cyclic AMP, and
them meiosis happens Thecal cells express LH
TGFβ
o This is also the 1st Meiotic Division receptor and produce
o Also known as Diplotene Stage (Prophase I) androgens (androstenedione)
3. Most of the primary oocytes undergo atresia so that at birth,
there will only be 1-2 million primary oocytes Antral Follicles
4. At puberty, meiotic division is resumed, but only 300,000- • Dependent on pituitary FSH for normal growth
400,000 oocytes are left • Primary oocyte grows rapidly in early stages until it becomes
5. During reproductive age, only 400-500 oocytes are left the arrested secondary oocyte
• Larger antral follicles gain meiotic competence but still
FOLLICULOGENESIS maintain meiotic arrest until the midcycle LH surge
• Meiotic arrest is achieved by maintenance of elevated cAMP
• The process of maturation of an ovarian follicle. Requiring levels in the mature oocyte
almost 1 year for a primordial follicle to grow and develop into • Granulosa cells differentiate into 3 distinct phenotypes based
the ovulatory stage on the position within the follicle:
• 3 states of ovarian follicles can be identified following puberty: 1. Antrum: fluid-filled spaces between the cells
1) Primordial Follicles o Periantral/antral cells – surrounds the antrum
§ Very prevalent; located in the ovarian cortex 2. Mural granulosa cells (stratum granulosum)
2) Growing Follicles 3 recognizable stages: o Outer wall of the follicle adherent to basal lamina
a. Early Primary Follicle o Differentiates into corpus luteum after ovulation
b. Late Primary Follicle 3. Cumulus cells (AKA cumulus oophorus/corona radiata)
c. Secondary (Antral) Follicle o The innermost layer maintains gap and adhesion
3) Mature (Graafian) Follicles - follicle reaches maximum junctions within the oocyte
size o Becomes corona radiata of the ovulated oocyte
• Folliculogenesis is also divided into two phases:
1. Preantral or Gonadotropin Independent Phase Early Antral to Preovulatory Follicles
2. Antral or Gonadotropin Dependent Phase • Mature preantral (0.1mm) → 25 days → early antral (0.2 mm)
• Includes 4 major developmental events: 45 days → antral follicles (2 to 5 mm) - recruitable
o Primordial follicle recruitment • Characterized by 100-fold increase in granulosa cells
o Preantral follicle recruitment • Larger antral follicles gain meiotic competence but still
o Selection and growth of the antral follicle maintain meiotic arrest until the midcycle LH surge
o Follicle atresia • Endocrine function of large antral follicles:
o Thecal cells: secrete androstenedione and
Primordial Follicle testosterone
• A small primary oocyte arrested in the diplotene stage of o Mural granulosa cells: secrete inhibin B during this
meiosis’s prophase I phase
• Represents the ovarian reserve of follicles
• A single layer of flattened or squamous granulosa cells DOMINANT (GRAAFIAN) FOLLICLE
closely opposed to the primary oocyte
• Establishes gap junctions with other follicle cells and the • Recruited around day 7 of the present menstrual cycle
oocyte o Secretes the highest amount of estrogen with greatest
• Age-dependent changes the in the number number of receptors
• Highest at mid-gestation (~ 5th month) o Most sensitive to FSH
o Highest mitotic activity
Primordial to Primary Follicle Transition o More vascularized theca cells to aid in ­ FSH-receptor
interaction
• Recruitment/primordial follicle activation
• Atretic follicle – demise of an ovarian follicle due to
• Histological hallmarks of recruitment: a change in shape from
apoptosis or atresia
squamous ® cuboidal, and the acquisition of mitotic
potential in the granulosa cells
• Growth of oocyte
• Atresia continuously accelerating
Pre-antral Follicles

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 OVULATION
MENSTRUAL CYLE
1. Stigma or macula pellucida: poorly vascularized bulge of
the uterine wall. Figure below: menstrual cycle showing the changes in hormones
2. Attachment of cumulus cells to mural granulosa cells (Boron, 2nd Ed. Pg 1155)
degenerates ® cumulus expansion
3. Granulosa cells secrete angiogenic factors ® rapid
vascularization to produce androstenedione

CORPUS LUTEUM

• In the luteal phase after ovulation, blood vessels invade the

remnant of the follicle, which is termed the corpus
hemorrhagicum.
• corpus luteum ® corpus albicans (after luteal phase) ®
apoptosis
• Lifespan of 14 ± 2 days is constant.
• ¯ LH and FSH due to negative feedback.

Table below: summary of hormones secreted by the following cells

Androstenedione
Theca cells
Testosterone
Estrone
Granulosa cells
Estradiol
Corpus luteum Progesterone (primary hormone)
note: Inhibin A: represses FSH secretion.

