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Anatomy.................................................................................................................................................. 2
Pelvic Anatomy ................................................................................................................................... 2
Female Reproductive Anatomy .......................................................................................................... 8
Male Reproductive Anatomy ............................................................................................................ 11
Histology ............................................................................................................................................... 15
Female Histology .............................................................................................................................. 15
Male Histology.................................................................................................................................. 16
Physiology ............................................................................................................................................ 18
Maternal Physiology ......................................................................................................................... 25
Foetal Physiology.............................................................................................................................. 31
Adaptation of Newborn to Extrauterine Life .................................................................................... 34
Pharmacology ....................................................................................................................................... 37
Signal Transduction .......................................................................................................................... 37
Autonomic Nervous System ............................................................................................................. 39
Cholinergic Pharmaceuticals ............................................................................................................ 44
Adrenergic Pharmaceuticals ............................................................................................................. 49
Reproductive Pharmacology ............................................................................................................. 54
Embryology – Week by Week Timeline............................................................................................... 57
Genetics ................................................................................................................................................ 73
Genetics Definitions.......................................................................................................................... 73
Types of Disorders ............................................................................................................................ 73
Hardy-Weinberg Law ....................................................................................................................... 74
Screening .............................................................................................................................................. 75
Definitions......................................................................................................................................... 75
Tests to Conduct ............................................................................................................................... 75
Perinatal and Maternal Mortality ...................................................................................................... 76
Microbiology......................................................................................................................................... 77
SG Content ............................................................................................................................................ 80
Indigenous and Pregnancy ................................................................................................................ 80
Menstrual Cycle and Fertility Awareness ......................................................................................... 81
Common Complaints in Pregnancy .................................................................................................. 82
Vaginal Delivery vs Caesarean Section ............................................................................................ 85
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Gestational Diabetes Mellitus ........................................................................................................... 86
Newborn Screening........................................................................................................................... 87
Cervical Neoplasia – Cervix Screening and Health .......................................................................... 88
Vaginal Infections, Endometriosis, Endometritis ............................................................................. 89
Other ................................................................................................................................................. 91
Anatomy
Pelvic Anatomy
Basic Bony Structures
− Definitions:
o Tubercle: A small rounded projection
o Tuberosity: A spongy, tuberous region
o Spine: A short prominence of bone
o Fossa: A deep groove
o Foramen: an opening/hole
o Ramus: A branch
− The pelvis is comprised of 2 Hip Bones and the Sacrum and Coccyx
− Each is comprised of 3 smaller bones: Iliac, Pubis and Ischium
− The Iliac
o Largest of the three hip bones and is posterosuperior
o Engages in a synovial joint with the Sacrum
o Has an anteromedial Iliac Fossa
o This is lined superiorly via the Iliac Crest
The edges of the crest form 4 Iliac Spines
These are Posterior/Anterior and Superior/Inferior
On the lateral side of the peak is an outgrowth known as the Tubercle of the
Iliac Crest
o The medial posterior surface is a large tuberous region
The main component is the Iliac Tuberosity
Inferior to that is the Auricular Surface
• An articular surface that is ear shaped
o The anterior and posterior surfaces are separated medially by the Arcuate Line
− The Pubis
o The anteroinferior bone that engages in a fibrocartilaginous joint with the
opposite pubis forming the Pubic Symphysis
This forms the Pubic Arch inferiorly
o Split into the Pubic Body and a Superior/Inferior Ramus
The pubic body engages in pubic symphysis whilst the superior ramus connects
to the Iliac and the inferior ramus connects to the Ischium
o Lateral to the pubic symphysis, there is an anterior outgrowth forming the Pubic
Tubercle
o Immediately lateral to the pubic symphysis is the Pubic Crest
o A small indent on the medial side forms the Obturator Groove
o The arcuate line continues as the Pectineal Line down to the Pubic Symphysis
− The Ischium
o The posteroinferior bone comprising of an Ischial Body and an Inferior
Ramus
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o On the posterosuperior surface of the body is the Ischial Spine
This forms 2 notches, the Greater Sciatic Notch superiorly in the Ilium, and
the Lesser Sciatic Notch inferiorly
o The posteroinferior surface of the body forms the Ischial Tuberosity
− These three bones join in a region known as the Acetabulum that forms the articular
surface for the femur
o During foetal development, the bones are connected by Triradiate Cartilage –
an epiphysial plate
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− The Sacrum
o A collection of 5 fused vertebrae with an overall winged shape
Although they are fused, they still have defined anterior Transverse Ridges
and Dorsal/Ventral Sacral Foramina
o The anterosuperior surface has an outgrowth → Sacral Promontory
o Wing-shaped Ala project laterally from the posterior surface
o Posteriorly are Spinous Tubercles that are collectively called the Medial
Sacral Crest
Smaller Lateral Sacral Crests exist to the left and right of the midline
o Has a matching Auricular Surface to the Ilium
− The Coccyx
o A small bony protrusion that is a vestigial remnant of a tail
− The Pelvis can also be split into a superior True Pelvis and an inferior False Pelvis
o These are separated by the Linea Terminalis
From posterior to anterior: Sacral Promontory, Sacral Ala, Arcuate Line,
Pectineal Line, Pubic Symphysis
o This forms the Pelvic Brim
− The main hole formed by the pelvis is the Pelvic Inlet from a “top-down” view whilst
the Pelvic Outlet is from a “bottom-up” view
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o The Iliolumbar Ligament connects the Iliac Crest to the transvers processes of
LV 5 on either side
Stops downward displacement of Sacrum due to pressure from the superior
parts of the body
− Other Ligaments
o The Anterior Longitudinal Ligament connects the Sacrum to the rest of the
spinal column
o The Obturator Membrane covers majority of the Obturator Foramen but
leaves room for a small Obturator Canal
o The Inguinal Ligament connects the Anterior Superior Iliac Spine to the Pubic
Tubercle and makes the Inguinal Canal
Pelvic Musculature
− Muscles of the Pelvic Wall
o Consists of 2 muscles that insert onto the head of the Femur
o The Piriformis Muscle extends from the Sacrum and pass through the Greater
Sciatic Foramen
o The Obturator Internus Muscle extends from both the Obturator Membrane
and Hip bone and passes through the Lesser Sciatic Notch
− Muscles of the Pelvic Diaphragm
o Composed of 2 main muscles, Coccygeus and Levator Ani
o The Ischiococcygeus Muscle (or Coccygeus Muscle) is the most posterior
It extends from the Ischial Spine and inserts on the last piece of sacrum and the
coccyx
o The Levator Ani Muscle comprises of 3 muscles
The Iliococcygeus Muscle extends from the pelvic aspect of the Ischial Spine
and the posterior aspect of the Tendinous Arch
• A thickening of pelvic fascia
The Pubococcygeus Muscle extends from he internal aspect of the Pubis and
the anterior aspect of the Tendinous Arch
• In males, medial fibres form a sling around the Prostate, forming
the Levator Prostatae
• Females attach to the posterior aspect of the vagina forming the
Pubovaginalis
• These muscles aid in micturition and orgasm → ejaculation
The Puborectalis are muscle fibres that arise from the posterior surface of the
pubic symphysis and forms a sling around the rectum
• Some fibres join fibres of the External Anal Sphincter
o The left and right sides of the Levator Ani meet posteriorly and form the
Anococcygeal Ligament
o All covered by Superior/Inferior Pelvic Diaphragm Fascia
− Pelvic Triangles
o When the Pelvic Outlet is viewed from a posterior perspective, it appears
diamond shaped
o This can be split into a posterior Anal Triangle and an anterior Urogenital
Triangle
o This whole region can be referred to as the Perineum
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− Anal Triangle
o Majority of muscles present in the anal triangle are the pelvic diaphragm
muscles
o The External Anal Sphincter surrounds the anal canal and regulates defecation
o The space inferior to the pelvic diaphragm is the Ischiorectal Fossa
Bounded medially by the External Anal Sphincter and laterally by the Ischial
Tuberosity and fascia of the Obturator Internus muscle
Bounded posteriorly by the Sacrotuberous ligament and anteriorly by the fascia
of the Inferior Fascia of the Urogenital Diaphragm
Roofed by the inferior Fascia of the Levator Ani
Filled with liquid fat
Contains the Internal Pudendal Artery/Vein and the Internal Pudendal
Nerve inside the Pudendal Canal
Outside of the canal are the Inferior Rectal Artery/Vein and the Inferior
Rectal Nerve
This space extends anteriorly between the Urogenital Diaphragm and the
Levator Ani to form the Anterior Recess of the Ischiorectal Fossa
– Urogenital Triangle and Diaphragm
o Bounded by the Superior/Inferior Fascia of the Urogenital Diaphragm
The Superior Fascia is separated from the Inferior fascia of the Pelvic
Diaphragm by the Anterior Recess of the Ischiorectal Fossa
The Inferior fascia is also known as the Peritoneal Membrane
o Between these two fasciae is the Deep Perineal Pouch/Space
This houses the Sphincter Urethrae and the Deep Transversus Perinei
Muscle
Perineal Body or the Tendinous Centre of the Perineum: a major site of
muscle attachment for muscles of the perineum and the Levator Ani
o Inferior to the Peritoneal Membrane is the Superficial Perineal Space/Pouch
Contains the Superficial Transverse Perinei which runs from the Ischial
Tuberosity to the Perineal Body
The Ischiocavernosus Muscle covers the Crura of the Clitoris
The Bulbospongiosus Muscle overlies the Bulb of the Vestibule in women
and the Bulb of the Penis in males
− Perineal Body
o Pyramidal Fibromuscular mass in the middle of the perineum at junction of
urogenital and anal triangle, essential for maintaining the integrity of the pelvic
flood.
o Location:
Males: Between membranous urethra and anus
Females: Between vagina and anus
o Attachments
Levator ani: Levator Prostate/Pubovaginalis
Deep and superficial Transverus Perieni
Sphincter Ani externs and Sphincter Urethrare
Bulbospongiosus
− Ischiorectal Fossa
o Laterally: Sacrotuberous ligament, ischiopubic ramus, fascia of obturator
internus muscle
o Medially: Anal canal and external anal sphincter
o Filling: Fat – fluid at body temperature
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o Anterior Recess: Between Levator Ani/UG diaphragm
o Roof: Inferior fascia of pelvic diaphragm, Floor: Superior urogenital
diaphragm fascia
o Inferior rectal vessels, nerves, branch of posterior femoral cutaneous nerve
and perforating cutaneous nerves found here
Pelvic Shapes and Foetal Skulls
− Pelvic Shapes
o Due to the role of Parturition, male and female pelvises differ
The Subpubic Angle is less acute in females
• Men ≈ 60°, Women = 85° - 90°
The pubic bone is wider in females and their Pubic Tubercles are further apart
The Subpubic Arch is wider in females and their Ischial Tubercles/Spines are
further apart
Men have a narrower, heart shaped, Android shaped pelvis as the pelvic cavity
is occluded by protruding Ischial Spines, the Coccyx and the Sacral
Promontory
Women have less prominent features and as such have a rounder Gynecoid
shaped pelvis; optimal for passage of foetal head
Men’s pelvises also tend to have more substantial muscle attachments and
thicker bones
o N.B. 23.5% of pelvic cavities have a greater length than width ← Anthropoid
Only 2.6% have a greater width than length ← Platypoid
− Pelvic Diameters
o The pelvis is naturally tilted with the Pelvic inlet at an angle of 50° - 60° and
the Pelvic Outlet at an angle of 15°
o There are 3 levels to the True Pelvic Cavity, the Pelvic Inlet, the Mid-Pelvic
Cavity and the Pelvic Outlet
o Each has its own Oblique, Transverse and Anteroposterior Diameters:
Transverse Oblique Anteroposterior
Inlet 13.1 cm 12.5 cm 11.2 cm
Mid-Pelvic 12.5 cm 13.1 cm 13.0 cm
Outlet 11.8 cm 11.8 cm 12.5 cm
o These govern the way the foetus’s head travels during Parturition
− Foetal Skull Features
o The foetal skull comprises of 4 superior plates and 1 posterior plate
The 2 anterior Frontal Bones connect to the posterior Parietal Bones at the
Anterior Fontanelle or Bregma
The 2 Parietal Bones join the Occipital Bone at the Posterior Fontanelle or
Lambda
o Anteriorly are the Orbits and the Mandible
o There are 2 Diameters in the foetal skull
The Frontocciptal Diameter spans from lambda to the orbit and is 10 – 11 cm
The Suboccipitalbregmatic Diameter spans from the inferior surface of the
Occipital Bone to the Anterior Fontanelle and is 8.5 – 9 cm
o Due to this, the baby “corkscrews” through the Pelvic Cavity:
1. Engagement, Descent and Flexion
2. Transversely
3. Obliquely
4. Anteriorly
5. Extension of Head (Occiput – superior, Face – Inferior)
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Female Reproductive Anatomy
Ovaries
– Round, Ovoid structures composed of multiple surfaces
o Lateral Wall ← Pelvic Wall in Ovarian Fossa
o Lateral Surface ← Obturator vessels and nerves
o Medial Surface ← Covered by Uterine Tube, s
Separated from Mesosalpinx by Bursa
o Tubal End (Superior): Fimbria + Suspensory Ligament of the Ovary
(SLO)
SLO contains Ovarian Vasculature ← Nerve & Vessels
o Uterine End (inferior): Rounded Ovarian Ligament
o Mesovarian border ← Attached to back of broad ligament by mesovarium
o Free border faces ureter
– Neurovascular
o Blood Supply: Abdominal Aorta/Uterine artery → Ovarian branches
o Venous Drainage: Pampinform plexus → Ovarian vein → inferior vena
cava or left renal vein
o Lymph Drainage: Lumbar or Paraaortic Nodes
o Nerve Supply: Ovarian plexus (extension of aortic plexus) → From vagus
nerve and T10 to 11 of sympathetic ganglia
Uterus
– Between Anterior Bladder (Vesicouterine pouch) and Posterior Rectum (Rectouterine
pouch)
– Components
o Body: Anterior/Posterior/Lateral Margins – receive attachment of round
ligament of uterus and Ovarian ligament
o Fundus: Superior surface above attachments of uterine tubes.
o Isthmus: Narrow region, lower uterine segment
o Cervix: 2.5cm in length
– Uterine Wall
o Endometrium: Mucosa
o Myometrium: Muscular Layer
o Perimetrium: Serosa – peritoneum and areolar tissue
– Uterine Ligaments
o 2 Broad Ligament: Extends from sides of uterus to lateral pelvic wall,
Parietal fold which cover uterine body
Mesometrium: Pelvic wall, to side of uterus. Contains Uterine
arteries, veins, ovarian ligament, round ligament, uterovaginal plexus
and ureter (parametrium)
Mesosalpinx: Mesentery supporting uterine tubes
Mesovarium: Extends posteriorly from above to ovary
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o 2 Uterosacral Ligaments: Fibrous tissue + smooth muscle in uterosacral
folds connecting uterus with sacrum
o 2 Round Ligaments of the uterus: 10 – 12 cm, lateral aspect of uterus →
anteriorly between layers of broad ligament → inguinal canal → insert on
labia majora
o Transverse (lateral) Cervical ligaments of Mackenrodt (cardinal ligament)
side of cervix → upper fascia of pelvic diaphragm
– Supporting Structures
o Pelvic Diaphragm
o Urogenital Diaphragm
o Uterosacral Ligaments
o Transverse Sacral Ligaments
o Perineal body
– Neurovascular
o Blood Supply: Iliac Artery → Uterine artery anastomoses with ovarian and
vaginal arty
o Venous Drainage: Uterine venous plexus → Internal iliac vein
o Lymph: Uterine fundus and body → lumbar and para-aortic nodes
o Nerve Supply: Parasympathetic Pelvic splanchnic nerves and sympathetic
sacral splanchnic nerves → inferior hypogastric plexus → Uterovaginal
plexus
Vagina
– Fibromuscular tube lined by stratified squamous epithelium.
– Anterior Wall (7.5cm): Urethra, base of bladder
– Posterior wall (9cm): Periotneum, upper quarter and lower down related to
– Laterally above: Levator Ani, pelvic facia, lateral cervical ligament and ureter
– Laterally below: Bulb of vestibule, greater vestibular gland, bulbospongiosus muscle
– Neurovascular/Lymph
o Blood Supply: Uterine, Vaginal, Middle rectal and internal pudendal
artery – form anterior/posterior azgyous arteries to vaginal wall
o Venous Drainage: Vaginal plexus veins → Internal iliac vein
o Lymph Drainage: External and internal iliac nodes and sacral nodes
o Nerve Supply:
Autonomic – Upper Vagina: Same as Uterus
Autonomic - Lower Vagina: Inferior hypogastric plexus →
Pudendal nerve
Somatic – Lower Vagina: Ilioinguinal nerve, genital branch of
genitofemoral nerve, perineal branch of posterior femoral
cutaneous nerve and perineal nerve (branch of pudendal nerve).
Cervix
– 2.5 cm in length, meets vagina at right angles and bulges out
– Vaginal and Supravaginal
– Uterus - Internal Os, Vagina - External Os (round in nulliparous, folded in parous)
– Fornix: Recess around cervix – lateral, posterior/anterior
– Longitudinal and Palmate Folds: Interlock – close and open during
menstruation/ovulation
– Lymph Drainage: Lower part drains into external, internal and sacral noteds →
Lumbar and paraaortic lymph nodes.
