Reproductive Health and Disease - Lecture 2 Infertility 02.02.23 For Moodle

Reproductive health and
disease, Part II
Dr Sarah Arrowsmith
s.arrowsmith@mmu.ac.uk
Phone 0161 247 1177

Room JD E228
Advanced Biological Aspects of Disease
Lecture 2 overview:
• Male factor infertility
• Sperm, testes and tubes
• Disorders of uterine function in pregnancy

• Physiological basis of uterine contraction
• Adenomyosis
• Aetiology of preterm birth, its prevention and treatment
• Aetiology of dysfunctional labour and postpartum haemorrhage and
treatment
Learning outcomes:
At the end of this lecture you should be able to:
1. Describe the physiological principles of male reproduction

2. Describe different factors contributing to male infertility
3. Explain how these factors can cause infertility (mechanism)
4. Identify and propose treatment strategies
5. Describe the physiological mechanisms which underlie uterine contractions
6. Explain the aetiology of different uterine contraction disorders and their
treatment
Male factor infertility accounts for ~40% of the cause of
infertility
Other
Chryptorchidism 7%
6%
Obstruction
6%
varicocele
Testicular failure 37%
9%
Semen disorders idiopathic

10% 25%
Investigating male infertility
• Diminished Sperm Count & Quality
• Tubal problems (Ductus deferens)
• Reproductive pathology
• Erectile dysfunction
• Problems ejaculating
Male reproductive system
Male Reproductive system
Quick Quiz
5.
4.
1.
2.
3.
6.
Testis
Spermatogenesis
• Begins at puberty until ~70 years
• ~64 day process
Mitosis
1st meiotic division
Meiosis
2nd meiotic division
Spermiogenesis
Seminiferous Tubles
Spermatogenesis
(nurse cell)
Seminiferous tubule
lumen
Spermatogenesis
Section through the seminiferous tubules of the testes

Role of Sertoli cells
• Provide a protective barrier between seminiferous tubules and
general circulation
- maintain stable conditions in lumen, protection from immune
system
• Produce fluid in lumen and regulate its composition
• Site of action for control of spermatogenesis by testosterone and FSH
• Provide nourishment for sperm for development
• Engulf cytoplasm extruded from spermatids during remodelling
• Secrete inhibin  -ve feedback of FSH release
Spermatozoa
Endocrine control of male reproduction
• Controlled by hormones from the

hypothalamus, anterior pituitary
and testes GnRH
• GnRH
• Follicle Stimulating Hormone
• Luteinizing Hormone FSH LH
• Inhibin
• Testosterone Testosterone
Inhibin
Activin
Endocrine control of male reproduction

Hypothalamus
and testes Gonadotrophin Releasing Hormone
• GnRH
• Luteinizing Hormone
FSH LH
Hormonal regulation of spermatogenesis

Hypothalamus
and testes Gonadotrophinreleasing
Gonadotrophin Releasinghormone
Hormone Negative
• GnRH feedback

• Luteinizing Hormone
FSH LH
• Inhibin Negative
feedback
• Testosterone
inhibin testosterone
Role of testosterone
• Promotes spermatogenesis
• Establishes and maintains male secondary sex characteristics
• Maintains accessory glands and organs of the male reproductive
system
• Stimulates muscle and bone growth
• Drives and maintains sexual behaviours
• Feedback to the hypothalamus to regulate its own release
(negative feedback)
Bringing it all together
Investigating male infertility
• Diminished Sperm Count & Quality
• Tubal problems (Ductus deferens)
• Reproductive pathology
• Erectile dysfunction
• Problems ejaculating
What is ‘normal’ sperm?
WHO 2010
WHO 2021
Semen analysis
Andrology Report
Original 2010:
Semen samples from over 4500 men in 14 countries on Semen volume: 1.4mL
four continents were obtained from retrospective and
Sperm Number : 39 x 106
prospective analyses on fertile men:
Men whose partners had a time-to-pregnancy (TTP) of Progressive

12 months Motility: 30%
Provided reference distributions for semen parameters Morphology

(normal forms): 4%
6th Ed – addition of 3500 more men in 12 countries
across 5 continents ( more global picture) Vitality: 54%
*lower reference limits,

fifth centile (95%)
Sperm Count, Motility & Morphology – Terminology!
Oligoasthenoteratozoospermia (OAT)
Oligozoospermia: Low sperm concentration Most common

cause of male
subfertility
Asthenozoospermia: Poor motility and/or forward progression
Teratozoospermia: Reduced percentage of morphologically normal sperm
Normozoospermia: Normal semen parameters
Azoospermia: No spermatozoa found in semen
Necrozoospermia: No live sperm in semen
Globozoospermia: Round headed acrosome-less sperm

Count
Sperm Conc. 15 million /

ml
Morphology
Other Measures of Sperm Health
DNA
Maturity:
fragmentation:
Hyaluronan –
COMET Assay
Binding Assay
Origio.com
DNA
fragmentation:
Sperm
Chromatin
Dispersion
‘halo’
Computer aided sperm analysis- technique
CASA Majzoub et al Asian Journal of Andrology (2016) 18, 205–212
Sperm motility (progressive)