OVARIAN STEROID BIOSYNTHESIS

Table below: Summary of changes taking place during menstrual
• StAR shuttles cholesterol so it goes toward the inner cycle
mitochondrial membrane. PHASES HORMONES STIMULATED / INHIBITED
(28 Day Cycle)
2-Cell, 2-Gonadotropin Hypothesis Menstrual phase ¯ progesterone, estrogen
• Based on the need for both theca and granulosa cells to be (3rd -5th day) ­ LH (minimally)
present within the dominant follicle for the ovaries to produce
estradiol/estrogen stratum functionale sloughs off because of
intensive coiling of spiral artery
Figure below: illustrates 2-cell,2-gonadotropin hypothesis where Follicular Phase / FSH induces recruitment of follicles ® ­
estrogen is only produced when both theca and granulosa cells are Proliferative estrogen secretion by granulosa cells
present (Boron, 2nd Ed. Pg 1160) Phase
(6th -13th day) estrogen stimulates the proliferation of
uterine walls as a result of which
endometrium gets thickened
Ovulation (14th Caused by LH surge, thus inducing of
day) Graafian follicle and release of ovum
Luteal Phase / ­ progesterone from corpus luteum for
Secretory Phase maintenance of thick endometrium
(15th -28th day)
In the absence of fertilization: ¯ LH and
progesterone ® new menstrual cycle and
formation of corpus albicans

Table below: summary of differences between granulosa cells

during Preovulatory period and granulosa lutein cells during luteal
phase
Table below: Comparison between theca cells and granulosa cells. Granulosa Granulosa-Lutein
Theca cells Granulosa cells Vascularization less more
Have the ability to take up Cholesterol more due to
They are found deeper within less
cholesterol + produce DHEA vascularity
the follicle.
and androstenedione. Receptor FSH receptor only both FSH + LH
They are found superficially progesterone [+] due to LH and
They are distal to the blood
which is closer to the blood Synthesis [-] presence of LDL
vessels and is surrounded by
vessels in order to take up cholesterol
LDL-poor follicular fluid
LDL cholesterol.
Have receptors for both FSH
Have receptors for LH
and LH
No aromatase Aromatase is present
Cannot convert
androstenedione to estrogen.
Testosterone → estradiol
Instead, androstenedione
diffuses towards the granulosa

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Regulation of Menstrual Cycle Table below: Functions of FSH and LH
Involves “dialogue” between ovary and pituitary gonadotropes FSH LH
• ­ estradiol by granulosa cells • ­ LDL receptors in theca
Figure below: illustration of the changes between the pituitary via activation of aromatase cells for androgen
hormones and ovarian hormones (Berne & Levy, 7th Ed. Pg 809) • Helps with follicular growth, production
maturation & dominant follicle • ­ progesterone in corpus
selection luteum
• Rescue of follicles from • Helps with follicular growth,
degeneration maturation, & dominant
follicle selection
• Induces ovulation
• Stimulates prostaglandin
synthesis for ovulation

PATTERNS OF GONADOTROPIN RELEASE OVER LIFETIME

• Neonatal: no pulsatility; FSH>LH

• Pubertal: pulsatile action established, but expressed only
during sleep; FSH>LH
• Reproductive years - LH pulsatility prevails throughout the
24-hour period in a monthly cyclic manner; LH>FSH
• Postmenopausal - ovaries lack sustained follicular
development; FSH>LH

OVARIAN STEROID HORMONES

Table below: Summary of Estradiol and Progesterone

• estradiol: 0.1 to 0.5 mg
lowest during menses
highest just before ovulation
Daily Secretion • progesterone:
0.5 mg: follicular phase
20-40mg: mid-luteal phase by corpus luteum
GONADOTROPINS Metabolism • degraded in the liver and kidneys

Gonadotropin Releasing Hormone (GnRH) • Sex Hormone Binding Globulin (SHBG):

Estrogen
• Primary action: ­ FSH and LH by gonadotrope under pulsatile (Berne: 60% bounded to SHBG) (Boron: 38%)
secretion • Albumin: Progesterone & Estrogen
o Greatest frequency of secretion during ovulation Transport
(Berne: 20%) (Boron: 60%)
Protein
• Free form
Regulation of GnRH Secretion
(Berne: 20%) (Boron 2%)
1. Long Feedback Loop • Cortisol-Binding Globulin (CBG):
• Stimulation and inhibition by ovarian steroids (E2, P4) Progesterone
and non-steroidal secretions (inhibin, activin, and
• ↑ SHBG: Estradiol, obesity and
Follistatin) Clinical hyperthyroidism
2. Short Feedback Loop Correlation • ↓ SHBG: Androgens and hypothyroidism
• Inhibition by gonadotropins (LH, FSH)
3. Ultra-short Feedback Loop
• Inhibition by GnRH

KISSPEPTINS Table below: Important functions of ovarian steroid hormones

(not limited to the list below)
ESTROGEN PROGESTERONE
• Neuropeptides produced by hypothalamic neurons within the
arcuate nucleus • ­ estrogen and progesterone • inhibition of synthesis of
• Receptor: G-protein coupled Receptor 54 (GPR54) receptor synthesis in target estrogen and progesterone
tissues e.g. endometrium receptors*
• Responsible for the following:
1) pulsatility and secretion of GnRH • ­ intracellular synthesis of
2) [ + ] and [ - ] feedbacks during gonadotropin secretion estrogen dehydrogenase
3) onset of puberty (converts estradiol to less
potent estrone)
FSH & LH *Although functions of estrogen and progesterone are
complementary, sometimes they act as antagonist of the other
• Structure: identical α subunit but different β subunits
• Secretion: common cell types – basophilic cells
• Generally, in female lifespan: LH > FSH secretion (FHS
inhibition results from ­ estradiol and ­ inhibin)
• Puberty and menopause: FSH > LH secretion