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Uterine and Vaginal position
– Anteversion: Long axis of cervix 90 to long axis of vagina
o Retorversion: Increases to 130 – 140
o Maintained by round ligament
– Anteflexion: Long axis of uterus body cavity 30 to long axis of cervix
o Retroflexion: Increases to 150 (30 degrees other way)
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Male Reproductive Anatomy
Testes
– Paired ovoid organs
o Superior/inferior end, medial/lateral surface, anterior/posterior margin
Posterior margin covered by Epididymis & lower Spermatic Cord
o Appendix of Testes lie on upper pole
Inferior to Head of Epididymis
Remnant of Paramesonephric Duct
o Supported by Spermatic Cord and Dartos Muscle ← Scrotum
– Tunica Albuginea (TA): Immediate dense CT covering
o Septa partition testes into wedge shaped Lobules
Each contains 1-4 Seminiferous Tubules
800 Seminiferous Tubules → 20-30 Straight Tubules
o Numerous Septa converge near the posterior margin ← Mediastinum
Site of Rete Testes
• Straight tubules → 15-20 Efferent Ductules
– Tunica Vaginalis: Covers Testes
o Remanent of foetal Processus Vaginalus Periotni ← Peritoneum
o Visceral Layer covers TA, medial/posterior surfaces of epididymis
Also Sinus of Epididymis laterally
o Sac ← Fluid filled space
o Parietal Layer ← Lines inside of scrotum
Epididymis
– Composed of a Head, Body and inferiorly pointing Tail
o Appendix of Epididymis ← Located on the head
Remnant of foetal Mesonephros
o Sinus of Epididymis ← between lateral surface and testes
o Ductus Deferens originates from tail and travels in the spermatic cord
– Neurovasculature of Testis and Epididymis
o Blood Supply: Aorta → Testicular A
o Venous Drainage: Testicular V →Lt Renal V (Lt) or IVC (Rt)
o Lymph Drainage: Lateral Nodes and Pre-aortic Nodes
o Nerve Supply: Testicular Plexus ← Travels with testicular Artery and Vein
Scrotum
– A cutaneous fibromuscular sac
o Supports testis, epididymis and lower spermatic cord
o The Scrotal Raphe divides into two halves
From anus to root of penis
o The Dartos Muscle helps maintain optimum temperature
Cremaster Muscle aids with elevation in cold conditions
Covered in thin, pigmented skin
– Vasculature is similar to labia in females
o See Female Reproductive Anatomy
Spermatic Cord
– 3 Arteries:
o Testicular A, Crematseric A, Artery of Ductus Deferens
– 4 Nerves:
o Genitofemoral N (Genital Branch), Cremasteric N, Testicular Sympathetic
Plexus, Ductus Deferens Plexus
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– 3 Other things:
o Pampiniform Plexus (Vein), Lymphatics, Ductus Deferens
– 3 Layers of Fascia:
o External Spermatic Fascia from External Oblique Muscle
o Cremasteric Fascia from Internal Oblique Muscle
o Internal Spermatic Fascia from Transversus Abdominis
Inguinal Canal
– Oblique passage through abdominal wall ← 3-5cm
o From Deep Inguinal Ring (DIR) to Superficial Inguinal Ring (SIR)
These are on top of the Inguinal Ligament
DIR = Middle of ASIS and Inguinal ligament
SIR = 1cm Lateral and Superior to Pubic Tubercle
– Passageway for contents of spermatic cord
o Spermatic cord fascia is formed as muscles pass through the SIR
– Potential Indirect Inguinal Hernia ← GIT through DIR and SIR
o Due to weak abdominal fascia/muscles
Seminal Vesicles
– Coiled tubular glands lateral to Ampulla of Ductus Deferens, posterior to base of
Bladder and anterior to Rectum
o Secretion contains Fructose, fibrinogen and prostaglandins
– Blood Supply → Inferior Vesical Artery and Middle Rectal Arteries
Prostate
– Secretory gland ← 4cm transversely, 3cm vertically, 2cm anteroposterioly
o Base ← Adjacent to bladder neck
o Apex ← Touches fascia on the sphincter urethrae
o Has posterior anterior and inferolateral surfaces
– Composed of Tubuloalveolar Glands, CT & smooth muscle
o Divided into Lobes (5):
2 Lateral Lobes
1 Median Lobe & Posterior Lobe
1 Anterior Lobe
o Can also be split into McNeal Zones (3):
Peripheral (70% tissue - 70% Cancer),
Transition (5% tissue - 25% Cancer),
Central (25% tissue – 5% Cancer),
o Hyperplasia occurs around middle age → Prostatic Urethra blockage
– Neurovascular supply:
o Blood supply: Inferior Vesical & Middle Rectal A
o Vein Drainage: Prostatic Plexus → Internal Iliac Vein
o Lymph Drainage: Sacral, External Node & Internal Iliac Node
o Nerve: Inferior Hypogastric Plexus
Bulbourethral Glands
– Secretory gland 1cm in diameter
o Enclosed by fibres of the sphincter urethrae
o Lateral to the Membranous Urethrae
o Superior to the Perineal Membrane/Penile Bulb
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– Secretions leave via the Excretory duct
o 3cm in length passing anterobliquely
Pierces perineal membrane → Intrabulbar Fossa of Spongy Urethra
← 2.5cm below perineal membrane
Penis
– Composed of an internal root and a free, external body
– Root of the Penis attaches to the Perineum
o Composed of Erectile Tissues (3):
2 Crura along the Ischiopubic Ramus
• Covered by Ischiocavernosus Muscle
The Bulb of the Penis lies between the crura
• Along inferior aspect of Urogenital Diaphragm Fascia
• covered by Bulbospongiosus Muscle
• Contains Songy Urethra through it
– Body of the Penis also contains erectile tissues (3):
o 2 Corpora Cavernosa continuous with the crura
Enclosed in tunica albuginea
• Meets in middle to form the Septum of the Penis
Contains many Trabeculae ← from fibrous sheaths
• In-between are Sinuses → When filled → Erection
o The Corpus Spongiosum is continuous with the bulb of the penis
Carries the spongy urethra
Expands distally to form the Glans of the Penis
• The Corona Glandis covers the corpora cavernosa
• The Navicular Fossa ← expansion of spongy urethra
The Prepuce/Foreskin is a layer of skin covering glans
• The Frenulum connects to the urethral surface
Preputial Glands secrete sebaceous Smegma
• Located on corona glandis and penile neck
o Supported by ligaments (2):
Fundiform Ligament ← from the Lower Linear Alba
• Splits into two Lamellae
• Skirt penis and unite at Scrotal Septum
Suspensory Ligament ← Attached to Pubic Symphysis
• Blends with penile fascia)
– Neurovascular supply
o Arterial Supply: Internal Pudendal A → Deep/Dorsal Penile As
Supplies 2 Central As & Helical As in Corpora cavernosa
• Helical As squish Peripheral Veins during erection
o Venous drainage:
Deep Dorsal V → Prostatic Plexus
Superficial Dorsal V → Great Saphenous v
o Lymph Drainage: Superficial/Deep Inguinal & External Iliac Nodes
o Nervous Supply
Pudendal N → Perineal N ← Urethra
Ilioinguinal N ← Root of the penis
Pudendal N → Dorsal N of the Penis ← Body of the Penis
Pelvic Plexuses → Autonomic Ns
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Erection and Ejaculation
o Dual Innervated system
Parasympathetic → vasodilation & erection
Sympathetic → ejaculation and vasoconstriction ← loss of erection
o 5 Steps to erection and ejaculation:
Vasodilation of the helicine As → ↑ Blood flow in cavernous spaces
↑ Pressure → Peripheral vein compression → ↓ Venous return
Blood flow in with no blood flow out → Constant pressure → Erection
• Bulbourethral secretions neutralise urethra
↑ Stimulation → Ejaculation ← Sympathetic activity
↑ Sympathetic activity → Vasoconstriction → ↓Blood flow → Flaccid
o Ejaculation ← Contraction of epididymis, ductus deferens, seminal vesicle and
prostatic smooth muscle
Some pelvic and UG diaphragm muscles contract → Expels semen
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Histology
Female Histology
– Ovaries
o Function: Storage of Oocytes, Site of Folliculogenesis, Hormone production
o Mesothelium: Simple Cuboidal cells continuous with Mesovarium
o Mesovarium: Germinal Epithelium
o Tunica Albuginea: Layer of CT around the organ ← Underneath Mesovarium
o Outer Cortex: Contains developing follicles ← All stages
o Central Medulla: Vasculature & dense CT stroma
– Oviduct
o Function: Site of Fertilisation, Transportation of Zygote to Uterus for
implantation
o Folded Mucosa:
Epithelium: Ciliated Simple Columnar, Peg cells & Basement
Membrane
• Cilia beat towards uterus
• Peg cells supply nutrients
Laminar Propria: Thin layer of areolar CT with Leukocytes
o Muscularis: Externa: Inner Circular & Outer Longitudinal Smooth Muscle
o Serosa: Thin layer of CT covered by Mesothelium
– Uterus
o Function: Site of Implantation, Nurture/support growing embryo/foetus
o Glandular Mucosa: Endometrium which lines the uterine cavity
Epithelium: Simple Columnar with or without cilia
Laminar Propria: Wide with Uterine Glands and Endometrial Stroma
Split into Strata (2):
• Stratum Functionalis (2/3) ← Degenerates during menstrual
cycle
• Stratum Basalis (1/3) ← Regenerates mucosa for next cycle
o Muscularis: Myometrium
o Serosa: Perimetrium
o Blood Supply:
Branches of Uterine A supply basal layer of endometrium ← Short,
straight
Spiral As supply functional layer
• Constriction during Menstruation ← Minimise blood loss
– Cervix
o Function: Passage for Menstrual blood, Sperm and Foetus
o Cervical Canal:
Epithelium: Simple Columnar → Stratified, squamous, nonkeratinized
Mucousal Glands: Cervical & Nabotian Glands
Deep branching folds ← Pilcae Palmatae
o Mucous Plug during pregnancy prevents sperm & microorganisms from entering
the uterus
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– Vagina
o Function: Passage for Menstrual flow and Foetus, Reception of sperm
o Mucosa: Folds which extend through the vagina
Epithelium: Stratified squamous, nonkeratniszed
• Glycogen rich ← Lactobacillus Acidophilus → ↓ Vaginal pH
Lamina Propria: Elastic fibres, Lymph nodules & Venous Plexus
• Filled with blood during sexual stimulation
o Muscularis: Smooth muscle layers continuous with myometrium
o Adventitia: Dense CT layer, elastic tissue, blood vessels, nerves, lymphatics
Blends into other organs
– Mammary Glands
o Function: Lactation ← Production of milk
o Modified sweat glands with 10-20 Lobes around a Nipple
Each lobe has a Lactiferous Duct → widens → Sinus → Opens
o Parenchymal tissue: Ducts and Acini lined with simple cuboidal epithelium
Partially surrounded by Myoepithelial Cells ← Secretion of milk
o Stroma of Lobe: Loose CT, adipose cells and collagen fibres
Male Histology
– Testes
o Function: Production of Sperm, Production of hormones
o Scrotum: Thin Skin → Dartos Muscle (smooth) → Cremaster (striated)
o Tunica Vaginalis: Layer of Peritoneum
Has Parietal & Visceral Layers with a Sac inbetween
o Tunica Albuginea: Collagen capsule
Forms septa that divides testis into 250 Lobules
• Each contains 1-4 Seminiferous Tubules
Converges on posterior surface of testis → Mediastinum Testis
– Seminiferous Tubules
o Function: Site of Spermatogenesis, Testosterone synthesis
o Sertoli Cells: Irregularly shaped Columnar Cells
Extend from basal lamina to lumen
Phagocytise excess cytoplasm released by maturing Gametes
• Spermatogonia → Primary Spermatocytes → Secondary
Spermatocytes → Spermatids → Spermatozoa
o Leydig Cells: Clusters of ovoid cells ← Produce testosterone
In between seminiferous tubules
– Ducts
o Straight Tubules/Tubuli Recti: End of Seminiferous Tubules → Rete Testes
o Rete Testis: Network of channels within Mediastinum → Efferent Ductules
o Ductuli Efferentes: 10-15 Tubules → Epididymis
Tall, Ciliated Columnar cells & shorter Secretory cells
Fuse into a single coiled tube before transfer → Head of Epididymis
Stirs Luminal Fluids ← Homogenous absorption of H2O
o Ductus epididymis: Storage for 30 days and maturation → Ductus Deferens
Initially sperm are immotile → Leave motile
Epithelium: Pseudostratified Columnar
• Principal Cells: Sterocilia (absorb 90% fluid) ← Not ciliated
• Basal Stem Cells: Sit on Basal Membrane
16
o Ductus/Vas Deferens: Transport from epididymis to Ejaculatory Ducts
Epithelium: Pseudostratified Columnar w/ Sterocilia
Muscularis: Trilaminar arrangement of smooth muscle:
• Inner/Outer – Longitudinal
• Intermediate – Circular
Adventitia: Vasculature supplying the ductus
o Ejaculatory Ducts: Ampulla of Vas Deferens and a Seminal Vesicle duct
Epithelium: Simple/Pseudostratified Columnar Cells with no muscluris
Paired ducts penetrate Prostate Gland → Urethra
o Urethra: Transitional Epithelium
– Accessory Glands
o Prostate gland: Encircles neck of bladder
Surrounded by CT with
• Penetrating Septa divides gland into Lobules
Parenchyma: 30+ lobules → Acini
• Simple Cuboidal Cells
• Concretions → Corpora Amylacea
Stroma: Smooth muscle with collagen & elastic fibres
o Seminal Vesicles: Paired, coiled tubular structures
Mucosa: Pseudostratified Epithelium
Muscularis: Inner/Outer Longitudinal Muscles
Adventitia: Fibroelastic
o Bulbourethral/Cowpers Gland: Small, paired structures
Both sides of base of Penile Urethra
Mucous glands
Alveoli lined by Simple Cuboidal/Columnar
– Penis
o Function: Pathway for urine, sperm ejaculation, sexual organ
o 2 Corpora Cavernosa (dorsally) and 1 Corpus Spongiosum (ventrally)
o Tunica Albuginea: Fibroeleastic Capsule surrounding Corpus Cavernosum
o Helicene arteries: Fills Sinuses with blood → Erection
o Glands of Littre: Secretions lubricate penile urethra
17
Physiology
Physiology of Female Reproductive Tract (FRT)
− Gametogenesis
Time Number of Gametes/Follicles
20 Weeks 6-7 Million Oogonia
Birth 2 Million Primordial Follicles
Puberty 500,000 Primordial Follicles
Menopause 1000 Primordial Follicles
o At 20 weeks gestation, Primordial Germ Cells differentiate into Oogonia
6-7 Million are formed → 2 Million at birth
• Loss due to Atresia
Undergo mitosis to form Primary Oocytes
o Begins Meiosis I but is arrested at Prophase I
Surrounds itself in Granulosa Cells
• This forms the Primordial Follicle
o By puberty, only 500,000 follicles are left for reproductive life
Only 500 are ovulated during reproductive life (average)
o Prior to ovulation, the primary oocyte undergoes meiosis I
Arrests again at Metaphase II
Meiosis I produce a small Polar Body
Must undergo meiosis late, due to immune response
o At menopause, 1000 follicles remain
Unresponsive to hormonal stimulation
− Hormonal Regulation
o Predominantly regulated by 3 hormones
Gonadotropin Releasing Hormone (GnRH)
• Tropical hormone released by the Hypothalamus
• Acts on Anterior Pituitary Gland (APG)
• Acts in a pulsatile fashion
Follicular Stimulating Hormone (FSH)
• Released by the Anterior Pituitary Gland
• Acts primarily on the Granulosa Cells
Luteinizing Hormone (LH)
• Released by the Anterior Pituitary Gland
• Acts primarily on Theca Cells
o Both Gonadotropins increase the production of Steroidal Sex Hormones
Oestrogen or 17-β Oestradiol and Progesterone
These generally have Negative Feedback on GnRH, FSH and LH
Trigger gene expression in the reproductive tract
− Ovarian Cycle
o 8 Stages of Folliculogenesis
Primordial Follicle → Primary Follicle (150 days)
• Granulosa Cells proliferate
• glycoproteins surrounds the oocyte ← Zona Pellucida (ZP)
• Outermost cells differentiate into Theca Cells
o Theca Interna makes hormones
o Theca Externa is a surrounding CT layer
18
• This process is independent of gonadotropins
• Also known as the Pre-antral Phase
Primary Follicle → Secondary Follicle (120 days)
• Antral Fluid collects in the follicle forming an Antrum
• Also known as the Antral Phase
• Independent of gonadotropins
Secondary Follicle → Graafian Follicle (65 days)
• Develops LH and FSH receptors
o Not enough receptors develop → Atresia
• Oocyte surrounded by mound of granulosa cells → Cumulus
Oophorous
o Layer touching ZP → Corona Radiata
Selection of Follicle (10 days)
• Under the influence of rising FSH, follicles start to grow
• Greater concentration of oestrogen → decreased FSH
o Causes competition for FSH → Only 1 follicle survives
o Other follicles undergo atresia
Maturation of Follicle (10 days)
• The follicle prepares for rupture and release
o Corona Radiata breaks off from granulosa cells
o Floats freely in the
• Total of 350 Days of development
Ovulation
• Primary Oocyte → Secondary Oocyte
• Oocyte, ZP, Corona radiata and Antral fluid released into
abdominal cavity
• Temporary blood clot forms → Corpus Haemorrhagicum
Follicle → Corpus Luteum
• Folds in on itself creating folds and pleats
• Granulosa cells → Granulosa Lutein Cells
o Large, clear cells that secrete Progesterone
o Abundant lipid droplets (hence Lutin)
The cholesterol is for steroidogenesis
• Theca cells → Theca Lutein Cells
o Secrete Progesterone
• If pregnancy occurs, luteum remains intact
o Swells to 1-3cm
o Functional for 3 months
o Produces oestrogen until parturition
Corpus Luteum → Corpus Albicans (10-14 days)
• Without presence of HCG, degradation occurs
• Leaves a white, dense CT Scar
o This is split into 2 phases separated by ovulation
The Follicular Phase
• Development into Graafian follicle
• Generally 14 days but has high variability
The Luteal Phase
• Development and degradation of the corpus luteum
• Generally 14 days and static
19
− Hormonal Regulation of the Ovarian Cycle
o From puberty, GnRH is released in pulsatile fashion
FSH and LH levels rise accordingly
FSH rises rapidly, LH rises slowly
20
− The Uterine Cycle
o In correspondence to the ovarian cycle, the uterine lining changes
o Menses is the shedding of the uterine lining
Occurs due to an abrupt drop in Progesterone and Oestrogen
Contracts Spiral Arteries → Ischemia
o Proliferative Phase sees the preparation of the uterine lining
In response to rising oestrogen levels
Endometrium grows 3-5x (8 – 10 mm)
Uterine Glands enlarge
Spiral arteries elongate
Smooth muscle hypertrophy
Upregulation of sex hormone receptors
o Secretory Phase is the endometrium preparing for implantation
Maintained by progesterone
Elongation and coiling of spiral arteries
Progesterone promoted differentiation of secretory cells
Uterine glands secrete Uterine Milk (glycogen-rich)
21
Physiology of the Male Reproductive Tract (MRT)
− Gametogenesis
o Primordial Germ Cells differentiate in embryonic life into Spermatogonia
These undergo rapid mitosis to increase population size
Arrested until puberty
o Spermatogonia are stored within Seminiferous Tubules
Ring of Sertoli Cells with a lumen surrounded by smooth muscle
• Aid in Spermatogenesis
• Smooth muscle moves immotile sperm out
Surrounded by Interstitial Cells of Leydig
• Produce Testosterone
o This process of Spermatogenesis takes roughly 70 Days ± 4