Causes of low sperm count and quality
Decline in Male Fertility
A global 50% decline

in sperm counts in
men over the previous
50 years (1992)
‘There has been a genuine decline in semen quality over the past 50 years’
Carlsen et al, 1992 https://doi.org/10.1136/bmj.305.6854.609

50-60% decline in sperm concentration between 1973 and 2011 in men from around the world (2017).
Dramatic decline in sperm concentration and overall
count over the last 40 years
The proportion of men with a normal total motile sperm
count declined by approximately 10% over the previous 16
years
Tiegs, AW, Total Motile Sperm Count Trend Over Time: Evaluation of Semen Analyses From 119,972 Men From Subfertile Couples,
Urology, Volume 132, 2019, Pages 109-116
Men today produce fewer sperm
than in the past, and the sperm are
less healthy
But why?
Lifestyle and Environmental Exposures
Content Header
Philos Trans R Soc Lond B Biol Sci. 2010;365(1546):1697-712
Testicular Dysgenesis Syndrome
• Bisphenol A
• Hypospadias
• Dibutyl phthalate
‘androgen • Cryptorchidism
• Phenols
• Poor semen quality
disruptors’ • Pesticides
• Testicular cancer
• Smoking / Alcohol
Environmental and genomic factors could affect the development of the male reproductive system in utero
Environ Health Perspect. 2007 Oct;115(10):1519-26.
Male development and

reproductive toxicity
Decreased anogenital
distance
Histological damage to
testes
Apoptosis of
seminiferous tubule cells
Lifestyle and Environmental Exposures in the Adult
Urinary:
• Mono-[2-(carboxymethyl) hexyl] phthalate (MCMHP)

• Lower total sperm counts & concentrations
• Mono-(2-ethyl-5- hydroxyhexyl) phthalate (MEHHP) Significantly
• Abnormal morphology
• Mono-benzyl phthalate (MBzP), associated
• Lower sperm motility
• Mono-isononyl phthalate (MNP)
• Mono-methyl phthalate (MMP)
• Mono-cyclohexyl phthalate (MCPP)
Obesity - Smoking - Diet - Diabetes
Glycation
Covalent attachment of sugar to a protein or lipid
Advanced glycation end product

Advanced Glycation Endproducts
1. Amino group of a protein

reacts with a carbonyl group of
a reducing sugar
2. Production of Schiff base

and Amadori products
- Reversible
3. Dehydration and
oxidation produces The amount of product
stable AGEs is dependent on the
concentration of glucose
so hyperglycaemia
accelerates AGE
production
Zhu, Life Sciences 2020
Consequences of AGEs
Zhu, Life Sciences 2020

Main Causes of Male Infertility
Genetics
Endocrinopathies
Varicocele
Infections and injury

Varicocele
• Enlargement of the veins in the scrotum
• Increased hydrostatic pressure in
intrascrotal pampiniform plexus and
testicular venules
• Diagnosed by physical examination and

confirmed by Doppler ultrasonography
• Found in ~15% of all males
• Most common cause of male infertility

~ 30-60%
• Present with oligoasthenoteratozoospermia

Varicocele
....is related to semen abnormalities,

decreased testicular volume and decline in Leydig cell function
Exacerbated by smoking and by infection or inflammation of the

accessory glands
Treatment:
Microsurgery Varicocelectomy
Infection
Genitourinary tract infections such as:
Urethritis
Epididmyitis
Orchitis
Prostatitis
Male Accessory Gland Infection (MAGI)
Urethritis
Infection
Microbiological cause:
Candida spp Neisseria gonorrhoeae

Chlamydia trachomatis
Trichomonas vaginalis STI
Ureaplasma urealyticum
Neisseria gonorrhoeae
Enterobacteriaceae spp
Streptococcus spp
Staphylococcus spp
Anaerobes
Infection
Epididymo-orchitis
An inflammation of the epididymis and/or testicle (testis)

Impact on fertility
• Changes in functional capacity of sperm –

Changes in membrane integrity
Reduced acrosome reactivity
Oxidative damage to DNA
Poor sperm motility (asthenozoospermia)
Low sperm count (oligozoospermia)
• Changes in semen biochemistry

• Decreased ejaculate volume
• High concentration of Reactive Oxygen Species (ROS)
• Affecting female fertility - male accessory glands may function as a reservoir for
pathogens, increasing probability of infection in females
Injury
Injury
Acute trauma to the testicles or
testicular torsion can result in a breach
of the Blood Testis Barrier (BTB)
BTB : highly specialized tight junctions