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 ACTIVIN, INHIBIN, FOLLISTATIN Table below: Actions of estrogen to promote sperm transport
Location Increased Decreased
Table below: summary of the functions of Activin, Inhibin, Ampulla Growth and -
Follistatin activity of the
Activin Follistatin
cilia
• ­ FSH release but not LH • AKA FSH-suppressing protein
Smooth muscle
• ¯ progesterone • Inhibits FSH synthesis and
­ estradiol secretion as well as the FSH contraction
• stimulation of thecal response to GnRH Isthmus Smooth muscle -
androgen production; • Binds to activin and decreases contraction
inhibition of oocyte its activity Cervix - Mucus viscosity
maturation Vagina Glycogen pH
Inhibin
• inhibits FSH over LH release Synchronization with Maternal Ovarian and Reproductive
• ­ progesterone; ¯ estradiol Tract Function
• stimulation of thecal androgen production inhibition of oocyte • The events between fertilization and implantation takes 6 days
maturation to complete
• Decline in secretion in perimenopause and menopause - • Implantation occurs at day 22 of the menstrual cycle
permissive factor in the rise of FSH levels o During this time, the ovary is in the mid-luteal phase
• Inhibin A: produced by corpus luteum during luteal phase • Histiotropic nutrition (1st trimester) ® Hemotropic nutrition
• Inhibin B: produced by granulosa cells during follicular phase o In histiotropic nutrition, provision of nutrients to the
embryo comes from the uterine glands which are
stimulated by progesterone
5.08 Pregnancy & Lactation o Hemotropic nutrition takes place when the placenta is
already formed and the nourishment to the fetus will now
FERTILIZATION be provided by the maternal blood.
• The window of receptivity, located in the uterine
• The following lists the steps in fertilization: endometrium, is induced by progesterone from day 20 - 24 of
1. Penetration of expanded cumulus by the sperm the menstrual cycle
o Hyaluronidase from the sperm head digests the
extracellular matrix of the cumulus oophorus Egg activation
2. Penetration of the zona pellucida by the sperm • In mammalian eggs, a large initial release of Ca2+ is followed
o Sperm binds to ZP3 ® release of acrosomal by a series of smaller Ca2+ oscillations that can last for hours.
enzymes ® acrosomal reaction ® sperm This wakes up the metabolically quiescent egg so it can
secondarily binds to ZP2 as zona pellucida is resume meiosis and begin embryonic development.
digested • The activated egg completes meiosis II as the sperm DNA
3. Fusion of the sperm and egg membrane decondenses and a pronucleus forms around it.
4. Ca2+ signaling cascade via the IP3-DAG pathway • The male and female DNA replicate as the two pronuclei are
5. Prevention of polyspermy pulled together
o Activation of the signaling cascade results to the • Once the pronuclei contact each other, the nuclear
exocytosis of cortical granules and release of their membranes break down, the chromosomes align on a
enzymes to the outside of the egg ® modify the ZP2 common metaphase plate, and the first cleavage occurs.
and ZP3 of the zona pellucida
o ZP2 can no longer bind acrosome-reacted sperm IMPLANTATION
o ZP3 can no longer bind capacitated acrosome-intact
sperm Blastocyst Components
6. The entire sperm enters the egg during fusion 1. Inner Cell Mass (Eccentric)
o Head disintegrates from body (where mitochondria o “embryoblast”; forms the embryo
is at) and tail, leaving the future embryo with o a cluster of cells located and attached on one wall of the
mitochondria from the mother outer trophoblast layer
o Once inside the egg, sperm DNA decondences 2. Trophoblast (epithelial-like layer)
o A pronucleus forms around the sperm DNA as the o “trophoectoderm”
newly activated egg completes the 2nd meiotic o surrounds the inner cell mass and a fluid-filled blastocyst
division cavity known as the blastocoele or the blastocystic cavity
o Develops into amnion, yolk sac, and placenta (fetal
Table below: Ovum and Sperm Transport portion)
Location Time of Percent of
appearance ejaculated sperm Table below: Event from Fertilization to Implantation
(minutes after Day Day According to Event
ejaculation) Fertilization
16-17 Fertilization
Fertilization site 30-60 0.001
(upper third of the 17-18 1-2 First 2 cleavages
oviduct) 19 3 Morula Formation
(16-Cell Stage at
Uterus 10-20 0.1
Oviducts)
Cervical canal 1-3 3
20-21 4-5 Blastocyst
Vagina 0 100 Formation
21 5 Fertilized ovum
ready for adherence
22-23/24 Implantation