Happens continuously through reproductive life
o Spermatogonia start at the periphery and move towards the lumen
Undergo differentiation into Primary Spermatocytes
Pass the Blood Testes Barrier
• Tight junction to stop immunogenic response
• Separates lumen from the rest of the body
o After barrier, primary spermatocytes undergo meiosis
Meiosis I to form Secondary Spermatocytes
Meiosis II to form Spermatids
o Spermatids then undergo Spermiogenesis to form Spermatozoa
The Acrosomal Cap is formed at the head
• Large vesicle containing enzymes and proteins
• Dissolves the ZP of the Oocyte
DNA is condensed and packaged
Elongation and formation of a tail from microtubules
• All mitochondria are contained in the midpiece
o Spermiation places the spermatids into the lumen
Excess cytoplasm is purged and consumed by Sertoli cells
Smooth muscles contract in a pulsatile fashion
This moves the spermatids towards the epididymis
Straight Tubules → Rete Testes → Efferent Ductules →
Epididymis
o Maturation occurs in the epididymis
Spermatozoa become motile
Capability of fertilisation
o Sperm undergo Capacitation in the female reproductive tract
Hypermotility
Destabilisation of acrosomal cap for ZP penetration
o ~2 million spermatogonia → 128 million spermatozoa/day
50-150 Million/mL required for fertility
< 20 Million/mL is infertile
o Sperm can survive for weeks in MRT
Only 24-72 Hours in FRT
The acidic environment of the vagina & immunogenic response kills
sperm
22
− Composition of Semen
o Sperm is ejaculated in a fluid medium known as Semen, 2-6 ml
o Composed of fluids from various organs in the MRT
Bulbourethral Gland – 10% (Pre-ejaculaation)
• Contains Mucoproteins to neutralise residual urine
o Also lubricates MRT
Prostate Gland – 20% (Ejaculation)
• Alkaline secretion to neutralise vaginal environment
• Contains Prostate Specific Antigen
o Breaks down fibrin clotting
• Contains Acid Phosphatase
o Activates spermatozoa
Spermatozoa – <10% (Ejaculation)
• 15-150 million per ml
Seminal Vesicle – 60% (Last of Ejaculation)
• Contains fructose, fibrinogen and prostaglandins
o Prostaglandins stimulate FRT contractions
23
− Other Effects of Testosterone and its Derivatives
Derivative Effect
Testosterone, E2 & Spermatogenesis
DHT ↑ Libido
Testosterone & DHT Development of Seminal Vesicles and Penis (Puberty
Testosterone & E2 ↑ Bone growth and Density
↑ Muscle mass
↑ Abdominal Visceral Fat
Testosterone (Pure) ↑ Red blood cell count
Larynx change (deeper voice)
Development of epididymis, Vas deferens and Seminal
Vesicles (intrauterine)
↑ Prostate function
DHT (Pure) ↑ Beard growth
↑ Sebum Production
Development of Penis, Scrotum, Urethra and Prostate
(intrauterine
24
Maternal Physiology
− The Foetal-Placental Unit
o Placenta secretes hormones → Physiological changes
Oestrogen, Progesterone, hCG and Human Placental Lactogen (hPL)
This rise is hCG is used for pregnancy testing
− Weight Gain
o Average 12.5 Kg increase in weight
Predominantly 2nd and 3rd trimesters
Mainly accumulation of maternal fat, foetus and blood volume
increase/fluid retention
− Blood Volume and Composition Changes
o Total Blood Volume increases by 1.5 L (30 – 40%)
By 34 weeks
Plasma Volume increased by 1.25 L (45%)
RBC Mass increased by 240 mL (400 mL w/ iron supplement)
o [RBC] decreases (Greater plasma increase than RBC)
Heamotcrit falls from 40% to 31%
[Haemoglobin] falls from 13.5% to 11%
Results in Dilutional Anaemia
• However, increased RBC Mass → greater total oxygen carrying
capacity
• Greater increase in capacity than use → Fail-Safe Gap
o WBC Count rises from 7000 Cells/ μL to 10/11000 Cells/μL
Mainly neutrophils to fight potential infections
o Total Plasma Protein increases but [Plasma Protein] decreases
From 7g/100mL to 5.5-6g/100mL
[Albumin] decreases → decreased Colloid Osmotic Pressure
• Results in Oedema and ↑ Glomerular Filtration Rate (GFR)
• Lower viscosity of blood → reduced strain on heart
[Globulins] increase (Angiotensinogen, thyroid-binding globulin)
o Fibrinogen, Clotting Factors (II, VII – X) & Platelet Turnover is increased
Faster coagulation in the case of haemorrhage
Decreased Antithrombin III and Fibrinolysis
Occurs due to Oestrogens affects on the Liver
More prone to DVT and Pulmonary Embolism
− Cardiovascular Changes
o CO is increased by 1.5L/Min
Mostly by week 13 and 14, plateaus and then increases again at labour
N.B. 𝐶𝐶𝐶𝐶 = 𝑆𝑆𝑆𝑆 × 𝐻𝐻𝐻𝐻
SV increases (64 mL/min – 71mL/min)
Hr increases 70 BPM – 85BPM
o BP falls due to vasodilation (oestrogen)
Falls mid-pregnancy but resumes at term
Total Peripheral Resistance falls
𝐵𝐵𝐵𝐵 = 𝐶𝐶𝐶𝐶 × 𝑇𝑇𝑇𝑇𝑇𝑇
o Venous Pressure in lower limbs is increased
Can be due to Mechanical Compression of Inferior Vena Cava (IVC)
by uterus, Shunted blood flow to uterus or Progesterone mediated
vasodilation
25
o Supine Hypotension via mechanical compression of IVC
Leads to a decreased CO → decreased BP
Alleviated by lying on left side
o Blood Flow Distribution changes during pregnancy for the foetus
Uterus: 15% CO (90% to Placenta), increases during pregnancy
Skin: Increased dissipation of metabolic heat (maternal & foetal)
Kidneys: 30% increase due to waste from 2 organisms
Breasts: Development of mammary glads
− Renal Changes
o Renal Blood Flow increases by 30%
Renal plasma flow also increases (increased [Plasma])
o Glomerular Filtration Rate increases by 50%
Due to ↑ Renal plasma flow and ↓ Colloid Osmotic Pressure
o Maternal Plasma Creatine/Urea Levels decrease
To facilitate diffusion of these waste products from the foetus
Must move from area of [high] → [low]
o Tubular Function Changes result in Glycosuria & increased AA Excretion
Due to ↑ GFR, cannot reabsorb all filtered nutrients
o Sodium Retention/Loss increased (retention predominant ~900mmol)
Loss: ↑ GFR, ↑ Plasma Volume, ↑ Progesterone and Prostaglandins
Retention: ↑ Renin-Angiotensin System, ↑ Aldosterone, Oestrogen and
cortisol
o Water Retention is concordant with Sodium retention
o Renal Pelvis and Ureters undergo dilation → ↑ Urine storage
Higher risk of UTI due to longer retention period
o Urinaration Frequency increased in early pregnancy (from week 6)
Due to ↑ GFR, Bladder Hyperaemia and uterine pressure
Subsides, but returns in late pregnancy due to ↑ pressure
− Respiratory Changes
o Minute Ventilation rises by 50%
Due to rise in Tidal Volume
N.B. respiratory rate doesn’t change
o PaCO2 drops (~ 30mmHg at term)
Requiared for diffusion of CO2 from foetus to mother
Mediated by progesterone
Mild respiratory alkalosis
o Softening of Thoracic Ligaments → greater expansion of thoracic cage
Compensates for raised diaphragm (result of progesterone & uterus)
o Residual Volume decreases by ~ 20%
o Forced Vital Capacity (FVC) increased
FVC% is higher in pregnant women
FEV1 remains unchanged
− Gastrointestinal Changes
o Stimulated appetite due to Orexigenic nature of progesterone
Leptin resistance also develops
o Morning Sickness is nausea and vomiting at any point during the day
o Gut Motility decreased due to progesterone’s relaxant effect
Leads to prolonged transport time → Constipation
o Diminished Lower Oesophageal Tone → Heartburn
o Impaired Gallbladder Contraction → ↑ likelihood of Gallstones
26
− Metabolic Changes
o General increase in metabolic rate
o Maternal Blood Glucose falls ← needed for foetal development
o Insulin levels rise in late pregnancy
Increased Insulin Resistance allows the foetus to consume the glucose
• Mediated by hPL
• Lowers glycogen stores
Can lead to Gestational Diabetes
o Due to increased AA excretion, High Protein Diet is required (500g)
o Maternal Fat becomes the main energy source
Mobilised Free Fatty Acids by hPL converted into glucose for foetus
Can trigger ketosis → accelerated starvation response
System Changes
Blood – ↑ TBV 1.5L (PV 1.25L, RBC Mass 240mL (iron = 400mL))
Volume & – ↓ Heamatocrit 40% → 30%, [Heamaglobin] 13.5% → 11%
Composition – ↑ WBC Count 7,000 cells/μL → 10/11,000 cells/μL
(8) – ↓ [Plasma Proteins] 7g/100mL → 6/5.5 g/100mL
– ↓ [Albumin] → ↑ GFR, ↓ Blood viscosity, Oedema
– ↑ [Globulins] e.g. thyroid binding, corticosteroid binding, ↑ [angiotensin] → ↑
BP,
– ↑ [Fibrinogen], [Clotting factors (II, VII, VII, IX, X)] and Platelet Turnover
rate
– ↓ [Antithrombin III] and Fibrinolysis
CV – ↑ CO 1.5 L/min, SV 64 mL/Min → 71 mL/Min, HR 70BPM → 85BPM
(5) – ↓ BP ← ↓ TPR (due to Oestrogen)
– ↑ Lower limb PaVenous ← Compression of IVC/↑ Uterine blood flow/Veins
more distensible due to progesterone
CO = SV x HR – Supine Hypotension ← Compression of IVC (Lie on left side)
BP = CO x TPR – ↑ Blood flow: Uterus 15% (Placenta 90%), Kidney 30%, Skin, Breasts
Renal – ↑ GFR 50% ← ↑ Renal plasma flow and ↓ Colloid Osmotic Pressure
(7) – ↓ Maternal Plasm Creatine, Urea levels → Facilitate foetal exchange
– ↑ Glucose excretion (Glycosuria), AA Excretion ← ↑ GFR
– ↑ Na+ Retention/Loss (Retention dominant) 900mmol
– H2O Retention
– Renal Pelvis/Ureter Dilation → ↑ Urine Storage → UTIs
– Bladder Symptoms: ↑ Urination Frequency ← ↑ GFR, Bladder hyperaemia,
Uterine pressure (until week 6, recurs in late pregnancy)
Respiratory – ↑ Minute Ventilation 50% ← ↑ Tidal Volume (Respiraptory rate unaltered)
(6) – ↓ PaCO2 30mmHg (Progesterone) → Foetal exchange, Mild alkalosis
– ↑ Thoracic Cage size (Costovertbral angle widens) ← Thoracic Ligament
Softening
– Diaphragm raised 4 cm ← progesterone, abdominal organs (Uterus)
– ↓ Residual Volume 20%
– ↑ FVC, FVC% (FEV1 unchanged)
GIT – ↑ Appetite ← Orexigenic effect of progesterone, Cravings
(5) – Morning Sickness → Nausea, Vomiting
– ↓ Gut Motility (Progesterone) → ↑ Transit Time → Constipation
– ↓ Lower Oesophageal Tone → Heartburn
– ↓ Gallbladder Contraction → Gallstones
Metabolic – ↓Blood Glucose levels ← Used for foetal development
(4) – ↑ Insulin, Insulin Resistance → Foetal glucose, Gestational Diabetes
– ↑ Free Fatty Acids ← Decreased glycogen stores ← Insulin resistance
– ↑ Weight 12.5Kg: Maternal Fat, Foetus, Blood, Fluid Retention etc.
27
Physiology of Labour
− Requirements for parturition
o Contractions of the Myometrium
Bundles of smooth muscle fibres with CT and vasculature
Myometrial Bulk increases 20-fold by weight
• Primarily due to oestrogen
• Hypertrophy, Hyperplasia & Glycogen Deposition increase
Muscle cells: Circular on inside, longitudinal on outside
• Contraction causes circumferential & longitudinal force
• Squeezes baby out of uterus
Gap Junctions → Electric Coupling → ~ Syncytium
• Signals from one neuromuscular junction affects all
Contraction relies on Spontaneous Pacemaker Potentials
• If the threshold is exceeded → Action Potential
• This increases Intracellular Ca2+
o Activates Calmodulin (CAM)
o Activates Myosin Light Chain Kinase (MLCK)
• Can be altered by changing pacemaker potential, changing
threshold and altering Ca2+ release
o Prostaglandins (PG) - enhance Ca2+ release
o Oxytocin - lowers threshold, stimulates PG formation
Neuropeptide released from APG
Release mediated via Neuroendocrine Reflex
• Foetal head compresses vaginal/cervical
nerves
• Positive feedback for oxytocin
Myometrial Activation prepares the myometrium for contractions
• ↑ expression of Contraction Associated Proteins (CAPs)
o Ion Channels (Na+, Ca2+)
o Agonist Receptors (PG, Oxy)
o Gap junctions (For Syncytium)
o Cervical Softening
The cervix has high CT content
• Collagen fibre bundles in Proteoglycan Matrix
• High resistance to stretching
Softening involves
• ↓ Collagen Fibres, ↑ Glycosaminoglycans
• Matrix Composition change
o Replacing Keratin Sulphate with Dermatan Sulphate
o Loosens collagen bundles
Induced by:
• PG (E2/F2α) intravaginally/cervically ← Induction of labour
o PG inhibitors can arrest premature softening
• ↑ Metalloproteases ← degrade collagen fibres
• ↑ Pro-Inflammatory Cytokines (IL-1/8) → ↑ Inflam cells
• ↑ Inducible Nitric Oxide Synthesise (iNOS)
o Produces NO → Relaxation of smooth muscle
28
− Oestrogen/Progesterone Ratio (O/P)
o For parturition to occur, O/P ratio must increase for the following effects:
↑ Release of Phospholipase A2 from lysosomes → ↑ PG synthesis
• Oestrogen labilises lysosomes, Progesterone stabilises
↑ Oxytocin receptors ← Oestrogen promotes, Progesterone inhibits
• Aids in ↑ PG release ← oxytocin triggers PG release
• Facilitates neuroendocrine reflex
↑ iNOS activity
↑ CAP gene expression ← Oestrogen promotes, Progesterone inhibits
• N.B. although mechanical stretching causes increased CAP gene
expression, without O/P ratio increase, this is not effective
− Theories on Timing of Parturition
o In sheep, maturations in the foetal HPA axis trigger parturition
Adrenocorticotropic Hormone (ATCH) acts on foetal adrenal gland
• Trigger secretion of Glucocorticoids → Placentome
↑ Oestrogen secretion, ↓ Progesterone Secretion → increases O/P ratio
Proved via inhibiting and stimulating labour
• Foetal hypothalamus/pituitary ablation → prolonged pregnancy
• Infusion of ATCH and Glucocorticoids → premature labour
o In humans, Cortisol has less of an effect on parturition
Malformations of adrenal gland don’t prolong pregnancy
Progesterone levels don’t decrease, only oestrogen levels rise
• Potential functional Withdrawal from progesterone
o PR-B Receptors are active
o PR-A Receptors are potentially inhibitory
o A/B ratio increases towards end of pregnancy
The human placenta doesn’t change Oestrogen → Progesterone
• Lacks 17-α Hydroxylase enzyme
However, influences placental oestrogen production
• Provides the substrate DHEAS
o Potentially Corticotropic Releasing Hormone (CRH)
Synthesised with corresponding binding protein (CRH-BP) in placenta
• Released into maternal/foetal blood
Maternal CRH levels rise exponentially in last month
• CRH-BP drops → rise in free CRH
Stimulates foetal pituitary → rise in ATCH → rise in O/P ratio
Stimulates Uterine prostaglandin production → Oxytocin potentiation
Preterm women have higher CRH earlier in gestation
o Potentially Cell Free Foetal DNA
Circulates maternal blood stream → immune response via TLR-9
• Triggers inflammation → Cervical softening, membrane rupture
and uterine contractions
• Premature delivers have maternal levels 2x higher than controls
• Top 5% → increased rates of preterm delivery
• 30% higher in twins → Earlier induction of labour
− Stages of Labour
o Contractures ← ↓ frequency/amplitude, non-painful, throughout pregnancy
Sometimes reffered to as Braxton-Hicks
29
o Contractions ← ↑ frequency/amplitude, painful, short duration, during labour
o Labour is split into 3 stages
Stage 1 → Onset of contractions & dilation/softening of cervix (long)
• Latent Phase ← slow dilation to ~3cm
• Active Phase ← Rapid dilation to 10cm
• Muscle cells do not regain size on relaxation → Contractions
• Fundal Musculature thickens → ↓ intrauterine volume
• Lower uterine segment becomes continuous with vaginal wall
o Does not undergo contractions
o Known as Effacement
• Retraction Ring moves up slowly
Stage 2 → From full dilation to birth (< 1 hour)
• Uterine Contractions + Abdominal Wall Contractions push the
foetus through the vaginal canal
Stage 3 → Delivery of the Placenta (very short)
• Placenta detaches from uterine wall after a few minutes
• Completely expelled via uterine contractions
o Aided by oxytocin or Syntometrine
o Aided by steady traction on Umbilical Cord
o Whole process varies in length but there are some standards
< 12 hours for Nulliparous women
< 8 hours for Multiparous women
− Premature Labour
o Full Term = 37-41 weeks post Last Menstrual Cycle (LMC, Amenorrhea)
Prior → Preterm, After → Post-term
Usually 280±14 days post LMC
o Risk factors of premature labour:
Premature rupturing of membranes
Previous preterm delivery
Uterine Abnormalities ← Short Cervix, Cervical Incompetence
Uterine Overdistention ← Multiple pregnancies, Polyhrdamnios
Infection ← Bacterial Vaginosis, UTI
Bleeding ← Placental Abruption, Abnormal Placentation
In-Vitro Fertilisation (IVF)
Foetal Abnormality
Medical indications ← Severe hypertension, Endagered Foetus
Other ← Stress, Age (<17, >35), Low BMI, Smoking, Drug abuse
o Management of Premature labour utilises multiple pharmaceuticals
Corticosteroids
Antibiotics ← Ruptured membranes
Tocolytic Agents (anti-contraction)
• Salbutamol, Oxytocin antagonists, PG synthetase inhibitors
Progesterone
• Administered vaginally or injected
Potentially CRH antagonists
30
Foetal Physiology
− Foetal Growth
o By week 8, organogenesis is complete ← growth from week 9 – Term
Males are born heavier than females
Indigenous babies are 200g lighter than non-indigenous
• 17% are small for gestational age
2.5kg – 4kg = normal,
• < 1.5Kg = very underweight, < 1Kg = extremely underweight
o Uterine Fundus rises during gestation
Can feel at 12 weeks, at naval by 20 weeks
Shrinks at 40 weeks ← engagement with Pelvic Inlet
Not just foetal growth ← Amniotic Fluid and Placenta
o Greater Water Content than adults → 95% in early pregnancy
Fluid moves from extracellular space to intracellular space
2/3 Intracellular in adult life
o Protein and Fat composition changes over gestation
Peak protein at 35 Weeks
Fat Storage starts Week 32 → greater than protein by Week 38
o Foetal Factors affecting growth (3):
Genetics ← Sex, Chromosomal/Single gene abnormalities, Parents,
Race
Hormones ← Insulin, IFG1, IFG2 (Growth factors)
• N.B. Not growth hormones or Thyroxine
Infection ← Rubella
o Maternal Factors affecting Growth (8):
Maternal Constraint ← Foetal size ∝ Maternal Size
Multiple pregnancies ← Singletons are bigger
Maternal Age ← Younger = smaller
Parity ← Nulliparous women have smaller babies
Nutrition ← extreme malnourishment before effects
Smoking/drug use ← smaller foetus
Maternal diseases ← Hypertension, Diabetes
Uterine Abnormalities
o Placental Factors affecting Growth (2):
Placental weight ∝ Foetal weight at term
True Placental Insufficiency unlikely to effect before Month 7
o Important as ↓ Weight → ↑ Morbiditiy/Mortality
Immature organs can’t function properly
• No alveolar surfactant, inadequate fat stores
Low birth weight ∝ increased risk of adult disease
− Placental Physiology
o A discoid 15-20cm structure, 3cm thick with 200 lobules
Weighs 1/6 foetal weight at term
o Functions of the placenta (3):
Facilitation of foetal/maternal exchange ← Gas, Heat, Nutrient, Waste
• Direct contact between maternal blood and chorionic