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 STAGES OF IMPLANTATION Table below: Hormone Concentration during Pregnancy
1st • Corpus luteum produces progesterone and
Stage 1: Apposition trimester estrogen
• Earliest contact between the blastocyst wall, trophoblast, and • HCG produced by placenta
the endometrial epithelium 2nd • Progesterone and estrogen are supplied by
• Usually occurs in a crypt in the endometrium trimester both the placenta and corpus luteum
• Occurs at the site where zona pellucida is ruptured
Stage 2: Adhesion 3rd • Corpus luteum does not secrete estrogen and
• Attachment of trophoblast via microvilli; embryonic pole trimester progesterone anymore
attaches to the uterine endometrium • Only placenta produces estrogen and
Stage 3: Invasion progesterone
• Trophoblastic cells rapidly proliferate and invade the
endometrium (decidua)
PATURITION
Maternal Responses to Implantation • Process of uterine contractions leading to childbirth
• In the case of pregnancy, Pre-decidual cells (in the uterus) ® • 3 Stages of labor:
Decidual cells 1. Strong uterine contractions forcing the fetus against
• Decidualization- enlargement of stromal cells as they become dilating and thinning cervix (several hours)
lipid and glycogen-filled decidual cells; at this time, the 2. Delivery of fetus (<1hr)
endometrium is called the decidua 3. Delivery of placenta with contractions of myometrium to
• TIMPs- factors secreted by decidua; regulates activity of
halt bleeding (<10 mins).
hydrolytic enzymes in the endometrial matrix as it helps to
control the invasion to not reach the myometrium • Final common pathway for the initiation of labor appears to be
activation of the fetal hypothalamic-pituitary-adrenal-axis
PLACENTA
Table below: possible factors responsible for initiation of
Table below: The trophoblasts will become cytotrophoblast and parturition
syncytiotrophoblast
Probable factors Effect
• Inner layer
• Provides feeder layer of ­ fetal size ­ uterine irritability
Cytotrophoblast continuously dividing cells Reversal of progesterone
block
Uterine distention Reflex to reduce size by
• Outer layer
• During implantation: start secreting fetal expulsion
the LH like protein human chorionic Fatty degeneration of Leads to interference in
gonadotrophin, which maintains the placenta and presence of fetal nutrition and
viability of the corpus luteum and infarcts separation process of
progesterone secretion fetus from uterus
Syncytiotrophoblast • By 10 weeks: syncytiotrophoblast
acquire the ability to make
Key Factors of Parturition
progesterone at sufficient levels to
maintain pregnancy independently • Role of Estrogen
of a corpus luteum o ↑ gap junctions of myometrial cells ® uterus able to
contract as a coordinated unit during labor
o Stimulated by ↑ in DHEA
Hormones Regulating Placental Function o Always antagonizes progesterone
• Human Chorionic Gonadotropin (hCG) • Role of Oxytocin
o Composed of a common a-glycoprotein subunit (a-GSU) o Does not initiate parturition, because it increases only
and a hormone-specific b subunit (b-hCG after the initiation, but helps in the progression of labor by
o Primary action: stimulate LH receptors on the corpus
increasing uterine contractions
luteum ® prevents luteolysis and allowing progesterone
production during the first 10 weeks (“morning sickness”) o ↑ oxytocin receptors in the myometrium ® higher uterine
• Progesterone responsiveness to low oxytocin levels
o Maintains a quiescent myometrium o Positive feedback: ® oxytocin ® ­ Prostaglandin ® ­
o used by the transitional zone of the fetal cortex to make uterine contraction
cortisol late in pregnancy o Released through neuroendocrine reflex in response to
• Estrogen stretch in the cervix
o ­ maternal estrogen level throughout pregnancy
• Role of CRH
o ­ uteroplacental blood flow
o Fetal zone releases DHEAS throughout most of gestation o “placental clock”: ↑maternal plasma CRH
• Human Placental Lactogen (hPL) or Human Chorionic o Stimulates anterior pituitary to produce ACTH ® adrenal
Somatommotropin (hCS) cortex stimulated to release:
o As the placenta grows, hPL secretion increases § Cortisol ® promote lung maturation by surfactant
o Protein anabolic and lipolytic § DHEA ® converted into estrogen
o Antagonistic action to insulin ® Diabetogenicity of
• Role of Inflammation/Inflammatory Cytokines
pregnancy
o Like PRL, it stimulates mammary gland growth and o ­ pulmonary surfactant ® ­ macrophages in uterus
development (mammary gland in pregnancy results from ­ macrophages, along with uterine stretching, produces
the actions of the hPL, PRL, estrogens, and progestins) nuclear factor kappa-B (NF-κB) ® ­ cytokines such as

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 IL-1, IL-6, and IL-8 ® ­ oxytocin receptors in • In the absence of placental
myometrium and prostaglandin production ® ­ Uterine progesterone, normal breast milk
production occurs within a few days
responsiveness to low levels of oxytocin ® ­ uterine
contraction After parturition • Stimulation of pituitary PRL along with
Table below: Opposing effects of progesterone and estrogen on the presence of normal levels of
factors involving parturition insulin, cortisol and thyroid hormone is
Progesterone Estrogen required for lactogenesis and
Myometrial quiescence + - maintenance of milk production
Myometrial activation - +
Myometrial gap junctions - + Neuroendocrine Reflex
Prostaglandin F2α and E - + • Prolactin
production o Secretion is stimulated by the suckling of the infant
Local oxytocin production NA + o PRL levels are directly correlated with the frequency and
Oxytocin receptors - + duration of suckling
Cervical rigidity + - o Dopamine secretion (the PRL release inhibitory factor) is
inhibited
Matrix metalloproteinase - NA
o GnRH also inhibited which is associated with lactational
Cervical ripening - + amenorrhea.
• Oxytocin
PLACENTA-FETAL ADRENAL ENDOCRINE CASCADE o Also stimulated by suckling
o Contraction of the myoepithelial cells induces milk let-
• Placental Corticotropin-Releasing Hormone (CRH) down or expulsion of milk from breast
o sensitizes uterus to prostaglandins and oxytocin = o Psychogenic stimuli e.g. mother hearing a baby crying or
promotes myometrial contraction thinking about her baby induces oxytocin release but
• Placental CRH accumulates in fetal circulation and does not affect PRL release.
stimulates fetal ACTH secretion.
• ACTH stimulates production of fetal adrenal cortisol and
feto-placental estrogen 5.09 Sex Differentiation
• Importance of increase cortisol in the placenta:
o Lung maturation SEX DETERMINATION
o Liver glycogen levels
o Liver gluconeogenesis • 6-weeks in utero: gonadal differentiation starts to occur
o ↑ intestinal transport and digestion
• Sex is determined at fertilization upon zygote formation (2n)
o Closure of the ductus arteriosus
• Can be classified according to:
In summary:
1) Genetic Sex: whether XY or XX carriers
­ placental CRH ® stimulation of fetal pituitary ACTH secretion ®
­ fetal adrenal gland activity ® ­ placental cortisol, ­ DHEA-S ® ­ 2) Gonadal Sex: whether gonads are testes are ovaries
estrogen ® ­ prostaglandins ­ oxytocin in placenta ® ­ oxytocin 3) Genital Sex: whether the person appears male or female
receptors in uterus ® ­ actin, myosin, & gap junctions in uterus 4) Psychological Sex: what the person identifies as

LACTATION GONADAL DEVELOPMENT

Table below: Hormonal regulation of mammary gland development • Before 6 weeks in utero: gonads are identical in both sexes
Stage Hormonal regulation
• Gonads: have cortex and medulla
At puberty Estrogen: ­ ductal growth and • After 6 weeks:
branching
o Male: medulla ® testes; cortex ® regresses
At onset of the Progesterone + estrogen: induce
luteal phase of ductal growth and formation of o Female: cortex ® ovaries; medulla ® regresses
the ovary rudimentary alveoli o Note that embryonic ovaries do not secrete hormones
• estrogen: ­ fat deposition
MALE GENITALIA DEVELOPMENT
• Adipose tissue expresses CYP19/
Non-pregnant aromatase, so accumulation of this
cycle tissue in the breast increases local • Presence of SRY gene from Y-chromosome ® production of
production of estrogen from circulating TDF (testis determining factor) ® gonads differentiate into
androgens testis (with Leydig + Sertoli cells) ® male phenotype
• Estrogen, progesterone, placental • Leydig Cells: secretion of testosterone ® differentiation of
lactogen, and a growth hormone Wolffian duct (mesonephric duct derived) into epididymis, vas
variant stimulate breast development deferens, seminal vesicles, ejaculatory ducts
• Estrogen ® ­ maternal pituitary PRL
• Sertoli Cells: secretion of AMH (Anti-Müllerian Hormone) ®
from pituitary lactotropes ® stimulates
lactotrope hypertrophy + proliferation regression of Müllerian Duct (paramesonephric duct derived)
During
pregnancy ® two-fold increase in pituitary
volume
• Progesterone inhibits the onset of milk
production and secretion
(lactogenesis)

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 FEMALE GENITALIA DEVELOPMENT
Table below: summary of embryonic derivatives
• Absence of SRY gene ® gonadal differentiation into ovaries Female
Anlage Male Derivatives
® secretion of estrogen ® paramesonephric duct Derivatives
differentiates into fallopian tubes, uterus, upper 1/3 of vagina Primordial gonad
- Testis
® female phenotype Medulla
Ovary Primordial gonad Cortex -
Table below: Female and Male Gonadal Sex Comparison Epididymis
FEMALE MALE Vas deferens
- Wolffian duct
XX XY Seminal
vesicles
10 weeks to 6 months 8 weeks to 7 months
Oviducts
Ovaries: Testis: Fallopian tubes
• Secrete Estrogen Descend at 7th month Műllerian duct -
Uterus
• Mullerian ducts Produce: Upper Vagina
develop • Testosterone Urethra
Urogenital sinus
• Left and right • Dihydrotestosterone Lower Vagina
mullerian ducts (DHT): Penile Urethra
Labia minora Urethral Folds
Penis shaft
develop to female masculinization of
Labia majora Genital Swellings Scrotum
phenotype: ovaries, male genitalia
Clitoris Genital tubercle Glans penis
fallopian tube, uterus • AMH ® Mullerian
and upper third of degeneration PRIMARY SEX CHARACTERISTICS
vagina • Directly related to reproductive organs and external
In absence of Y genitalia.
chromosome, at 10
weeks of gestation, Table below: list of primary sex organs in respective sexes
there will be no TDF. Female Male
Therefore, ovaries will Ovaries Testis
develop from the cortex. Fallopian tubes Penis
Uterus Scrotum
• Dr. Bareng’s Mnemonic: Vagina Seminal vesicles
Prostate gland
- Paramesonephric—P for F: Female
- Mesonephric—Male—Medial (to Müllerian duct)
SECONDARY SEX CHARACTERISTICS
- Müllerian—Mrs. Mulle (female)
- Wolffian—Mr. Wolffe (male) • External characteristics that are not directly involved in
- Ovary—cortex reproduction that distinguishes males and females.
- Testis - medulla
Table below: onsets of secondary sex characteristics by age
Figure below: Diagrammatic Summary of normal sex determination,
Male Age Female
differentiation, and development (Ganong, 2nd Ed. Pg 394) ­ adrenal steroids 6 ­ adrenal steroids
7 (Adrenarche)
(Adrenarche) 8 Breast enlarge
(Thelarche)
9 Straight pubic hair (Pubarche)
10 Ovaries enlarge
Straight pubic hair 11 Adult pubic & axillary hair
(Pubarche) (Menarche)
Testes, penis, 12 Height spurts at peak
scrotum enlarge
Voice deepens 13 Pelvic growth & breast
development
First ejaculation 14 First ovulation
(Thorarche) (Ovularche)
Height spurts at peak 15 Pelvic growth, breasts enlarge,
nipple darkens
Adult pubic & axillary 16 Acne
hair
Acne 17 Voice deepens
18 Linear growth arrests
Facial and body hair 19
20 Peak of brain development
Linear growth arrests 21