membrane ← Haemochorial
Secretion of pro-pregnancy hormones ← hPL, hCG, Progesterone
Immunological Barrier
31
o Mechanisms of exchange
Syncititrophoblast decreases around villi → ↑ exchange
• Placental Conductivity increases over gestation
Gases exchange passively ← 45% O2 with relatively high O2 content
• Greater Heamatocrity + Foetal haemoglobin has ↑ affinity
Glucose exchanged via facilitated diffusion ← GLUT1 protein
AA exchanged mainly via active transport
Only 50% Foetal fatty acid from mother, rest synthesised
Urea is passively exchange from Foetus to mother
Water moves freely along concentration gradients
− Amniotic Fluid Formation
o Stored in the amniotic cavity and composed of 2 substances
Foetal Urine ← Large, Diluted volume
Lung Liquid ← Clear/Colourless, Plasma isosmotic, high Chloride
content, important for lung development
o Leaves the cavity in 2 ways
Swallowing ← important for GIT development
Equilibration across membranes ← Foetal and Maternal Plasma
o Functions of Amniotic Fluid (7):
Insulation against trauma ← liquid cushion
Facilitates Symmetrical Growth
Lung Development
Barrier between foetus and Amnion ← Prevents sticking
Enables Foetal Movement ← Swallowing, Limb/Respiratory
Movement
Maintenance of constant body temperature
Potential source of liquids and electrolytes
− Foetal Circulation
o Foetal Circulation is similar to adult circulation with 2 major differences
Blood circulates to the placenta
• 2 Umbilical Arteries branch from the L/R Internal Iliac
Arteries carrying deoxygenated blood
• 1 Umbilical Vein carries oxygenated blood (85%) back
As oxygenation occurs at the placenta, not lungs, there are 3 Shunts
• Ductus Arteriosus connects the Pulmonary Artery to the
Descending Aorta ← Bypasses lungs
• Ductus Venosus connects Abdominal Umbilical Vein to IVC
o Bypasses the liver (55%) ← already filtered
• Foramen Ovale connects right atrium to left atrium
o Allows oxygenated IVC blood to bypass lungs
Minor Differences
• Varying PO2 in arteries
• Half of adult Arterial Pressure
• High Combined Cardiac Output (CCO)
• ↓ BP, ↑ HR ← Reverses during Hypoxia
• Kidneys receive 2% - 3% CCO, Lungs receive 7% CCO
o Pulmonary bed has very high resistance ← ↓ Flow
This results in a 2-pump system, where both pump systemically
• Right is dominant (2/3 of CCO, thicker Right Ventricle Wall)
32
o Pathway of Blood
Umbilical Arteries (Deoxy) → Placenta (Oxygenated)
Umbilical Vein (85% Oxy) → Liver
• 55% shunted to the heart ← Ductus Venosus
Ductus Venosus → Posterior Left Stream of IVC (40% IVC)
IVC → Right Atrium
• 27% shunted to the Left Atrium ← Foramen Ovale
Right Atrium → Right Ventricle (Anterior Right Stream IVC, SVC)
Right Ventricle → Pulmonary Artery (50% - 52% Oxy, ~65% CCO)
• 93% shunted to Descending Aorta ← Ductus Arteriosus
Left Atrium → Left Ventricle
• Mixes with Pulmonary Arteries (Deoxy, 7% CCO)
Left Ventricle → Ascending Aorta (60% - 65% Oxy, ~35% CCO)
• 20% to head, 3% to heart, 10%-15% Descending Aorta
Ascending Aorta → Descending Aorta (55% - 58% Oxy)
Descending Aorta → Rest of Body + Placenta
Descending Aorta → Internal Iliac Artery → Umbilical Artery (Loop)
33
Adaptation of Newborn to Extrauterine Life
− Cardiovascular Adaptations
o The Umbilical Artery must close → Haemorrhage of foetus
Must close immediately after birth ← Patent during pregnancy
Consists of 4 muscular segments with different contraction effects
Muscle Segment Trigger Effects
Circular High PO2* Narrowing Lumen
Lengthen Vessel
Longitudinal Stretching Non-circular lumen
Vessel shortening
Small Coiling 27°C ± 2°C Twisting → Final closure of lumen
Helical Stretching Coils the cord
High PO2
• * PO2 is increased by Epinephrine, Norepinephrine and
Antidiuretic Hormones (ADH) ← Important in vitro
o Umbilical Veins and the Ductus Venosus close passively
Thin walled vessels with no blood flow
Complete anatomical closure at ~3 Months
o Increased Pulmonary Circulation
Fluid within the vasculature is displaced on first breath
• Through trachea and mouth ← Thorax Compression
• Absorbed into Pulmonary Capilaries
• Absorbed into Pulmondary Lymphatics
Pulmonary vasculature dilates → ↓ Vascular Resistance → ↑ Flow
• Reduced lung expansion
• Ventilation of O2
• High PO2
Reversed Ductus Arteriosus flow → a lot of pulmonary blood flow
o The Foramen Ovale closes due to pressure changes
Decreased IVC blood flow to right atrium
Increased Pulmonary vein flow to left atrium
Causes closure of the valve
Permanent anatomical closure at 1 Year ← 10% don’t
o This stabilises as Transient Neonatal Circulation
Ductus Arteriosus (DA) is still patent but is now a L-R Shunt
• Changes in pressure cause reversal in flow
• Pulmonary vasculature dilation ↓ Pullmonary Pressure
• Removal of low resistance placenta ↑ Systemic Pressure
• Occurs after Umbilical Occlusion → Reverse Flow
May be advantageous ← increased neonatal oxygenation
Will continue as long a DA is open and PaPulmonary > PaSystemic
• Could be minutes to hours
o Ductus Arteriosus closes predominantly due to changes in PGE2
PGE2 maintains DA patency in utero
• ↓ PGE2 levels/receptors → constriction of DA
↑ PO2 and ↓BP also aid in DA constriction
PG inhibitors can be used therapeutically to force DA closure
DA constriction → Vasa Vasorum occlusion → wall Hypoxia
• Creates growth factors (TGFβ, VEGF) → Apoptosis
34
− Respiratory Adaptations
o Surfactant decreases Alveolar Surface Tension
Easier inflation and extended inflation time
Made by Type II Alveolar Cells
• 90% Phospholipids, 10% Proteins
Produced in last 4 Weeks ← Cortisol stimulation
• Enzymes present from Week 20/22
• Corresponding production of Lecithin ← Surfactant marker
Prematures have ↓ surfactant → Respiratory Distress Syndrome
• Hyaline Membrane Disease
Given Betamethasone ← Glucocorticosteroid
• Matures Lung Architecture & ↑ surfactant
Can be given synthetic surfactant postnatally ← ↓ Mortality
• No protein → not as effective
o Foetal breathing movements are episodic ← Not sustainable
The first postnatal breath is the hardest ← No Residual Volume
• Requires large Negative Intrathoracic Pressure
Achieved through various mechanisms
• ↑ Arousal ← Sensory stimulation, ↓ Temp, gravity, nausea
• Elastic recoil from Thoracic Compression
• Lack of facial immersion → No “Diver’s Reflex”
• Asphyxia and ↑ Chemorecptor Activity ← For O2 and CO2
Unstable breathing is common in prematures → Apnoea
• Could be related to Sudden Infant Death Syndrome (SIDS)
o In rare circumstances, there is insufficient surface area
E.g. Diaphragmatic Hernia
Generally not a problem after 26 Weeks
− Body Temperature Maintenance
o Initial 2°C drop after birth ← fades after a few hours
o Neonates have difficulty maintaining body temperature due to
Poor Shivering Mechanism
↑ Surface Area (SA) : Body Weight (BW)
↓ Subcutaneous Fat ← Insulation
Wet at birth
No Behavioural Adaptations
o This is especially bad for Premature infants ←Kept in an Incubator
Higher Thermo-Neutral Zone
Lower Fat stores
Greater SA:BW
Thin Skin
o Can use other mechanisms to warm
Chemical Thermogeneis via Brown Fat
• Brown fat has a central nucleus, ↑ mitochondria/fatty vacuoles
• Mitochondria use Fatty Acids ← Uncoupling of Oxidative
Phosphorylation
• Around kidneys, nape of neck, sternum, great vessels etc.
Flexed Posture ← ↓ Exposed SA
Vasoconstriction ← ↓ Heat dissipation ← Negligible (thin skin)
o Cold Stress → ↑ Neonatal mortality ← Infants produce heat rapidly
35
− Nutritional Requirements
o Foetus has continuous maternal nutrient supply
o In last trimester, Cortisol stimulates preparations
↑ Glycogen Stores in Liver, Muscle, Heart, Lungs and adipose tissue
• Cardiac = 10x higher than in adults, Skeletal muscle = 3.5x
• Glycogenolysis enzyme activity only postnatal
Liver undergoes enzymatic changes
• ↑ Glucose-6-Phosphotase → Glycogenolysis
• ↑ Phosphoenolpyruvate Carboxykinase → Gluconeogenesis
• Low activity at 4 months → Rapid increase at term
Fat stores are deposited ← 1Kg
o Hormonal environment at birth is ideal to use stores
↑ Glycogen, ↓ Insulin, ↑ Catecholamines
o However, stores are limited ← Hepatic Glycogen lasts 12 Hours
Worse if Premature or had poor in-utero nutrition
Used quicker in distress ← more energy is needed
o Plasma Glucose levels decrease after birth
Low limit of normal = 1.7 mmol/L
No clinical signs generally until < 1.1 mmol/L
Neonatal Hypoglycemia → brain damage
• Intra Uterine Growth Retardation (IUGR) → High risk
36
Pharmacology
Signal Transduction
– Heterotrimeric G-Proteins
o Proteins made up of 3 Subunits
α, β, γ
o They are the inactive form of G-Proteins
When activated, it splits into an α unit and a βγ unit
• α interacts with plasma membrane enzymes
• βγ signals i.e. ion channel activation, kinase activation etc
o There are 3 main types of α subunits
Gαs – Stimulates the production of Cyclic AMP (cAMP)
Gαi – Inhibits the production of cAMP
Gαq – Increases Diacylglycerol (DAG) and Inositol Triphosphate
(IP3) production
o When a G-Protein Coupled Receptor (GPCR) is activated by a ligand, the
conformational change allows it to activate heterotrimeric G-proteins
o Gαq Subunit
Activates the membrane enzyme Phospholipase C-β (PLCβ)
• This cleaves PIP2 into DAG and IP3
IP3 moves into cytoplasm and activates an ion channel on ER
• This releases stored Ca2+ into cytoplasm
DAG actives Phosphokinase C (PKC)
o Gαs Subunit
Activates the membrane enzyme Adenylate Cyclase
• This converts ATP into cAMP
cAMP activates a Phosphokinase A (PKA)
PKA phosphorylates Myosin Light Chain Kinase (MLCK)
• Leads to muscular relaxation
Myometrial Relaxation and Contraction
– Increasing Intracellular Ca
– Oxytocin (agonist) stimulates Oxytocin Receptors (GPCR) inducing a
i. Induces a Conformational Change
– GPCR interacts with inactive, Heterotrimeric G protein, activating a G⍺q
subunit (more conformational change) → ⍺ and β𝛾𝛾 split
o This occurs as GDP attached to ⍺-subunit disassociates, the affinity for
GTP builds up. GTP will bind and drive the movement of the G⍺q
– G⍺q interacts with and activates membrane enzyme called Phospholipase C – β
(PLC-β)
– PLC-β cleaves PIP2 into secondary messengers - DAG (lipophilic) and IP3
(hydrophilic)
– IP3 moves into cytoplasm and interacts with a ligand gated ion channel on the
Endoplasmic/Sarcoplasmic Reticulum inducing a conformational change.
o DAG activates a kinase enzyme – Phosphokinase (PKC)
– Calcium (Ca2+) released into the cytoplasm, increasing intracellular [Ca2+].
Muscular Contraction
– Ca2+ binds and activates calmodulin, forming a calcium calmodulin complex (CaCM)
– CaCM binds to and activates Myosin Light Chain Kinase (MLCK).
37
– MLCK catalyses the transfer of phosphate to myosin head to activate the myosin head
ATPases.
– Muscular contraction occurs
i. Cross bridge Formation: Myosin head attaches to actin (ADP + Pi)
ii. Power Stroke: Release of ADP + Pi, myosin head bends and pulls actin
filament
iii. New ATP is attached to myosin head releasing the cross bridge
iv. ATP Hydrolysis: ATP → ADP + Pi, cocks head back in position – myosin
head pulled back
38
Autonomic Nervous System
− Cholinergic Transmission
o Responsible for innervation of parts of the PNS
All Postganglionic Neurons
All Somatic Motor responses
All Parasympathetic responses
Some Sympathetic responses (glands)
Adrenal Medulla
o All are achieved through the secretion of ACh
Has a positively charged quaternary ammonium group and a partially
negative ester group ← easily hydrolysed
Quickly hydrolysed and not selective
o There are 5 steps in ACh’s life cycle
1. Choline is absorbed into the cell via the Na+-Dependant
Transporter
2. Choline is combined with Acetyl-Coenzyme A (AcCoA) via
Choline Transferase
• Stored in vesicles via Vesicular ACh Transporter (VAT)
3. Due to the influx of Ca2+, exocytosis of the ACh occurs
• Mediated by Vesicle Associated Membrane Proteins
(VAMPs)
ACh binds to receptors on target tissues to produce cellular affects
• Also interacts with receptors on the surface of the releasing
neuron to induce negative feedback → ACh release decreased
ACh is metabolised into Choline and Acetate by Acetylcholinesterase
o There are 2 main receptor types for cholinergic interactions
Nicotinic Receptors are ligand gated ion channels and come in 2
isotypes
• NN Receptors exist on all postganglionic neurons, adrenal
medulla and the CNS
• NM Receptors exist on skeletal muscle
• Composed of combinations of α, β, γ, δ and ε subunits
o 5 subunits per receptor – must have 2 α for ACh
• NN is only α or α and β
• NN uses all 5 receptors
Muscarinic Receptors are GPCRs and come in 5 isotypes (3
important ones)
• M1 Receptors located on CNS and Glands
• M2 Receptors located on the heart and smooth muscle
• M3 Receptors located on smooth muscle and glands (most
common)
• M4 Receptors located on nerves
• M5 Receptors with unkown function
• M1, M3 and M5 are coupled to Gαq → increased Ca2+
• M2 and M4 are coupled to Gαi → inhibited cAMP production
39
o Locations of muscarinic receptors in detail:
Organ Type Effect
Eye M3 Pupil Constriction
Adjustment for near vision
Salivary glands M1 Increases saliva secretion
Heart M2 ↓ HR
↓ CO
Bronchioles M3 Bronchoconstriction
GIT M1, M3 Increased secretion of HCl and digestive enzymes
Increased motility (M3 only)
Urinary Bladder M3 Contraction of Detrusor muscle
Increased urination
Rectum M3 Contraction of smooth muscle
Increased defecation
− Adrenergic Transmission
o Involves the release of Catecholamines
Epinephrine and norepinephrine
o Released from postganglionic fibres of the Sympathetic System
As well as Adrenal medulla
o All catecholamines are synthesised from Tyrosine
It undergoes biosynthetic reactions
Tyrosine → Dopa → Dopamine → NE → E
o Both are oxidised by Monamine Oxidase (MAO) and then Catechol-O-
methyltransferase (COMT)
Initially converted into 3,4-dihydroxymandelic Acid
COMT converts that into Vanilymandelic Acid (VMA)
In the liver, the intermediary products are Metanephrine and
Normetanephrine
o Norepinephrine is stored within Vesicles in the preganglionic neuron
Synthesised from dopamine or collected from reuptake via
Norepinephrine Transporter (NET)
o With an action potential, the vesicle undergoes exocytosis
This release is also mediated by a norepinephrine negative feedback
cycle
Norepinephrine binds to α2-Adrenoreceptors on the preganglionic
neuron, inhibiting further exocytosis
• This occurs due to activated α2 adrenoreceptors inhibiting
adenylate cyclase → reduces cAMP formation → reduction in
Ca2+ influx → no action potential
o There are 2 major Adrenoreceptor subtypes
α-Adrenoreceptors can be split into α1 and α2
• α1 is a Gαq GPCR → Stimulates sympathetic response
• α2 is a Gαi GPCR → Inhibits sympathetic response
β-Adrenoreceptors can be split into β1, β2 and β3
N.B. All 1 receptors have a stronger affinity to norepinephrine whilst
all 2 receptors have a stronger affinity for epinephrine
• The 3 receptor has equal affinity
o Various organs have adrenoreceptors and some are dual innervated
40
Organ Receptor Effects
Types
Eyes α1 Contraction of radial muscles →
Mydriasis
β2 Ciliary muscle relaxation → Far
vision
Salivary Glands α1 Increased fluid secretion
β2 Increased protein secretion
Heart β1 Increased HR
Increased Conduction velocity
(Chronotropic)
creased Contractility (Inotropic)
Lungs α1 Vasoconstriction
β2 Vasodilation
Pancreas α2 Decreased Insulin
β2 Increased Insulin
α1, β2 Increased Glucagon
Upper GI Tract α1 Sphincter contraction
β2 Decreased motility/tone
Liver α1, β2 Stimulate Glycogenesis and
Gluconeogenesis
Abdominal Blood α1 Vasoconstriction
Vessels β2 Vasodilation
Kidneys β1 Increased Renin secretion →
Increased BP
Bladder and Prostate α1 (Bladder) Sphincter contraction
α1 (Prostate) Prostatic contraction
β2 Relaxation of Detrusor Muscle
Adipose Tissue β3 Increased Lipolysis
Increased Thermogenesis
o N.B. the Adrenal Medulla also secretes E and NE into the blood stream
The adrenal medulla is stimulated by cholinergic transmission and has
NN receptors
41
– Summary Table
Mechanism Neurotransmitter/Me System Receptors Receptor Location
ssenger hormone
Physiology of Neurotransmission
1. Reuptake of choline – Inhibition of
Hemoicholinium
2. Transport of ACh into vesicles –
Blockage vesamicol
3. Exocytosis of ACh – Inhibition
Botulinum toxin and Ca channel
blockers
4. Interactions between ACh and
receptors – Agonists/antagonists
5. Termination of ACh effects by
acetylcholinesterase – AChE Inhibitors
42
43
Cholinergic Pharmaceuticals
– Muscarinic Agonists
M Agonist Drug Carbachol
Mechanism of Action Parasympathomimetic – Mimics the action of ACh
Indications Topical application - Glaucoma – pressure in aqueous humour, dry mouth
Intraocular administration for cataract surgery
Can activate nicotinic
Contraindications Mitotics are contraindicated where constriction is undesirable – acute iritis
Adverse Effects Rare when topical uses, ciliary spasms when resultant temporary decrease
visual acuity may occur
Routes of Oral, Topical, Injection
Administration
M3 Drug Pilocarpine
Selective Mechanism of Action Parasympathomimetic – Mimics the action of ACh
Agonist Indications Treating glaucoma (topical application), Dry mouth, diagnostic for CF
Contraindications Asthma, Coronary insufficiency, peptic ulcers, intestinal obstruction,
hyperthyroidism
Adverse Effects Excessive sweating, salivation, bronchospasm, bradycardia, hypotension,
diarrhoea, ciliary spasms and meiosis (excessive constriction)
Routes of Oral, Topical
Administration
M3 Drug Bethanechol
Selective Mechanism of Action Parasympathomimetic – Mimics the action of ACh
Agonist Indications Postoperative urinary retention
Contraindications Asthma, Coronary insufficiency, peptic ulcers, intestinal obstruction,
hyperthyroidism
Adverse Effects Dizziness, lightheadness, nausea, vomiting, abdominal pain, increased
urination, saliva, sweating, headache, watery eyes,
Routes of Oral, Subcutaenous
Administration
44
– Muscarinic Antagonists (Anti-muscarinic)
Non- Drug Atropine
selective M Mechanism of Action Blocks the receptors as to reduce the effects of ACh
antagonist Indications Resuscitation: Injection used in treatment of bradycardia in cardiac arrest
(M2, M3) after MI (M2)
Antidote: For AChE inhibitor overdose or organophosphate poisoning (M,N)
- cholinergic crisis.