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 Table below: Comparison of primary and 2ndary sex
characteristics, adapted from the lecture ppt.
5.10 Male Reproductive Physiology
Primary Sex Secondary Sex
Characteristics Characteristics TESTES
Sex
before, during, after during and after puberty
puberty • Composed of up to 900 coiled seminiferous tubules
• penis and scrotum • genitalia enlargement • Temp in the scrotum is kept 2°C lower than body
• testes – mature during • lowering of voice pitch temperature for optimal sperm development
male puberty • redistribution of muscle • Divided into 2 compartments as listed in the table below:
tissue and fat, pubic,
body and facial hair Intratubular Compartment Peritubular Compartment
• vagina + other internal • genitalia enlargement § Sertoli cells § Leydig cells
genitalia • breast development § Sperm cells § Connective tissues
• Vulva + other external § Peritubular capillary
Female • pubic and arm pit hair
genitalia network
• ovaries – mature during
puberty
SPERM DEVELOPMENT
CHROMOSOMAL DISORDERS
Spermatogenesis
Gonadal dysgenesis (XO and variants) • Spermatocytogenesis: meiotic stages of spermatogenesis
• Turners Syndrome (female with XO) • Spermiogenesis: maturation of spermatids ® spermatozoa
• Spermiation: release of spermatozoa from Sertoli cells
• Only 1 X chromosome
• No ovaries but female external genitalia develop Steps in Spermatogenesis
• No sex maturation at puberty 1. During embryogenesis: primordial germ cells migrate into the
gonads ® immature germ cells or spermatogonia ®
Superfemale (XXX) undergoes mitotic division
• Extra X chromosome. 2. Type A spermatogonia under goes mitosis ® Type A + Type
• No characteristic abnormalities. B spermatogonia
3. Type B spermatogonium differentiates into primary
Seminiferous tubule dysgenesis (XXY and variants) spermatocyte ® migrates to the adluminal compartment of
seminiferous tubules
• Klinefelter’s Syndrome: XY and additional X
4. Primary spermatocyte undergoes meiosis I ® produces 2
secondary spermatocytes
True hermaphroditism
5. Secondary spermatocytes undergo meiosis II ® 4 spermatids
• Presence of both gonads. 6. Spermatids undergo spermiogenesis to become mature
• Rare condition due to XX/XY mosaic pattern spermatozoa

DEVELOPMENTAL DISORDERS Table below: spermatogenesis stages and corresponding ploidy &
number of chromatids
A pseudohermaphrodite is an individual with the genetic Ploidy # of chromatids
constitution and gonads of one sex and the genitalia of another. spermatogonium diploid 2
1˚ spermatocyte diploid 4
Female Pseudohermaphroditism 2˚ spermatocyte haploid 2
• Female exposed to androgen during the 8th– 13th week of spermatid haploid 1
gestation spermatozoa haploid 1
• Congenital virilizing adrenal hyperplasia of fetus
4 Phases of Spermiogenesis
• Genetically female but have male genitalia 1. Golgi phase
• Excess maternal androgen o development of polarity – head and tail
• Virilizing ovarian tumor o secretion of enzymes that will be acrosome
o nucleus condenses
• Iatrogenic: treatment with androgens or certain synthetic
2. Cap/ Acrosome phase
progestational drugs o Golgi surround the nucleus to form acrosomal cap
3. Formation of tail
Male Pseudohermaphroditism o due to the elongation of the centrioles
• Female external genitalia in genetic male 4. Maturation phase
o excess cytoplasm and organelles are shed off and
• Androgen resistance
engulfed by Sertoli cells
o 5α-reductase deficiency = DHT is not formed
o Various mutations in the androgen receptor gene Regulation of Spermatogenesis
• Defective testicular development • Intrinsic
• Genetically male but have female genitalia (no MIS) o Testosterone (intratesticular role)
o Neurotransmitters (neuroendocrine substances)
• Congenital 17α-hydroxylase deficiency o Growth Factors (from Leydig cells)
• Congenital adrenal hyperplasia due to blockade of o Blood vessels
pregnenolone formation o Seminiferous Tubules (lamina propria)
• Various non-hormonal anomalies o Sertoli cells
• Extrinsic
o Hypothalamic and hypophyseal control of pulsatile
secretion of GnRH ® FSH and LH
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 SPERMATOZOON CAPACITATION

• Head: contains hyaluronidase and proteolytic enzyme • Process by which the spermatozoa acquire the ability to
• Neck: concentrated with mitochondria penetrate the zona pellucida of the ovum
• Tail: contains axoneme – 11 microtubules • Involves the removal of protective vesicles from the sperm cell
• Motility: back and forth movement ® rhythmical longitudinal membrane to permit acrosomal reaction
sliding motion • Ca2+ cause changes in the activity of the flagellum and
changes in the cellular membrane of the acrosome ®
SERTOLI CELLS facilitating the release of acrosomal enzymes
• Normally requires 1 - 10 hours
• Aid in sperm cell viability and development • In the epididymis, protective vesicles coat the head of the
• Function is temperature-dependent sperm to prevent the immediate release of acrosomal
• Tight junctions connect adjacent Sertoli cells, forming the enzymes
blood-testis barrier • When sperm cells are introduced into the semen, they are
• Engulf residual bodies through phagocytosis exposed to plasma proteins, which coat the vesicles. This
• Express the following receptors: toughens the covering of the acrosome, further preventing the
o Androgen release of the acrosomal enzymes
o FSH • When sperm cells are ejaculated into the female tract, the
• Produce the following: vesicles are gradually released from the head of the sperm
o Androgen-binding protein cells as they swim
o Bathing medium for developing sperm cells • Upon coming in contact with the ovum, sperm cells will be
o CYP 19 (aromatase): converts testosterone ® ready for the acrosomal reaction
dihydrotestosterone (DHT)
• Secrete the following hormones: ACROSOMAL REACTION
o Inhibin: inhibits FSH production
o Aromatase: converts testosterone to estrogen • Stored enzymes in the acrosome are released to dissolve the
o Anti-Mullerian Hormone (AMH) granulosa cell layer and penetrate through the zona pellucida
• Hyaluronidase: depolymerizes the intercellular element that
LEYDIG CELLS holds the granulosa cells
• Proteolytic enzymes: digest proteins
• Primary endocrine cell of testis – secretes testosterone in • These enzymes are inactive until acrosomal reaction occurs
presence of LH
• Testosterone production is unaffected by temperature ANDROGENS
changes
• Testosterone indirectly affects development by regulating • Any cholesterol-derived hormone that has masculinizing
Sertoli cell function effects
• Regulate blood flow in the intertubular microvasculature o Testosterone – primary androgen
o Dihydrotestosterone (DHT) – more potent than
LEYDIG-SERTOLI INTERACTION testosterone
o Androstenedione – less potent androgen
Figure below: Physiology and interaction between Leydig cell (Left) • 5a-reductase: located in SER; enzyme responsible for
and Sertoli cell (Right) (Boron, 2nd Ed. Pg 1133) testosterone ® DHT conversion
• 5a-reductase has 2 isoforms listed in the table below:
5a-reductase Type 1 5a-reductase Type 2
• Found in the skin • Found in male urogenital
• Contributes to sebaceous tract, genital skin, hair
gland activity and acne follicles, and liver
• Onset occurs at puberty • For masculinization of
genitalia in utero and
puberty, male 2ndary
characteristics

TESTOSTERONE

• Produced by:
o Leydig Cells
o Adrenal Cortex (Zona reticularis)
• Mnemonic: LH = Leydig; FSH = Sertoli o Adipose, Brain, and Muscle Tissue
• Net effect of LH to Leydig cell: testosterone production • Most are sequestered by Androgen Binding Proteins
• Net effect of FSH to Sertoli: production of growth factors and produced by Sertoli cells
substances needed by Leydig cells for testosterone • Others in circulation are bound to:
production o Sex Hormone Binding Globulin (SHBG) – 60%
o Albumin – 38%
PATHWAY OF SPERM o Unbound/Free – 2% - Exerting biologic actions
• An anabolic hormone with the following effects:
Seminiferous tubules ® Rete testis ® vas deferens ® head of o ­ muscle mass
epididymis ® duct of epididymis ® vas deferens ® ampulla ® o RBC production
ejaculatory duct ® urethra o Secondary sex characteristics
o Affect cholesterol level (­ VLDL­ LDL ¯ HDL)
o ­ Libido
o Male pattern Baldness

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Metabolism of Testosterone
• Primary sites:
o Liver: converted to 17 ketosteroids
o Prostate: converted to DHT
• Small percentage can be detected in the urine
o Urinary testosterone: <2% of daily testosterone
production
• Some are converted to estradiol via aromatase

Peripheral Effects of Testosterone and its Metabolites

• Direct action: DHT and estradiol
• Effects of DHT
o Growth of the prostate gland
o Facial and body hair
o Sebum formation
• Male pattern baldness
o baldness of men at the vertex of the head during
advanced age; unknown definite mechanism
o Due to the interplay between genetic factors and levels of
testosterone (especially DHT)

AGE-RELATED HORMONAL CHANGES

Table below: Variations of testosterone levels and associated

effects over time
Testosterone
Age Event
Levels
development of male reproductive
Before Birth ­ system
Few Months
¯ remain low until puberty onset
after Birth
Childhood ¯ remains low
steady increase and surge
Puberty • Controls 2 primary functions:
­­ pubertal changes, sperm production
steady increase of testosterone o Spermatogenesis
Adulthood ­ levels and rate of sperm production o Androgen biosynthesis in Leydig cells
Old Age ¯¯
Decline, but sperm cell production • Sexual function begins with the stimulation of GnRH in
but does not cease hypothalamus ® ­ LH & FSH from anterior pituitary
• Effects of testosterone’s negative feedback loop:
MALE CLIMACTERIC 1) Rapid effects:
- Hydrolysis of cholesterol esters
• ¯ testosterone levels that is partly responsible for the ¯ male - New expression of StAR protein
sexual function 2) Less acute effect:
• Also known as: - ­ steroidogenic enzyme gene expression
o Androgen Deficiency in the Aging Male (ADAM) - LDL and HDL receptor expression
o Partial Androgen Deficiency in the Aging Male (PADAM) 3) Long-term effect:
o Late Onset-Hypogonadism (LOH) - LH promotion of Leydig cell growth and proliferation
o Testosterone Deficiency Syndrome (TDS)
• Inhibin: negative feedback at the anterior pituitary gland ® ¯
o Andropause (≠ menopause as to steroid levels -
FSH
misleading)
• Can be associated with symptoms similar to menopause SEMEN
HYPOTHALAMIC-PITUITARY TESTIS AXIS
Sperm cells (10%) origin of secretion
Figure on the other side of this page: illustration of the Seminal Plasma Seminal vesicles
hypothalamic-pituitary-testis axis and the negative feedback loops (90%) (70%)
(Boron, 2nd Ed. Pg 1131) prostate, epididymis, and
bulbourethral glands
(20%)

MALE SEXUAL ACT

Erection
• Psychoneuroendocrine and peripheral neuro-vascular event –
can be stimulated by any form of stimulus
• Parasympathetic control
• Involves atrial dilation (nitric oxide release) and increased
blood flow to erectile tissues.