Premedication in anaesthesia: Inhibition of bronchial and salivary secretions
and reflex bronchoconstriction (M3)
Anti-spasmodic and anti – diarrhoea: GIT Inhibition (M3)
Routes of Oral, Intravenous (IV), Intramuscular (IM), Rectal
Administration
Competitive Drug Tolterodine, Oxybutynin, Darifenacin
Non- Mechanism of Action Block the M3 receptor on the bladder detrusor muscle, resulting in:
selective M – Increased bladder (vesical) capacity
receptor – Diminished the frequency of contractions of the detrusor muscle
antagonists – Delayed the initial desire to void
Urgency and frequency of both incontinent episodes and voluntary urination
Indications Overactive Bladder
Selective
Routes of Tolterodine Oxybutynin Darifenacin
M3 receptor
Administration Both drug and p.o. 5 mg 2-3 daily p.o. 7.5 or 15mg once
agonist metabolite are active Half life 2 hours daily
p.o. 1 or 2mg twice Half life > 12 Hours
daily
Half life – 2-6 hours
All Adverse Effects Gut motility is reduced leading to constipation
Muscarinic Retention of urine
Antagonists Blurred vision, photophobia
Exocrine gland secretions inhibited: Decreased saliva secretion, dry mouth
and decreased sweating hyperthermia
Increased heart rate – tachycardia M2 mediated
Some anticholinergic agents cross BBB can cause CNS excitation (agitation,
disorientation, hyperactivity)
Toxic doses → depression, circulatory and respiratory failure → Treat with
physotigmine (AChE inhibitor)
Contraindications Glaucoma,
Gastrointestinal obstruction, Urinary retention,
Acute haemorrhage,
Excess exercise and
High Ambient temperature
45
– Nicotinic Agonists
Non Drug Nicotine
selective Mechanism of Action Stimulation followed by depression at nicotinic receptors, strong
psychologic, physical dependence
Indications Aid for relief of nicotine withdrawal symptoms/nicotine dependence
Contraindications
Adverse Effects
Routes of Inhalation, Oral, Transdermal, Rectal,
Administration
Partial Drug Varenicline (Champix)
agonist at Mechanism of Action Agonist action: Selectively stimulates receptors to alleviate symptoms of
NN craving/withdrawal
Antagonist action: Blockade of rewarding and reinforcing effects of smoking
by preventing nicotine binding to receptors
Indications Quit smoking
Contraindications Schizophrenia, Angina, Heart attack, Alcholism Seizures, Cardiovascular
risk, Depression, Renal impairment
Adverse Effects Nausea, headache, vomiting, drowsiness, gas, constipation, sleeping
torubles, unsual dreams
Routes of Oral
Administration
– Exocytosis Inhibitor
Botulinum Drug Botox
Toxin Mechanism of Action Inhibits Ca2+ dependant ACh release
1. Boutlinum toxins enter cell by endocytosis
Reduces 2. Release light chain
ACh action 3. Toxin breaks SNARE proteins which result in inability to form
SNARE complexes, thus vesicle and synaptic membranes cannot
fuse and ACh release is blocked
Indications Dystonia:
– Strabismus (crossed eye)
– Blepharospasm (excessive blinking)
– Cervical dystonia (head, neck muscle spasm)
– Stuttering
Hyperhidrosis (excessive sweating)
Achlasia (failiure of lower oesophageal sphincter to relax )
Chronic migraine
OAB by local injection
Movement disorders with stroke, multiple sclerosis, Parkinson’s disease,
cerebral palsy, diabetic neuropathy, wound healing, excessive salivation
Cosmetic uses
Contraindications Infection, MG, Decreased lung function
Adverse Effects Causes muscle twitching before paralysis
Apnea, Hyperkalemia, Bradycardia (preadminstering atropine to reduce this
risk)
Routes of IM, SC, Intradermal, Into glands
Administration
Other No Tetanic Fade: All twitches are uniformly decreased
46
– Neuromuscular Nicotinic Receptors
o Nerve Terminal: Action potential
triggers ACh release
o Motor End Plate: Two Ach molecule
bind to a subunit of N receptor
o Opens cation channel → Na+ influx
o Membrane depolarised → Muscular Contraction
− Neuromuscular Blocking Agents Somatic – Skeletal muscle
Depolarising Drug Succinylcholine
Blocking Mechanism of Action Imitates the action of ACh at NMJ; paralyses all skeletal muscles including
Agents those for breathing
Maintains muscle depolarisation
Nicotinic 3 – 5 minutes → Plasma cholinesterase hydrolysis
Indications Skeletal muscle relaxant during emergency tracheal intubation procedures
Agonist
for ventilation
Contraindications Acute phase injury, major burns, multiple trauma, extensive denervation of
skeletal muscle
Adverse Effects Causes muscle twitching before paralysis
Apnea, Hyperkalemia, Bradycardia (preadminstering atropine to reduce this
risk)
Routes of IV, IM
Administration
Other No Tetanic Fade: All twitches are uniformly decreased
Non- Drug Vecuronium, Pancuronium
Depolarising Mechanism of Action Does not depolarise
Blocking Fast onset, shorter duration of action
Agents Indications Adjunct to general anaesthesia for all surgical procedures (improves safety)
Relax muscles during surgery
Do not cross BBB
Competitive
Contraindications Lack of ventilatory support, neuromuscular disease,
Antagonist
Adverse Effects Do not cause muscle twitching
Block of presynaptic receptors causes decrease in ACh release
Pure NM Tetanic Fade
Blocker Routes of IV
Administration
Other Tetanic Fade: Twitch responses slowly decrease
47
– AChE Inhibitors
o AChE usually terminates ACh: ACh → Acetate + Choline
o AChE Inhibitors ↑ ACh → Agonistic function
Autonomic: bradycardia, ↑ saliva secretion, ↑ gut contractility
Neuromuscular: Repeated firing → twitching and ↑ contraction
Long to Drug Physotigimine
Medium Indications Glaucoma
Duration Anticholinergic poisoning (overdose of atropine) Rapid onset of actions
Contraindications Cholinergic Crisis
Adverse Effects Can cross BBB and cause profound CNS effects
Routes of IV, IM, Ophthalmic
Administration
Medium Drug Neostigmine
Duration Indications Myasthenia Gravis
After surgery to reverse neuromuscular junction blockage (i.e. vecuronium)
Contraindications Cholinergic Chrisis
Adverse Effects Do not cross BBB
Routes of IV, IM, Subcutaneous
Administration
Medium Drug Pyridostigmine
Duration Indications Myasthenia Gravis*,
Treatment of urinary retention
Contraindications Cholinergic crisis
Adverse Effects Do not cross BB
Routes of Oral, IV
Administration
o *Myasthenia Gravis → Grave Muscle Weakness
Also called Ragdoll Syndrome
o Neuromuscular Autoimmune disease
Antibodies destroy the neuromuscular junctions
Resulting muscle weakness and fatigue.
o Symptoms:
Eyelid drooping
facial paralysis/Drooping head
hoarseness/Changing voice
difficulty talking
difficulty breathing
Fatigue
o Life-threatening breathing problems → Myasthenic Crisis
48
Adrenergic Pharmaceuticals
– β Agonists
β-non- Drug Isoprenaline
selective Mechanism of Action β1 on the heart – increases strength (inotrophic) and rate (chronotrophic) of
agonist heart contraction
β2 on smooth muscle – relaxes smooth muscle of bronchi, skeletal muscle
vasculature and gastrointestinal tract
Indications Heart block, cardiac arrest, acute asthma attack
Contraindications Tachyarrhythmia, angina pectoris
Adverse Effects β1 on the heart - palpitations, increased heart rate
β2 on vessels of the skull - Headache and flushing
β2 on skeletal muscle – mild tremors
β2 on blood vessels – hypotension
Routes of IV
Administration
Other Pharmacokinetic parameters: ½ life 2 minutes, metabolised by COMT, poor
susbtrate for MAO
β1-selective Drug None exist.
agonist Denopamine, dobutamine and xamoterol are partial agonists
Mechanism of Action Being partial agonists, they act as antagonists where a full agonist (Na, A)
Only partial is present
So, at rest β1 receptors will increase heart rate, but will inhibit an increased
agonists
heart rate when exercising.
β2-selective Drug Salbutamol (aka. ventolin)
agonist Mechanism of Action Β2 on smooth muscle – causes relaxation of the smooth muscle of the
bronchi, uterus and blood vessels
Β2 on skeletal muscle - decreases duration of skeletal muscle contraction
Β2 on liver - increases glycolysis and glycogenolysis
Indications Treatment of bronchospasm in asthma or chronic obstructive pulmonary
disease (COPD)
Pre-term labour
Contraindications Precautions (not quite contraindications): Hypertension or heart disease
Adverse Effects Inhalation (limits systemic effects):
β1 on heart – tachycardia
β2 on vessels of the skull - Headache and flushing
β2 on skeletal muscle – mild tremors
IV/oral:
Tachycardia, palpitations
Peripheral vasodilation with associated hypotension
Flushing and headache
Disturbance of carbohydrate metabolism and ketosis
Hand tremors
Obstetric use: as above with increased fetal heart rate
Routes of Inhalation (limits systemic effects), IV/oral, obstetric use
Administration
Other A substrate for COMT
Β3-selective Drug Mirabegron
agonist Mechanism of Action Stimulation of B3 – AR causes relaxation of bladder smooth muscle,
decreasing voiding frequency
Indications Symptomatic treatment of urgency, increased micturition frequency and
urgency incontinence in patients with severe OAB
Contraindications Severe uncontrolled hypertension, patients taking drugs metabolised by
CYP2D6
Adverse Effects Mild to moderate adverse effects: hypertension, tachycardia,
nasopharyngitis, UTI and headache
Routes of Oral
Administration
49
– ⍺ Agonists
⍺1 Drug Phenylephrine
Adrenergic Mechanism of Action α1 on heart → vasoconstriction → redistribution of local blood flow →
Agonist reduced oedema of nasal mucosa → improved ventilation and drainage
Indications Nasal decongestion, Facilitate ophthalmology and cataract surgery, treatment
of uvetis, mydriasis
Contraindications Cardiac conditions, antidepressants (monoamine oxidase inhibitors)
Adverse Effects Hypertension, tachycardia, arrhythmias
CNS stimulation (anxiety, dizziness, nervousness, irritability, excitability,
insomnia, restlessness, trembling, headache, hyperactivity)
(Children and elderly are more susceptible)
Routes of Orally – it is metabolised by MAO
Administration
- β Antagonists
β-non- Drug Propranolol
selective Mechanism of Action Blocks β1 on heart -> decreased heart rate -> reduction in cardio output ->
antagonist improved oxygenation of myocardium
Blocks β1 on kidneys -> suppression of renin release -> decreased blood
pressure
Blocks β2 on pancreas -> decreased insulin levels
Blocks β3 on adipose -> decrease serum free fatty acid concentrations and
increased triglyceride levels
Blocks β2 on eye -> reduce aqueous humour production -> reduce intraocular
pressure
Indications Glaucoma
Hypertension, angina, cardiac dysrhythmias
Migraine, anxiety tremor
Contraindications Congestive heart failure, hypotension
Patients prone to hypoglycaemia (diabetics)
Asthma
Adverse Effects Blocks β1 on heart – cardiac failure
Blocks β1 on lungs – bradycardia
Blocks β2 on lungs – bronchospasms in susceptible patients
Blocks β2 on pancreas -> hypoglycaemia in susceptible patients
Cold extremeties, fatigue
Routes of Topical, Oral dose, Injection dosage
Administration
β1-selective Drug Metoprolol
antagonists Mechanism of Action Blocks β1 on heart -> decreased heart rate -> reduction in cardio output ->
improved oxygenation of myocardium
Blocks β1 on kidneys -> suppression of renin release -> decreased blood
pressure
Indications Oral:Hypertension, angina pectoris, myocardial infarction, migraine
prophlaxis
IV:Disturbances of cardiac rhythm, in particular supraventricular
tachyarrhythmias
Contraindications Congestive Heart failiure, hypotension
Adverse Effects Blocks α1 on blood vessels -> postural hypotension
Blocks α1 on eyes -> contraction of radial muscle -> blurry vision
Nasal congestion
Priapism (painful erection that lasts for hours)
Tachycardia, palpitations
Routes of Oral, IV
Administration
o Beta blockers do not affect blood pressure of normal subjects
Effect hypertensive patients by reducing Renin levels.