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Figure below: illustration of the flow of events leading up to penile SEXUAL RESPONSE CYCLE
erection
A. Excitement Phase
• Engorgement of penis + testis
• ­ muscle tension (myotonia)
• ­ heart rate + blood pressure
• Flushing of the skin

B. Plateau Phase
• Continued ­ engorgement and elevation of the testis
• Cowper’s gland secretes fluid to help in the lubrication
(parasympathetic effect) and protection of sperm

C. Orgasm Phase
• “Culmination of sexual excitation”
• Involves emission and expulsion
• Cognitive correlation of ejaculation
• Climactic; shortest phase of the cycle
• Muscles contract involuntarily, muscles of the feet spasm.
• HR, BP and Breathing rate peak.
• Flush may appear all over the body
• Types of Erection • Release of muscle tension
1) Psychogenic Erection
o Triggered by neural impulses originating from the D. Male Refractory Period (MRP)
discrete loci of PNS and CNS • A period of inhibition of erection and ejaculatory response
o Centrally perceived sensual input is relayed by following ejaculation.
neural signals to thoracolumbar center • Affected by serotonin and prolactin.
o Stimulation without physical contact! (wow) • “Resting phase”
2) Reflex Erection • Men are only capable of one orgasm at a time as composed
o Created by tactile stimulus to the penis or genital
to women with multiple orgasms.
area which activates a reflex originating at S2-S4
(sacral erection center) E. Resolution Phase
o Needs physical contact
• Characterized by:
o Decrease/Disappearance of sexual excitement
• Lubrication
o Urethral glands and bulbourethral glands secrete o Descent and ¯ size of testes
mucus, which flows to the urethra to aid in lubrication o Thinning of scrotum
during coitus. • Occurs within 1-2 minutes
o Involves parasympathetic control • May be a result of:
o Cessation of NO release
Emission o Breakdown of cGMP by phosphodiesterase
• Contrary to erection, emission involves sympathetic control o Sympathetic discharge during ejaculation
(T12-L2)
• Movement of ejaculate (semen) into the prostatic urethra CLINICAL CORRELATIONS
through peristaltic contractions of the:
o Vas deferens A. Cryptorchidism
o Seminal vesicles • Aberrant retention of testis in the abdominal cavity.
o Prostatic smooth muscles “Undescended testicle”

Ejaculation B. Male Hypogonadism

• Also involves sympathetic control • Condition in which the body does not produce enough
androgen (testosterone). Leading to absence of secondary
• Forceful expulsion to external environment.
sex characteristics, infertility, muscle wasting, etc.
• Consists of 2 phases:
• 2 Types of hypogonadism in males as listed in the table
o Emission phase below:
o Expulsion phase Classification Organ Causes Effect
• Ejaculatory reflex and control Affected
o By T12 - L2 level of spinal cord (Thoracolumbar Primary Testis Genetic: ↑ GnRH
erection center) (Hypogonadotropic) Klinefelter’s ↓ LH, ↑ FSH,
o Process for sending signal to the brain: Hypogonadism syndrome ↓Testosterone
Congenital:
1. Thoracolumbar erection center sends sensory Anorchia
stimulation to the brain Toxins: Alcohol,
2. Stimulus is perceived by brain therefore creating Heavy metals
psychogenic stimulation Orchitis
Tauma
3. Message goes back to the spinal cord and causes
Aging
erotic stimulation Secondary Hypothala Pubertal delay ↓ GnRH
4. Muscles of pelvic floor, anal sphincter and (Hypogonadotropic) mus GRH analogues ↓ Testosterone
cavernous bodies detect stimulation, leading to Hypogonadism Pituitary Aging ↓ LH, ↓ FSH,
ejaculation gland ↓ Testosterone

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C. Male Infertility
• Inability of a male to cause pregnancy in a fertile female after
12 months or more of regular, unprotected intercourse.
• 4 main categories
o Endocrine and systemic disorders
o Primary testicular defects
o Sperm transport disorders
o Idiopathic male infertility
• Causes include:
o Chromosome anomalies
o Meiotic disorders
o Azoospermia or abnormal spermatozoa
o Other medical or environmental causes

D. Nocturnal Penile Tumescence

• Spontaneous erection of the penis during sleep or upon
waking up.
• Caused by the cessation of discharge of inhibitory
neurons (noradrenergic neurons of locus ceruleus) to penile
erection during REM sleep.

E. Erectile Dysfunction
• Inability of a man to develop or maintain an erection for
satisfactory sexual intercourse.
• Causes include:
o Insufficient androgen production
o Neurovascular damage
o Structural damage to the male sex organ
o Psychogenic factors
o Use of certain substances (nicotine, alcohol and
antidepressants)

F. Priapism
• Persisting, painful and abnormal tumescence that can occur
without any sexual stimulation and does not subside after
sexual intercourse or masturbation.
• Erection lasts for more than 4 hours without any form of
physical or mental stimulation.

G. Retrograde Ejaculation
• Failure of internal urethral sphincter to constrict
• May be a result of any interference of the innervation of vas
deferens and bladder neck
• May be indicated by the presence of 15 sperms/HPF in the
urine after ejaculation

H. Premature Ejaculation
• Characterized by:
o Ejaculation occurring prior to or within 1 minute of vaginal
penetration
o Inability to delay ejaculation during penetration

I. Nocturnal Emission
• Informally known as “wet dreams”
• Occurs in some stages of sexual life, especially in the pre-
pubertal or pubertal period.

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