– Benign Prostatic Hyperplasia
o Smooth muscle of prostrate predominantly express ⍺1A-AR
Stimulation → Contraction → Further urethral occlusion
o Smooth muscle of blood vessels belonging to older muscle express ⍺1B
50
– ⍺ Antagonists
α1-selective Drug Prazosin
antagonist Mechanism of Action Blocks α1 on blood vessels -> inhibits vasoconstriction -> decrease in total
peripheral resistance
Blocks α1 on smooth muscle -> inhibits smooth muscle contraction
Indications Hypertension
Benign prostatic hyperplasia
Raynaud’s phenomenon (small arteries in constrict)
Contraindications Hypotension
Adverse Effects Blocks α1 on blood vessels -> postural hypotension
Blocks α1 on eyes -> contraction of radial muscle -> blurry vision
Nasal congestion
Priapism (painful erection that lasts for hours)
Tachycardia, palpitations
Routes of Oral
Administration
α1A-selective Drug Tamsulosin
antagonist Mechanism of Action Blocks α1A on smooth muscle -> inhibits smooth muscle contraction
Binds to α1A on prostate -> relaxation of smooth muscle -> improvements in
urodynamics
Indications Relief of urinary tract symptoms (LUTS)
Associated with benign prostatic hyperplasia (BPH)
Contraindications Cataract surgery
Adverse Effects Abnormal ejaculation
Amblyopia (poor pupil dilation)
Dizziness
Hypotension (with overdose)
Priapism (very rare) and floppy iris syndrome are due to tamsulosin having
an off-target affinity for the dopamine D3 and serotonin 5HT1A receptors
Routes of Oral
Administration
51
– Pre-synaptic Drugs
Indirectly acting Drug Amphetamine, ephedrine, tyramine
sympathomimetic Mechanism of Structures similar to noradrenaline -> taken up by NET-1 -> taken up by
amines Action VMAT -> packaged in vesicle and forces noradrenaline out of the nerve
terminal -> increased activation of adrenergic receptors
(NET-1 drug
Transporters are converted to bi-directional exchange transporters
target)
Indications CNS stimulants in narcolepsy,
ADHD,
Appetite suppressant,
Nasal decongestion (ephedrine)
Contraindications
Adverse Effects β1 on heart – tachycardia
α1 on brain – insomnia, anorexia
α1 on blood vessels – pulmonary hypertension
Acute psychosis with overdose
Dependence
Routes of IV, IM,
Administration
NET inhibitors Drug Cocaine Desipramine
52
− Role of Adrenergic Receptors in Pregnancy
o Embryogenesis and Implantation
Activation of β-ARs by agonists can → Preimplantation embryonic
cell proliferation
β2 ARs in Oviduct regulate secretory function & ovum transport
Mice with ↓ α1 AR → ↓ Embryonic implantation
o Uterine Contractility
⍺1A and ⍺1D regulate pregnant uterine contractility → Myometrial
Contraction
Onset of Labour may be influenced by modulation of AR levels
• Could trigger preterm labour
Uterine Reactivity can be modulated by myometrial ARs
• ⍺1B → Oxytocin effects, β → Oxytocin secretion
• ⍺2 ARs ← Cervical Contraction
o Changes In mother
Changes in function/distribution of ARS in smooth muscle
↓ Vascular responsiveness → Gestational Hypertension →
Preeclampsia/Eclampsia
o Placenta
β2 and ⍺1 are found in Placental Vasculature
⍺2B → Vascular development
o Sperm
⍺1 are needed for normal male sexual function ← Transport of
spermatozoa
β ARs involved in Acrosome Reaction
53
Reproductive Pharmacology
Estrogen Progestin*
Physiological Actions
Neuroprotection Decreases oestrogen mediated endometrial
Cardioprotection proliferation
Influence on mood Maintenance of pregnancy
Reduction of intraocular pressure Changes in endocervical gland→production of
Amelioration of skin aging thick mucus
Arterial vasodilation Increase in basal temperature
Maintains bone density in both men and women Diuretic
Growth and proliferation of breast tissue Affects mood
Promotes normal sleep
Putative reduction in risk of colon cancer
Facilitates thyroid hormone function
Increased production of liver protein such as
Regulates insulin release
coagulation factors and hepatic lipoprotein Increases the use of fat for energy
receptors Stimulates new born formation
Growth and differentiation of and water Anti-inflammatory properties
retention in primary sex organ, risk factor for
endometrial cancer
Adverse Effects of Exogenous
Cancer - increased risk of endometrial Weak androgenic actions can cause acne and
carcinoma hirsutism (male pattern unwanted hair growth) –
Thromboembolic disease progestin is converted to testosterone
Hypertension Thromboembolism
Increase in gallbladder disease - due to increase Fluid retention, weight change
cholesterol levels in bile Change in libido, mastalgia (breast discomfort)
Migraine
o Natural = Progesterone,
o Synthesised = 17-ethinyl testosterone derivatives; 19-nortesteosterone derivative
– Hormonal Contraception
Combined Drug Oestrogen combined with progestin
Oral Mechanism of Action Oestrogen inhibits FSH secretion from anterior pituitary – Negative
Contraceptive Feedback
Progestin decreases frequency of GnRH release from hypothalamus,
99.7% reduces plasma gonadotropin (FSH/LH) pulses
Estrogen and Progestin alter endometrium to prevent implantation
Indications Contraception
Endometriosis
Contraindications Thrombophlebitis, Thomboembolic phenomena,
Cardiovascular, Cerebrovascular disorders, breast cancer
Caution: Liver disease, asthma, eczema, migraine, diabetes,
hypertension
Adverse Effects Mild: Nausea, mastalgia, breakthrough bleeding, Edema
Moderate: Weight gain, skin pigmentation, acne, hirsutism, urogenital
factors
Severe: thromboembolism.
Routes of Administration Oral. 21 consecutive days and 7 hormone free days
o 1st Generation: Risk of DVT and PE
o 2nd Generation: Androgenic reaction
o 3rd Generation: Progestin more potent, ↓ Androgenic action, ↓ Lipid metabalism
Potentially increased risk of Thromboembolism
54
Contraindications:
Absolute – previous thromboembolic event or stroke history of oestrogen dependant tumour,
active liver disease, pregnancy, undiagnosed abnormal uterine bleeding,
hypertriglyceridemia, women over 35 who smoke >15 cigarettes a day
Relative – hypertension, women receiving anticonvulsant drug therapy
Disease risk:
Increased – hypertension, coronary heart disease (only in smokers), venous thrombosis
(markedly increased with factor V Leiden mutations or similar), stroke, cerebral vein
thrombosis, cervical cancer
Decreased – ovarian cancer – 50% risk reduction; endometrial cancer – 40% risk reduction
Reasons to use:
Hypertension, Superficial thrombophlebitis (inflammation of veins),
History of thromboembolism, Biliary tract disease, Thyroid disease,
Epilepsy, Diabetes without vascular disease, Breast-feeding (COC
reduces rate and duration of milk production)
Contraindications Active thromboembolic disorders, pregnancy, severe hepatic disease
Adverse Effects Irregular/unpredictable spotting and breakthrough bleeding, acne,
headache, decreases in HDL levels, increases in lDL levels,
decreased bone density
Routes of Administration Oral taken once a day, everyday at the same time
Back up contraception (abstinence) for first 48 hours
Post-Coital Drug Levonorgestral
Emergency Mechanism of Action Prevents implantation or causes regression of CL, may alter tubal
Contraceptives transport of sperm/ova, may cause endometrial changes
Indications Oral emergency contraceptive for within 27 hours of unprotected sex
Contraindications Pregnancy, severe hepatic dysfunction
Adverse Effects Nausea, vomiting, fatigue, mastalgia, dizziness
Routes of Administration Two doses of 0.75mg 12 hours apart (80%)
Two doses of 0.25mg + 0.05 mg of ethinyl estradiol 12 hours apart
(60%)
55
– Erectile Dysfunction
PDE-5 Drug Sildenafil
Inhibotor Mechanism of Action Selective inhibitor of
phosphodiesterase 6, responsible
for degradation of cGMP in
corpus cavernosum and smooth
muscle of pulmonary vasculature
– Infertility
Infertility Drug Clomiphene
treatment Mechanism of Action Estrogen agonist + Antagonist
Racemic Antagonist predominate at low estrogen levels – Cis-isomer bind to
mixture estrogen receptors in hypothalamus for long durations → Interferes
with recycling, depleting estrogen receptors and inhibiting negative
feedback.
Day 5: Estrogen negative feedback interrupted because clomiphene
is bound to estrogen receptors → FSH secretion increases →
maturation of multiple follicles
Day 10: Late follicular phase still bound to receptors → Increases
estrogen has no effect on hypothalamus → no negative feedback →
Multiple dominant follicles and ovulations
Indications Infertility with intact hypothalamic pituitary axis + adequate
estrogen production
Contraindications Liver disease, abnormal uterine bleeding
56
Embryology – Week by Week Timeline
57
Compaction • Compaction starts at the 8-cell stage
(3 – 4) o Cells in the centre form the Inner Cell Mass or
Embryoblast
These cells will from the Embryo Proper and
the transient Hypoblast
o Cells in the periphery form the Trophoblast
Primary cells for the Foetal Component of the
Placenta
Blastocyst
Formation – Around day 4, the morula begins to absorb liquid
(4 – 5) o Aided by trophoblastic Na pumps
o Forms a Blastocoel/Blastocyst Cavity filled with
Blastocoelic Fluid
– The embryoblast moves to one side ← Embryonic Pole
o The opposite is the Abembryonic Pole
– Trophoblast becomes single layered epithelium
– This forms the Blastocyst
58
o The remaining cells form a multinucleated Syncytium
← Syncytiotrophoblast
Releases Proteolytic Enzymes to break down
Endometrial ECM
Produces Active Processes which penetrate
between endometrial cells
– These 2 interactions allow the blastocyst to be pulled into the
uterine wall
– Syncytiotrophoblast proliferates to encompass blastocyst
o Complete by day 9 except for site of implantation
(Coagulation Plug)
o Secretes Human Chorionic Gonadotropin (HCG)
and oestrogen/progesterone
Stimulates the Corpus Luteum
Amniotic Cavity • Beginning of day 8, fluid begins to collect between epiblast and
Formation trophoblast
(8) o This forms the Amniotic Cavity
• A thin layer of epiblast cells proliferates around the cavity
towards the embryonic pole
o This forms the Lining of the Amnion
59
Utero-Placental • On day 9, Trophoblastic Lacunae form in the
Circulatory Syncytiotrophoblast
System o Local maternal capillaries expand into Maternal
(9-Week 3) Sinusoids
o These fuse with Lacunae and fill with blood
• Develop during days 11-13
o Projections of the cytotrophoblast extend into the
Lacunae ← Primary Chorionic Villi
o At day 16 they fill with Extraembryonic Mesoderm
← Secondary Chorionic Villi
o At the end of week 3 they contain differentiated blood
vessels ← Tertiary Chorionic Villi
Yolk Sac and • Starting on day 9, hypoblast cells proliferate around the
Chorionic Cavity blastocoel
Formation o Forms the Primary Yolk Sac or Exocoelomic
(9) Membrane
• Concurrently, the blastocoel develops Extraembryonic
Mesoderm
• By day 12, the mesoderm has split to form the Chorionic
Cavity
o Eventually surrounds the embryo
• The primary yolk sac is displaced towards the abembryonic
pole via a new layer of hypoblast cells
o This gives rise to the Definitive Yolk Sac
• By day 13, the embryo proper is attached to the Chorion by a
thick stalk of extraembryonic mesoderm
o The Connecting Stalk
60
Gastrulation • At day 15, a thickened, rostro-caudal band of epiblast cells is
(15 – 16) visible ← Primitive Streak
o Extends caudally from midway
Defines the Axes of the embryo
o Expands cranially, forming the Primitive Node
Has an indent in the centre ← Primitive Pit
o Forms a ridge along the midline called the Primitive
Groove
– Shortly after, epiblast cells migrate towards, down and out of
the groove ← Gastrulation
o The first cells replace the hypoblast
This forms the Endoderm
Precursor to epithelium and glands of GIT,
Respiratory tract and Renal Bladder
o The second cells fill the space between the epiblast and
the endoderm
This forms the Mesoderm
3 Precursor to all CT of the body (excluding
cranial), Muscles of the body
o The left-over epiblast forms the Ectoderm
CNS and PNS, Epidermis, Sensory Placodes,
Adrenal Medullary cells
– This forms the Trilaminar Embryo
Notochord Formation – Some cells migrate through the primitive node cranially
(16 – 20) o Continues to form along the embryonic midline
o Forms an axial, rod like structure in the mesoderm, The
Notochord
Transient Structure that is responsible for
signalling and patterning via Sonic Hedgehog
(SHH)
It also aids in folding of the embryo
In humans, becomes the nucleus pulposus
– The mesoderm lateral to this forms the Paraxial Mesoderm
61
o A precursor to Somites
– Lateral to this is the Intermediate Mesoderm
o A precursor to Kidneys
– The remaining mesoderm forms the Lateral Plate
Neural plate formation – The signalling of the notochord induces a thickening of the
(18 – 20) overlying ectoderm
o This forms the Neural Plate
Forms in between the buccopharyngeal
membrane and the primitive node
Transformation of Cuboidal to Columnar
o This plate has a broader Brain Plate and a narrower
Spinal cord region
Has 3 components: Floor Plate, Neural Plate,
and the Neural Crest
– At days 18-19 the neural plate begins to invaginate along the
3 midline
o Forms a longitudinal median Neural Groove
Flanked on either side by Neural Folds
The peaks of the folds form the Neural Crest
Cells
– The neuroectodermal cells continue to proliferate and the
groove deepens
o 3 regions of the groove proliferate less and form Hinge
Points
2 Lateral Hinge Points and 1 Median Hinge
Point
This causes the plate to buckle
o The regions near the crest of the neural folds have
specialised glycoproteins that stick to each other and
fuse
– By the end of the third week, the neural folds have begun to
fuse and form the Neural Tube
o Starts near the midline and continues rostro/caudally
62
Leaves 2 Neuropores at either end as the last
to close
The Anterior Neuropore closes by day 25
The Posterior Neuropore closes by day 27
Failure to close results in Neural Tube Defects
– After closing, the tube sinks and is covered by Surface
Ectoderm
o The neural crest cells break away and form the Neural
Crest
Lateral to the neural tube and ventral to the
surface ectoderm
These cells give rise to the PNS and CT of the
skull and neck
Formation of the
Intra-Embryonic – On day 17, a collection of fluid builds up within the lateral plate
Coelom forming the Intraembryonic Coelom
3 (17) o This will eventually form the 3 “P” cavaties
Pleural, Pericardial, Peritoneal
o This splits the lateral plate into the Somatic Mesoderm
(Dorsal) and the Splanchnic Mesoderm (ventral)
The somatic gives rise to the inner lining of the
body wall and parts of the limbs
The splanchnic gives rise to the Mesothelial
Covering of the viscera
63
Early Cardiogenesis – Around day 18 cells within the splanchnic mesoderm undergo
(18 – 20) differentiation
o This occurs laterally and cranially to the Neural Plate
o Blood Islands begin to form containing
Heamangioblasts which can differentiate into 2 cells
Angioblasts form endothelial cells
Heamocytoblasts form blood cells
– Blood islands caudal to the buccopharyngeal membrane form
twin Endothelial Tubes
o This is known as the Cardiogenic Plate
o These are brought ventrally and caudally during folding
– At day 20, these tubes fuse together to form the Primitive
Heart Tube
o Anchored Cranially and caudally to the Pericardium
Developed from the folding endoderm
o Is inverted in structure, with atria residing caudally
Below this lies the Sinus Venosus
3 Cranially lie the Primitive Ventricle, Bulbus
Cordis, Truncus Arteriosus and Ventral
Aorta
The atria, ventricle and bulbus start to bulge
o The endothelium is surrounded by Visceral
Pericardium ← Epicardium
The space between the endothelium and
epicardium is filled with Cardiac Jelly
Eventually invaded by Myoblasts →
Myocardium
Collectively referred to as the Myoepicardial
Mantle
Vasculogenesis and – Other blood islands within the embryo and the extraembryonic
Angiogenesis mesoderm start to develop Lumens
(18 – 20) o The angioblasts flatten into endothelial cells and
surround the caverns
64
o Many endothelium lined cavities fuse and form
networks ← Vasculogenesis
Additional vessels reach into other areas via
budding ← Angiogenesis
This network undergoes constant remodelling
as the embryo develops
o The mesenchymal cells surrounding the channels
differentiate into the CT and Smooth muscle of the
vessels
– The new vasculature carries blood from various sites of gaseous
exchange to the heart tube
o Vitelline Veins carry blood from the yolk sac
o R/L Umbilical Veins carry blood from the placenta
The cytotrophoblast has expanded and formed
the Cytotrophoblast Shell
Anchoring Villi attach the extraembryonic
mesoderm to the shell
3 Branch like Stem Villi form a robust network
for maternal/foetal gaseous exchange
o Cardinal Veins carry blood from the embryo
o These veins join the sinus venosus whilst other
primitive arteries join the truncus arteriosus
E.g. the 2 Ventral Aortae
65
Folding – During the fourth week, the embryo undergoes a series of
(19 – 30) folding process
o Occurs due to differential growth of different tissues
– Cranial-caudal body folding occurs due to growth of cranial
neurofolds
o The buccopharyngeal membrane is brought to the
future position of the mouth
o The primitive heart, Septum Transversum and
pericardial coelom fold under the notochord
This causes part of the yolk sac to be
incorporated as the Foregut
o Post folding, the septum transversum lies caudal to the
heart and becomes the diaphragm
– The caudal end follows a similar pattern but occurs later
o The cloacal membrane moves ventrally
Part of the yolk sac is incorporated as the
Hindgut
4 o Post folding, the primitive streak lies caudal to the
cloacal membrane
– Each lateral body wall folds towards the midline to form a
cylindrical embryo
o Part of the yolk sac is incorporated as the Midgut
Simultaneously, the connection to the yolk sac
is reduced to the Yolk Stalk
– This forms the primitive GIT
o Endoderm forms epithelium and glands
o Mesoderm forms mesentery and CT
o Ectoderm contributes to the Enteric Nervous System
through neural crest cells
– Folding also gives rise to the beginnings of the respiratory
system
The Respiratory Diverticulum forms
This is a precursor to the trachea, larynx and
lungs
66
Somitogenesis – The formed somites differentiate into 2 regions
(19 – 32) o The dorsolateral Dermomyotome
This breaks into 2 parts, the Dermatome and
Myotome
The dorsal dermatome spreads out and forms
the CT of the skin
The ventral myotome further breaks down into
a dorsal portion which migrates and forms the
Epaxial Muscles and the ventral portion which
forms the Hypaxial Muscles
o The ventromedial Sclerotome
Engulf the notochord and form the axial
skeleton
– The intermediate mesoderm forms 3 kidney-like structures
o Pronephros
o Mesonephros
Predominantly transient but can contribute to
4 male reproductive tract
o Metanephros
67
– After closure of the neuropores, the front part of the neural tube
forms the 3 Primary Vesicles
o The Prosencephalon, Mesencephalon,
Rhomebncephalon
o These are bent at 2 flexures
The Cephalic Flexure between the
rhomben/mesencephalon
The Cervical Flexure between the
rhombencephalon/Spinalcord
68
Limb Bud – Mid 4th week the upper limb bud develops at C5-8
Development o 2 days later, the lower limb bud forms at L3-5
(24) – Initially just ectodermal covered mesoderm
o Eventually invaded by blood vessels and myotome
Cardiovascular – The primitive heart tube grows and buckles → U-shaped tube
Development → S-Shaped tube
(21 – 28) o Due to fixed nature of the ends
o Ventricle enlarges, lengthens and twists left
Absorbs bulbus cordis to form the
Bulboventricular Loop
o Atrium moves to lie dorsally such that inflow is behind
outflow
– This places the atrium cranially and the ventricle caudally
o Complete by day 28
– Embryonic circulation is established
4 o Deoxygenated blood is brought to the placenta via L/R
Umbilical arteries
1 Umbilical Vein returns oxygenated blood
69
Cardiovascular – Septation occurs during week 5 as the heart becomes a 2-pump
development o Cells from the dorsal and ventral walls grow towards
each other forming Endocardial Cushions
The fusion of them creates L/R
Atrioventricular Canals
o The midline of the atria proliferates as the Septum
Primum
This creates the Foramen Primum
As the septum primum extends towards the
endocardial cushions, apoptosis creates a
Foramen Secundum
o The Septum Secundum grows from both the cephalic
side of the atrial wall and the endocardial cushions
These two growths don’t meet forming the
Foramen Ovale
o Both the foramen secundum and ovale allow for blood
flow from left to right atrium
5 Foramen Primum acts as a backflow valve
– Post atrial septation, ventricular septation occurs
o The Pars Muscularis grows 2/3 of the way up to the
endothelial cushions
Forms the Interventricular Foramen
o The endocardial cushions start to regress and become
fibrous
This is in preparation for becoming valves
Some cells close the foramen and form the
Pars Membranacae
– Within the ventricles, the myocardium differentiates into
Papillary Muscles
o Parts stay attached to the endocardial cushions and
become tendinous
These form the Chordae Tendinae
Occurs whilst valve formation occurs
70
Continued Neural – Neural development continues as the primary vesicles split to
Development form the 5 Secondary Vesicles
o The prosencephalon splits into the Telencephalon and
the Diencephalon
o The rhombencephalon splits into the Metencephalon
and Myelencephalon
– Along with this, there are now 3 flexurs
o The Cephalic Flexure is between the
dien/mesencephalon
5 o The Pontine Flexure is between the
myelen/metencephalon
o The Cervical Flexure is between the
myelencephalon/Spinal Cord
Hearing Development – The Otocyst has developed into cavernous inner ear
o During week 5 the cochlea part of the otic vesicle
elongates
Respiratory – The respiratory diverticulum branches into L/R Bronchial
Development Buds
o These push into the Pericardiopertioneal Cavities
Precursor to the pleural cavity
Outflow Septation – Within the common outflow tract of the ventricles
(Conotruncus) small ridges develop
o These are the Truncal and Bulbar Ridges
They are continuous within the conotruncus
and grow helically
– The fusion of the ridges forms the Aorticopulmonary Septum
o This divides the pulmonary and systemic outflow
6 – This is mediated largely in part due to migrating
Cardiovascular Neural Crest Cells
Limb Development – By week 6, limb buds have developed primitive hands and feet
with Digital Rays
o Apoptosis triggers cell death between the digits
– Upper limb bud nerves enter the hand plate
71
– Myoblasts become spindle shaped and orient along the axis of
each limb bud
72
Genetics
Genetics Definitions
– Genome: Complete genetic composition
– Genotype: What Alleles are carried (both alleles)
– Phenotype: Physical manifestation of a genotype
– Locus: Region on chromosome where a gene is located
– Allele: Form or variant of a gene or locus
– Heterozygote: 2 different alleles at locus
– Homozygote: 2 same alleles at locus
– Dominant: Determines phenotype in heterozygote
– Recessive: no affect in heterozygote ← Only affect in homozygote
– Law of Segregation: Each allele in a pair will separate into a different gamete
– Law of Independent Assortment: Alleles of different genes on different homologous
chromosomes assort independently during gamete formation
– Multiple Alleles: >2 Alleles code for a characteristic e.g. Blood Types
– Incomplete Dominance: Phenotype of a heterozygous organism is intermediate
between two homozygous parents
o This is not blended inheritance.
–
Co-dominance: Both alleles visible in phenotype
o E.g. A and B are co-dominant, give rise to Type AB (Roan Cattle)
– Linkage: 2 chromosomes that tend to cosegregate (move together).
o Alleles on same chromosome,
o ↑ Distance → ↓ Linkage → greater chance of exchange by crossing over
– Non-parental: Recombinant gametes where DNA is not similar to either parent
o 0% Recombination: All parental
o 25% Recombination: 75% gametes match parents, 25% gametes non-parental
o 50% Recombination: Cannot measure distance greater than this
Same as being on different chromosomes
Types of Disorders
– Autosomal Recessive: Albinism, Cystic Fibrosis, Sickle Cell Anaemia
o Appears in progeny of Unaffected Parents ← Aa X Aa
o May skip generations
o Males and females affected equally
– Autosomal Dominant: Achondroplasia (Dwarfism), Hypercholesterolemia, Porphyria
(mental derangement episodes)
o Occurs in all progeny that inherit disease
o Present in every generation
o Males and females effected equally
– X-Linked Recessive: Red-green colour blindness, Duchenne Muscular Dystrophy,
Haemophilia
o Males more likely to be affected than females
Cannot inherit another dominant X to cover up the gene
o Affected fathers cannot pass condition to their son
Make Obligate Carrier daughters
o Mothers can pass to sons
o Males with trait are Hemizygous
73
– X-Linked Dominant: Hypophosphatemia (skeletal deformities)
o Affected males pass conditions to all daughters, but not sons
Affected son → Affected mother
– Y-Linked: Deafness
o Only transmitted father to son
– Mitochondrial Linked Disorder: Kearns Sayre Syndrome (short stature, retinal
degeneration)
o Maternally inherited organelles
– Other modes of inheritance:
o Non-Disjunction: Homologous chromosomes don’t spate in meiosis. Haploids
n-1 or n+1. Fertilisation leads to aneuploidy: 2n+1 or 2n -1.
Downs syndrome: Trisomy 21
Klinfelter Syndrome: XXY
Turner Syndrome Monosomy: X
o Pleiotropy: One gene affects multiple traits
Sickle Cell Anaemia → ↓ Haemoglobin → Other systemic effects
o Epistasis: Expression at one locus dependant on the genotype of another locus
o Polygenic traits: Some traits influenced by many genes
Quantitive traits e.g. Height
o Complex/Multifactorial traits: Environment, Polygenic, Epistasis and other
factors all relevant.
Hardy-Weinberg Law
The frequency of alleles and genotypes in a population will remain constant from generation
to generation if the population is stable and in genetic equilibrium (not evolving).
– 5 Exceptions to law
1. Non-random Mating
2. Migration: Genetic exchange of isolated populations
3. Finite population size: Random genetic drifts
4. Mutation: Only source of new alleles
5. Natural Selection: Not an equal chance of allele survival
– Genetic Drift: Changes in allele frequencies due to chance
events in small populations
– Bottleneck Effect: Disaster limits variation
– Founder Effect: Founders of new land are few people, limiting
variation
– Non-Random Mating: Positive (Like + Like), Negative (Like + Unlike)
– Natural Selection: Environmental or artificial, positive or negative, modes:
o Stabilising: extremes eradicated
o Directional: Towards one triat
o Disruptive Selected: Average trait is not selected → Distribution is bimodal
– Sickle Cell Anaemia example:
o Heterozygote: HbS/HbA less susceptible to malaria than HbA/HbA but also
don’t have severe symptoms of sickle cell anaemia like HbS/HbS.
74
Screening
Definitions
– Sensitivity: How good is the test at correctly
identifying people who have the diseases i.e.
Proportion of diseased people did the test detect
as positive.
– Specificity: How good is the test at correctly
identifying people who do not have the disease i.e.
Proportion of the non-diseased people did test
detect as negative.
– Positive Predictive Value: Proportion of those
with positive tests who have the disease.
– Negative Predictive Value: Proportion of those
with negative tests who do not have the disease.
Tests to Conduct
– Pre-Pregnancy
o Immunisation (Rubella, Varicella) and Past History (Hepatitis, HIV)
o Health Optimisation: BMI/Obesity, Smoking, Alcohol, Recreaitonal Drugs, Folate
– Pre-natal counselling
o Family genetic testing
o Infections that might cause pregnancy issues
– Early Pregnancy Tests (6 Weeks Post LMP)
o Pregnancy Test: Urinary b-HCG and serum progesterone (Confirmation)
o Blood Test: Reduce risk of vertical transmission
o Blood Grouping (ABO, Rh)
o Infection: Rubella, HIV, Syphilis, Hepatitis B
o Blood Disorders: Hb electrophoeisies Thalassemia, Anaemia in the mother
o CMV
– Ultrasounds:
o 1st Trimester (Up to 12 – 14 Weeks)
Confirmation of pregnancy
Dating
Location of pregnancy
Aneuploidy risk assessment
Multiples and Chorionicity – twins in 1% of pregnancy
Early morphological assessment
o 2nd Trimester (Up to 28 Weeks)
Chromosomal aneuploidy (soft markers increase risk – large nuchal fold, short
humerus or femur)
Anatomical Assessment (2-3% have an anomaly_
• Facial Profile – Cleft Lip
• Spina Bifida
• Septal Defects, Hypoplastic left heart
• Abdominal Wall - Gastroschisis
o 3rd Trimester
Fetal Biometry: Growth – normal vs abnormal
• Bipareital diameter, Occiptofrontal diameter, head circumference,
abdominal circumference, femur length
Doppler Assessment (Fetal wellbeing)
Placenta position and nature
75
Amniotic fluid volume assessment
– Aneuploidy (Chromosomal Abnormalities) And Genetic Disorders
o Screening:
Nuchal Translucency Assessment (13+6 Weeks) - Gives revised risk of Down’s
Syndrome
Non-Invasive Prenatal Testing (NIPT) (> 9 weeks): Blood test of cell-free
circulating fetal DNA. Test for Trisomy 21, 18, 13 and sex abnormalities
Serum Biochemistry β-HCG higher in chromosomally abnormal, PAPP-A is lower
2nd Trimester: Chromosomal Assessment and Soft markers by ultrasound
(observation of physical features which increase risk but may be transient features)
o Diagnostic: Chorionic Villus Testing (11 – 14 Weeks) – Placental Tissue
0.5-1% Miscarriage
Mosaicism
Culture Failure
FISH/PCR
PV Spotting, Crampy period Like Pain
Test for: Down’s Syndrome, Cystic Fibrosis
o Diagnostic: Amniocentesis (>16 Weeks) – 12-20 mLs of amniotic fluid
0.5-1% Miscarriage
Ultrasound guidance
Skin and Bladder cells
Test for: Down’s Syndrome, Cystic Fibrosis, Neural Tube Defects: Spina bifida
– Other Pregnancy Tests (Antenatal testing)
o Gestational Diabetes (28 Weeks)
o Group B Streptococcus (28 or 34 Weeks)
o Pre-eclampsia or Hypertension (2nd or 3rd Trimester)
o Clinical Estimation of Fetal Growth: Fundal Height and Crown rump Length
Screening Vs Diagnosis
- Screening: should be applicable to anyone within the population and carry no risk to the
individual while undergoing the screening process
- Diagnosis: provides a definitive answer as to whether there is the presence of a pathology or not,
although the tests generally carry an element of risk to the individual.
o DMD, Down’s Syndrome
o Clinical Suspicion, confirm a diagnosis or without specific diagnosis
o Chromosome Microarray: Comparison of DNAs – deletions or duplications
o Sequencing Methodologies: Sanger Sequencing (single-gene) and Next Generation
Sequencing (targeted gene panel, exome, whole genome)
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Microbiology
Sexually Transmitted Diseases
Bacteria Chlamydia Trachmoatis Neisseria Gonorrhoea Syphilis
Causative Agent Obligate intracellular parasite- Gram negative Treponema Pallidum
+ Description No gram stain Diplococci, Thin coiled organism, Sluggishly
Enter via minute abrasions in Fastidious, Human motile
mucosal surface, growth pathogen Multiplies extracellularly
restricted to columnar + Affects Columnar or Penetrates skin/mucous membranes
Transitional epithelial cell cuboidal epithelium Incubation 2 – 6 weeks
Elementary Body: Extracellular
survival, Initiation of infection, Incubation: 2 – 7 Days
binds to epithelial cell receptors
Reticulate Body: Intracellular
replication
Clinical 50% asymptomatic 20% after first sex Genital ulcer
Presentation: Dysuria, Testicular Pain, encounter Chancre
Males Anorectal symptoms Urethral: Non-tender, well define
Purulent urethral
discharge, pain/burning
on urination.
Females Rectal/Throat
75% asymptomatic 50% after first sex
Dysuria, vaginal discharge, encounter
pelvic pain, post-coital bleeding, 50% asymptomatic
Anorectal symptoms Purulent vaginal
discharge, pain and
burning on urination
Rectal/Throat: Mostly
Asymptomatic
Complications Males: Epididymo-orchitis, Males: Secondary Syphilis: Organisms
Reactive Arthritis, Urethritis escape lesions
Spread systematically via lymph
Females: PID → Infertility, Females: Cervical nodes
Ectopic pregnancy, Cervicitis, Infections Flu like illness, myalgia, headache,
urethritis 15% may develop PID fever, mucotenous rash
→ Infertility,
Bacteraemia Latent: Develop 3-30 years later
Gonococcal arthritis
Fever, chills, skin Congenital: Abortion, still birth,
lesions, Arthralgias multiple organ failure, CNS defects,
Peri-natal infection deformed bones/teeth
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Serotypes A, B1, B2, C: 20 – 34 years (Males Gummas: Soft, noncancerous
Trachoma predominance) growth
Serotypes D-K: Genital ATSI Further dissemination/Invasion
infection, ocular and respiratory Aortic lesion → Heart failure
infection
Serotypes L1, 2,3: Systemic
infection - Lymphogranuloma
Venerum
PID: Infection induced inflammation of female upper reproductive tract and surrounding CT
Endometritis: Lining of Uterus, Salpingitis: fallopian tubes, Oophoritis: Ovaries
Pathogenesis of C Trachomatis
o C. Trachomatis mostly infects columnar epithelium (macrophages). EB binds to epithelial cells
and enters via endocytosis
o Epithelial cells detect C trahcomatis by innate receptors on cell surface, endosome and cytosol
which leads to production of pro-inflammatory cytokines/chemokines + immune cell recruitment
o Inflammatory response leads to damage and scarring
Pathogenesis of N. Gonorrhoeae
1. Infecting epithelial cells of urogenital tract (columnar epithelium) induces inflammatory
responses that trigger PMN influx
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Symptoms of PID
– Pain in lower abdomen/pelvis, back pain
– Uterine or Adnexal or Cervical Motion tenderness
– Abnormal vaginal discharge, yellow/green, unpleasant odur
– Pain or bleeding during intercourse (dyspaneuria)
– Pain during urination (dysuria)
– Bleeding bwetwenn periods
– Also: fever, chills, vomiting, severe abdominal, pelvic pain
Laboratory Diagnosis
– Clinical Signs can produce a diagnosis
– Positive finding supports PID, negative finding does not exclude PID
– Pregnancy Test, Ultrasound CT Scan, Laparoscopy, Urine analysis, ESR, C-Reactive Protein,
WBC count
– Isolation of N. Gonorrhoeae
o Chocolate Blood Agar
o Gonococcal Medium: CBA with Vaocomycin, Colisin and Nysatin (inhibit growth of
vaginal bacterial flora)
o Biochemical Tests: Oxidase(+), Sugar Fermentation: Glucose Sucrose(+), Maltose(-)
Differential Diagnosis: Ectopic pregnancy, endometriosis, ovarian torsions, ovarian cysts, UTI, acute
appendicitis, gastroenteritis, cholecystitis
Clinical Classification: Acute (≤30 Days), Chronic (> 30 days) Subclinical (C trachomatis, N
gonorrhoeae)
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SG Content
Indigenous and Pregnancy
Median ages – Life expectancy
Indigenous males 54.9 years
Indigenous females 61.5 years
Indigenous males 78.6 years
Non-Indigenous females 84.9 years
Maternal Deaths
- In 2008-2012, 8 out of 87 maternal deaths were indigenous women (where indigenous status
was reported) – 9%
- Difference in frequency of maternal deaths:
o Indigenous: 13.8/100,000, Non-Indigenous: 6.6/100,000
Consumption of Alcohol
- Survey from 2012-2013 people aged 15 and over:
Indigenous Non-Indigenous
Consumed in the past year 72% 77%
More than 12 months prior 13% 7%
Never consumed 14% 11%
Unsure of last consumption 1% 5%
Risk Guidelines
- Lifetime Risk Guidelines
o 18% of Indigenous Australians exceed the Lifetime Risk Guidelines
Males – 26%, Females – 10%
o 18.6% of Non-Indigenous Australians exceed the Lifetime Risk Guidelines
Males – 28%, Females – 10%
- Single Occasional Risk Guidelines
o 54% of Indigenous Australians exceed the Single Occasional Risk Guidelines
Males – 64%, Females – 44%
o 43% of Non-Indigenous Australians exceed the Single Occasional Risk Guidelines
Males – 56%, Females – 31%
- N.B. After adjustment for age structure, the percentage of people exceeding Lifetime Risk
was similar between Indigenous and Non-Indigenous
o Aboriginal and Torres Strait Islanders are more likely in exceeding Single
Occasional
- Rate Ratio: 1.1 for males and 1.2 for females
Distribution of Aboriginal Population
- Highest population of aboriginals in NSW with 31% of Aboriginal population
- NT has highest by proportion with 29.3% of state population
- Distribution in 2011:
o 35% in major cities
o 22% in inner regional
o 30% in outer regional and remote
o 15% in very remote
Leading causes of indigenous death
- 24% from circulatory/cardiovascular diseases
- 20% from neoplasia
- 15% from external causes
- 9% from endocrine, nutritional and metabolic diseases
- 8% from Respiratory diseases
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Menstrual Cycle and Fertility Awareness
Follicular Phase
– Endometrium proliferate/thicker
– Cervix: Higher softer and open
– Mucus becomes thinner and waterier, increase by 10%. Spinnbarkeit effect: Allows cervical
mucus to be stretched or drawn into a thread – at ovulation, exceeds 10cm
o Fertile Mucus: Fern like pattern on glass slide
– Body temperature unchanged
Luteal Phase
– Progesterone → Endometrium secretion of glycogen rich fluids in preparation for implantation.
– Cervix: Lower, firmer and closed
– Mucus: Thicker and stickier, hostile – prevents penetration – dense network of filaments – sperm
killed by acidic vaginal environment
Fertile Phases
– Pre-ovulatory relatively infertile phase following menstruation
– Fertile phase either side of ovulation – cervical mucus indicates this by abundant stretchy mucus
(sperm survive 3-5 days).
– Post-ovulatory infertile phase – cervical mucus/temperature sign, until menstrual phase.
o Fairly consistently 14 days; variability in cycle is due to pre-ovulatory phase
– Short Cycle: Ovulation at day 7, Normal Cycle: Few preovulatory infertile days, Long Cycle:
many Preovulatory infertile days
Basal Body Temperature
– Increase in 0.2 – 0.5 degrees confirms ovulation
– Sustained increase in temperature of 3 days indicates onset of post-ovulatory infertility
– Rule of 3 over 6: Post ovulatory infertile phase after 3 days of raised temperature, must be higher
than previous 6 days by at least 0.1 degrees and one temperature should be 0.2 degrees higher.
o Length of shortest cycle (of last 6) – 20 indicates last infertile day.
o Length of longest cycle – 10 indicates last fertile day
Indicators of Fertility
– Infertility: Low, long, tilted, firm, closed dry cervix
– Potential Fertility:
– Fertility: High, short, straight, soft, open, wet, slipperiness, transparent, slippery stretch mucus
o Mittleschmez/Ovulation Pain 2 hours, Breast tenderness. Increase in libido.
Factors affecting fertility
– Fever, strenuous exercise, bad sleep, holidays, travel, other women, shift work, stress , illness ,
medication
Natural Family Planning
Advantages Disadvantages
No interference normal physiology Time to learn/recognise/chart fertility symptoms
Requires no drugs or devices Requires initial teaching from NFP teacher
No known physical side effects Some women find charting difficult.
Can be used at all stages of reproductive life Fear of unplanned pregnancy because though
Partners share responsibility for family planning. method failure is low, there is a higher user failure
May improve communication about sexuality rate particularly during the learning phase.
May help sub-fertile couples to conceive Both partners require a high degree of motivation,
Enables a couple to take control of their fertility and commitment. Modifications to sexual
Women can monitor changes in sexual health. behaviour are needed to ensure abstinence during
Morally and culturally acceptable when artificial the fertile phase.
contraception is unacceptable. There may be difficulty using natural methods at
Cost-effective - Once properly taught, couples do times of stress, after childbirth, after taking the
not require medical supervision. contraceptive pill and during the pre-menopause.
No protection against STDs.
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Common Complaints in Pregnancy
Nausea/Vomiting (60% of women symptoms until week 12, 9% beyond week 16)
Definition: Sensation of unease or discomfort in stomach with urge to vomit
Cause: Unclear
- High levels of estrogen/hCG
- Gastric reflux
- GIT dysfunction
- Vitamin B6 deficiency
- Overactive thyroid gland → increased thyroxine
- Other causes: Liver disease, intracranial lesions e.t.c More problematic in multiple pregnancy
NB: Morning sickens not always in morning (due to relative hypoglycaemia after overnight fast)
Effect on Baby: Actually beneficial, better pregnancy outcomes, functional role – heightened sense
of smell and keeps insulin low to facilitate placental growth
Management: Frequent, small meals, avoid smells/food cause nausea, drink small amounts often,
rest, ginger, Vitamin B6 supplementation
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Other: Night urination - increased Na excretion at night, fluid is mobilised at night while lying down,
pressure is relieved, gravitational effect, increased pumping of accumulated sodium (collected in
lower extremities during the day due to gravity, venous stasis, uterus pressure on large veins to heart)
Temperature Changes
- Progesterone has thermogenic effects, maternal metabolism is altered and basal metabolic rate
increases, increased blood volume is a greater area of heat storage i.e. more heat during
pregnancy
- Extra head is dissipated by vasodilation of peripheral vessels and increases in skin blood
flow, hands and feet are effected most and blood flow here is increased most
Swollen ankles/feet
Cause:
- Capillary Hydrostatic pressure favours movement of fluid from capillaries to the interstium,
compression of iliac vein and inferior vena cava by pregnant uterus increases pressure in
lower extremities
- Colloid osmotic pressure: Favours fluid movement from interstitial to capillaries. Reduced
albumin reduces colloid osmotic pressure → Oedema
- Capillaries walls may also be more permeable during pregnancy
Management: Avoid supine position, avoid upright position for extended periods, elevate feet/legs
regularly, avoid tight clothing on lower extremities, exercise regularly, limit consumption of salty
foods and rinks, water immersion may help to mobilise fluid
Varicose Veins
Definition: Superficial veins that have become dilated/tortuous because of a defect in valves within
vessel or weakness of vessel wall. Valves become incompetent no longer prevent back flow, affected
session of vein dilate and become engorged with blood/tortuous.
Cause:
- Progesterone dilates veins, softens valve leafles → preventing closure
- Venous pressure increases in pelvic/lower extremities because of pressure of gravid uterus on
iliac vein and inferior vena cava
- Family history of varicose veins
Management: Similar measures as for dependant oedema. Will generally disappear following
pregnancy but can possibly return and get progressively worse.
Haemorrhoids
Definition: Varicosities of rectal veins
Cause:
- Obstruction of large veins of pelvic region by pregnant uterus – exacerbated by constipation
- Varicose veins – genetic predisposition
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o Inferior vena cava can be bypassed by collateral circulation and uterovarian
circulation dilation.
Anaemia
Definition: Deficiency in red blood cells, haemoglobin → reduces oxygen carrying capacity of blood
Cause:
- Iron Deficiency: Iron requirements increase during pregnancy → needed for haemoglobin
production
- Folate Deficiency (megaloblastic): Folate demand increases 3 fold → DNA synthesis for new
cells such as maternal blood cells (also Vitamin B12 deficiency)
- If haemoglobin < 6-8mg/dL → fetal mortality or decreased growth. Fetus is protected at
expense of mothers stores otherwise.
Symptoms: Dyspnoea because of anaemia.
Management: Iron supplementation can be given to replenish maternal iron store
NB: Physiological anaemia of pregnancy: Adequate iron and folate, RBC and haemoglobin
production. Increased plasma concentration results in reduced concentration of haemoglobin, but
overall increase in amount.
Shortness of Breath
- Progesterone resets respiratory centre in brain → Hyperventilation
- Uterus pressure on diaphragm, restricts movement of lungs → breathlessness
Back Ache
- Growing uterus to back pain in later gestation, shifting centre of gravity lower → Stress on
muscles/ligaments on lower back and spine.
- Lordosis (increased curvature of lower spine) to counter act weight, exacerbated by stretching
and decreased tone of abdominal muscles
- Relaxing/progesterone → soften ligaments and increase elasticity of CT collagen and
widening and increased mobility of sacroiliac joints and pubic symphysis. → can lead to back
pain
Pubic Pain
Cause: Pelvic bones joined anteriorly by pubic symphysis, joint widens during pregnancy, joint may
become unstable or very tender when walking and moving
Management: Good posture, care with bending and pillows can help, pelvic support belt, hospital for
bed rest, pain relief and physiotherapy.
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Vaginal Delivery vs Caesarean Section
Medical Reasons for Elective Caesarean Section
– Shape of pelvis
– Position of Baby – breach, transverse position, oblique, shoulder arm presentation
– Large baby
– Placenta previa
– Multiple pregnancies
– Traumatic vaginal delivery
– Maternal request
Disadvantages Increased perineal pain post delivery Increased rate of maternal mortality
Unable to plan date and time of Greater Maternal Loss
delivery Greater risk of wound infection
Takes longer post-delivery for Increased likelihood of neonatal
mother to find sexual intercourse respiratory distress in the newborn
pleasurable. Increased likelihood of fetal laceration
Maternal apprehension of pain during Longer recovery time
delivery. Increased risk of deep vein thrombosis
Potential for coccyx displacement Increased risk of still birth in
resulting in lower back pain. subsequent pregnancies
Increased complications of anaesthesia
Increased risk of inadvertent premature
delivery.
Increased risk of placenta accreta in
future pregnancies
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Gestational Diabetes Mellitus
Definition: Temporary diabetes that occurs during pregnancy. 1 in 20 women experience it around the
24th to 28th week of pregnancy.
Cause: Human Placental Lactogen increases blood glucose level so baby can get nutrients it needs
from higher serum glucose. hPL increases insulin resistance and increases in direct relation to length
of gestation. Mother’s pancreas has to produce more insulin to compensate and maintain normal
glucose homeostasis, insufficient response = GDM develops
Risk Factors: 50% of women with GDM do not have any risk factors
– Individual Characteristics:
o Age: > 430/0 years old
o Ethnicity: Asian, Indian, ATSI, Pacific islander, Maori, Middle Eastern Non-white
African.
o Above healthy weight range: Pre-pregnancy BMI > 30
– Individual History
o Elevated blood glycose in past or previous GD in previous pregnancy
o Polycystic ovary syndrome
o Previously given birth to a large baby (macrosomia > 4.5kg or 90th %ile)
– Other Risk Factors
o Family history of Type 2 diabetes, First degree relative who has had GD/sever
hyperglycaemia
o Antipsychotic or steroid medications
o Gained weight too rapidly
Treatment:
– Healthy diet: Ca, Fe, Folate, reduce intake of saturated fats and higher sugar food
– Keep active and monitor blood glucose, maintain habits post-partum
– Oral tablets not safe for foetus, consider insulin injections.
Consequences
– Short term: No Obvious symptoms,
o Maternal Hyperglycaemia → Fetal Hyperglycaemia→ Fetal hyperinsulinemia →
macrosomia - enlarge bay and possible hypoglycaemia postnatally
o Miscarriage or still birth, blood glucose, blood pressure or pre-eclampsia will usually
return to normal
– Long term: Hypoglycaemia in foetus (potential brain damage), jaundice, increased change of lung
immaturity, increased risk of developing type 2 diabetes later in life.
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Newborn Screening
PKU – Phenylketonuria
Definition: Amino-acid breakdown disorder, toxic build-up of phenylalanine (PHE) → Toxic for
developing neurons
Inheritance Type: Autosomal Recessive Disorder
Cause: Inactivating mutation of Phenylalanine hydroxylase enzyme → inability to breakdown
phenylalanine and convert to tyrosine
Incidence: 1:10,000, 8-10 cases in NSW, 1 in 50 carriers
Symptoms: Intellectual disability, Behavioural Problems, Seizures
Testing: Raised levels of PHE - > 200 μmol/L (further action after 150), high sensitivity
Treatment: Infant – special formula, life avoid foods with phenylalanine (milk, cheese eggs), tyrosine
supplements required
Outcome: Normal development – unmanaged in women can lead to microcephaly, mental retardation,
congenital heart disease and LBW
CH – Congenital Hypothyroidism
Definition: Insufficient Thyroxine
Inheritance Type: Sporadic occurrence/Autosomal Recessive
Cause: Iodine biosynthetic defects, partial or complete loss of function of thyroid gland – failure to
develop completely
Incidence: 1: 3,500, 28 Cases in NSW, 1/170 are carriers
Symptoms: Mental, growth retardation, macroglossia, dry skin, umbilical hernias, hoarse cry, hypotnia, low
metabolic rate = constipation, lethargy
Testing: Elevated thyroid stimulating hormone - some false negatives
Treatment: Thyroxine replacement therapy
Outcome: Normal development – dependant on ongoing management
Galactosaemia
Definition: Build-up of galactose in blood
Inheritance Type: Autosomal Recessive Disorder
Cause: Deficiency of GALT (Transferase gene) – enzyme required for conversion of galactose to
glucose → Accumulation of galactose
Incidence: 1:40,000, 2 cases per year in NSW, 1/112 are carriers
Symptoms: Cardinal features: Hepatomegaly (liver enlargement), cataracts, intellectual disability
Newborn: Failure to thrive, lethargy, vomiting, jaundice, sepsis
Testing: Flurometric assay of Galactose and galactose 1 phosphate, high sensitivity – can detect mild
forms of treatment
Treatment: Eliminate dietary galactose – use soy-based formula
Outcome: Normal development, often low IQ, learning difficulties despite treatment
Cystic Fibrosis
Definition: Hereditary disorder affecting exocrine glands
Inheritance Type: Autosomal Recessive Disorder
Cause: Mutation of cystic fibrosis transmembrane conductance regulator (CFTR) (chloride channels in
apical membrane of epithelial cells)
3 base pair deletion → loss of phenylalanine residue at position 508 (F508 mutation)
Incidence: 1/2500 pregnancies, 1/3500 babies, 1 in 25 are carriers
More common in Northern Europeans, Mediterranean/Middle Eastern and parts of India
Symptoms: Pancreatic insufficiency → Meconium ileus (bowel blockage – mucus plug) → smelly chunky
poo, failure to thrive and nutritional deficiencies
Recurrent/Chronic Lung Disease
Increased Sweat electrolytes
Testing: Guthrie Card Blood Test:
– Elevated concertation of Immunoreactive Trypsin in blood (pancreatic enzyme)
– Homozygous F508 → Clinic, Heterozygous F508 → sweat test
Sweat Test: Chloride > 35 mmol/L (> 60 mmol/L is consistent with CF)
– When sweat produced, chloride/sodium cannot be reabsorbed
– Gauze w/ pilocarpine (sweat inducer) and electrolyte solution on skin of arm or leg.
Electrode placed on pad, mild electric current → sweat collected for 30 minutes → Levels
of chloride/sodium determined.
Treatment: Enzymes replacements, physiotherapy and antibiotics -
Outcome: Shortened life expectancy, no direct treatment – methods exist improve quality of life (exercise
regimen)
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Cervical Neoplasia – Cervix Screening and Health
Transformation Zone: Lies between old SCJ and New SCJ and contains metaplasic squamous
epithelial cells. (Simple Columnar → Stratified Squamous Epithelium) – Take samples from here
HPV 16, 18, 31, 33, 35, 45, 52, 58 account for 90% of Cervical Cancer
HSIL: Severe cellular abnormalities, persistent infection, invasive cancer (CIN II or CIN)
– Small Cells: Round/oval with scant cytoplasm
– Enlarged irregular nuclei: Increased N:C Ratio (>1/2)
– Plemorphism: Contour, size, Shape
– Wrinkled nuclear membrane
– Hyperchromatic: Dark Staining
Action: Higher risk result → Refer to gynaecologist for colposcopy and tissue biopsy, if CIN 2 or
CIN 3 confirmed → Excisional Treatment (LEEP or LLETZ), ablation (laser)
Pap Smear:
– Every 2 years
– Speculum Exam
– Relies on cytology – detects pre-cancerous changes in cervical cells due to hPV infection
– Slide directly on a microscope slide
– Sensitivity: 50-70% (30-50% false negatives – very high)
Vaccination
– Gardisl 9: HPV 6, 11, 16, 18, 31, 33, 45, 52, 58
– Vaccination does not supplant need for routine cervical screening tests, many at risk women
already infected and other oncogenic HPV genotypes not vaccinated.
Action: If HPV 16/18 detected → Gynaecologist for colposcopy assessment
88
Vaginal Infections, Endometriosis, Endometritis
Endometritis Endometriosis
Definition Inflammation of the endometrium (lining of A condition resulting from the appearance
the body of the uterus). of endometrial tissue outside uterus and
causing pelvic pain especially associated
with menstruation
Technically chronic inflammation. “Ectopic
endometrial glands and stroma”
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Candidiasis (Thrush) Bacterial vaginosis Trichomoniasis
Pathophysiology Sexually associated but can occur Not sexually transmitted Only sexually
without sexual content. transmitted out of
three
Overgrowth of yeast on oral mucosa Gardnerella vaginalis
leads to desquamation of epithelial creates a biofilm which
cells and accumulation of bacteria, allows other
keratin, and necrotic tissue. Debris opportunistic bacteria to
combines to form a survive.
pseudomembrane, which may Risk factors include
closely adhere to the mucosa. This douching, new or
membrane is usually not large but multiple sex partners,
may rarely involve extensive areas antibiotics, and using an
of edema, ulceration, and necrosis of intrauterine device.
the underlying mucosa.
Affected neonates typically
colonized by C albicans during
passage through the birth canal.
Increased risk when mother has an
active vaginal yeast infection.
Predisposing factors:
immunosuppression (DM, AIDS,
steroids), antibiotics, pregnancy
Other Approx 75% of women have 1 Female who have sex Trichomoniasis is the
information episode in their lifetime with other females will most common
have a higher risk to get curable STD
bacterial vaginosis Women > Men,
Pre-term labour, pre- Older> younger
term birth and Increase risk of STI
postpartum e.g. HIV
Preterm babies and
LBW
Discharge The discharge is often thick, white Thin, watery, white or Yellow green,
and, curd-like (almost like cottage grey discharge a strong malodorous, diffuse,
cheese). The discharge will be or unusual odour from frothy.
odorless. the vagina, often
described as a ‘fishy
smell’.
90
redness and/or swelling of the Absence of Occasionally irritated
vagina or vulva vulvar/vaginal irritation tender vulva, dysuria,
stinging or burning when passing frequency
urine.
Other conditions, such as genital
herpes or urinary tract infection may
have similar symptoms, so it is
important to have the diagnosis
confirmed.
Saline wet A diagnosis can be made if When approximately High vaginal swab
mount pseudohyphae or yeast buds are 20% of cells are clue Wetmount in high
present cells (usually vaginal swab
Gardnerella Vaginalis, Wetmount
KOH slides can be used, KOH kills cells dotted with (insensitive):
off bacteria & cells, while leaving coocbacilli). Also has • Motile,
yeast. presence of white blood flagellated
Low vaginal swab. KOH wet mount cells, infection. When organisms
reveals oval yeasts with mixed with KOH has a • Many PMNs
pseudohyphae fishy smell. Trichomonas PCR is
Paucity of WBC & the most common
lactobacilli, test.
Positive whiff test
Treatment Antifungals (topicals are the most Antibiotics as pills or gel Metronidazole or
common) (Metronidazole, Tinidazole
Oral (azoles) Clindamycin,
Vaginal(applied topically) Tinidazole).
(azoles, nystatin)
Other
Ectopic Pregnancy 1-2% of pregnancies.
Clinical Manifestations
- Abdominal/Pelvic Pain , Amenorrhoea, Vaginal Bleeding: irregular, scant, dark brown
- Nausea, Vomiting, Fainting, Sycnope – reflex vasomotor disturbances
- Risk of haemorrhage/Shock
Diagnosis
- Transvaginal US, High levels of B-HCG, Laparoscopy/Endometrial biopsy, Decidual
reaction
Clinical Outcomes
- Medical Emergency due to rupture: Extrusion into abdominal cavity, Acute abdomen due
to intraperitoneal bleeding, Hypovolemic Shock, DIC/Infections
- Intratubal Haemorrhage
- Spontaneous regression
Long-term Consequences
- Infertility: Loss of reproductive organs post surgey, pelvic adhesions and peritubal
scarring
- Damage to adjacent structures
- Incomplete removal of trophoblastic tissue (low risk choriocarcinoma)
- Rh disease
- Another ectopic
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An Infertile Couple
Male:
Cause Investigation Treatment Options
Failure of Sperm Production Initial semen analysis Surgical sperm collection
Hormone assessments Donor sperm
Testicular biopsy
Blocked/Absent Vas Deferens Scrotal examination Unblock microsurgically
Screen for CF Surgical sperm collection with
IVF/ICSI
Low Sperm Numbers and/or Poor Semen analysis (sperm count) Intrauterine insemination (IUI), IVF,
Sperm Movement intracytoplasmic sperm injection (ICSI)
High Numbers of Abnormal Forms Semen Analysis IVF, ICSI
Antisperm Antibodies Antisperm antibody screen Sperm preparation for IUI, IVF, ICSI
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