(zonula occludens) between
neighbouring Sertoli
Restricts the passage of larger

hydrophilic molecules.
Exists to prevent reactions against

autoantigens associated with
spermatogenesis
Injury
Breach of the BTB through injury
infection or surgery can result in
autoimmune infertility
Antisperm antibodies (ASA) significantly

impairs sperm’s fertilizing capacity by
affecting:
• Sperm motility
• The acrosome reaction
• Penetration of the cervical mucus
• Binding to the zona pellucida
• Sperm–oocyte fusion
Congenital Factors
Klinefelter syndrome is the most common

sex chromosome disorder
1 in 600 new born males
Affected males carry an additional X

chromosome, which results in male
hypogonadism, androgen deficiency, and
impaired spermatogenesis.
Klinefelter syndrome
Characteristics: Treatments:
Abnormal body proportions Testosterone replacement therapy

Gynecomastia once puberty begins
Sparse pubic, armpit, and facial hair
Small, firm testicles
Tall height Fertility treatment e.g. artificial
Azoospermic / cryptozoospermic insemination or ICSI
Low testosterone levels Breast reduction surgery

Elevated estradiol
Elevates FSH
Anabolic Steroid Use
Prolonged use of anabolic steroids induces

reversible Hypogonadotrophic Hypogonadism
Decreased serum testosterone, testicular

atrophy and impaired spermatogenesis
- Azoospermia
Why?
Anabolic Steroid Use
Negative feedback of androgens on

the hypothamic-pituitary axis
-ve
GnRH
FSH LH
Discontinuation of anabolic steroid

use may restore fertility.
Patients may need therapeutic

intervention to recover fertility in
heavy users.
Tubal problems (Ductus deferens)
Obstructive Azoospermia
Obstruction of the ductal system is responsible for ~

40% of infertility cases
Normal size testes and normal serum FSH levels.
The obstruction is total and either intra-testicular,

in the rete testis, or extra-testicular, in the
epididymis, vas deferens or ejaculatory duct.
Obstructive Azoospermia
May result from:
• Epididymal, vasal, or ejaculatory duct pathology

• Surgery (Vasectomy)
• Genitourinary infections,
• Iatrogenic injury during scrotal or inguinal surgical procedures
• Congenital anomalies (congenital bilateral absence of the vas
deferens (CBAVD))
• Cystic fibrosis
Treatment: Surgical Sperm Retrieval and ICSI

Sexual and /or Ejaculatory Dysfunction
Relationship problems
Infrequent sexual intercourse
Semen allergies
Lack of experience!
Premature ejaculation
Erectile dysfunction
Retrograde ejaculation
Summary of male factor infertility
• Sperm
• Semen analysis and markers of good sperm health
• Causes of poor sperm health
• Testes and Tubes
• Injury
• Infection
• Varicocele
Further reading
• https://www.ncbi.nlm.nih.gov/books/NBK279145/
• Papers on Moodle
Disorders of uterine function in pregnancy
and labour
The uterus
• Smooth muscle
• Myogenic
➢ 50% have/had one

➢ 100% were ‘in’ one
Uterine contractions are important for multiple reproductive
functions
Menstruation Labour
Pregnancy
Conception Delivery
(Baby Eve)
Uterine (myometrial) contractions
How does the myometrium contract?
- What proteins are involved?
- What signalling pathways are activated?
- What initiates contraction?
- How can we regulate contractions?

Physiological basis of myometrial contraction
- From excitation to contraction: Excitation-Contraction Coupling (ECC)
We need:
Depolarization
? Vm
A stimulus
A signalling messenger
Myofilament activation
? Smooth muscle cell
Contraction
We need:
Depolarization Vm
A stimulus
‘Excitation’
Change in Myofilament activation
membrane
potential (Vm)
Smooth muscle cell
Contraction
Opening of Voltage Operated We need:

Calcium channels (VOCCs)
Depolarization Vm
A stimulus
Ca2+
‘Excitation’ VOCC
membrane Ca2+
potential (Vm)
Smooth muscle cell
Contraction

Calcium channels
Depolarization Vm
A stimulus
Ca2+
membrane Ca2+
potential (Vm) Activation of
Calmodulin Ca-CaM Smooth muscle cell
Contraction

Calcium channels
Depolarization Vm
A stimulus
Ca2+
membrane Ca2+
Calmodulin Smooth muscle cell
Ca-CaM
Myosin
Activation of MLCP
MLCK
Myosin light chain Myosin-P
kinase + Actin
Contraction
- From excitation to contraction: Excitation Contraction Coupling (ECC)

Calcium channels
Depolarization Vm
A stimulus
Ca2+
membrane Ca2+
Calmodulin Smooth muscle cell
Ca-CaM
Myosin
Activation of MLCP
MLCK
Myosin light chain Myosin-P
kinase + Actin
Contraction
Phosphorylation
of Myosin
Excitation Contraction Coupling (ECC)
Depolarization Vm
Ca2+
VOCC
Ca2+
Ca-CaM
Myosin
MLCP
MLCK
Myosin-P
+ Actin
Contraction
Burdyga et al., 2009 EJOGRB

Excitation-Contraction Coupling (ECC)
We need
Stimulus – Action potential

Depolarization Vm
Signalling messenger – Calcium

Ca2+
Myofilament activation - MLCK

VOCC
Ca2+
Smooth muscle cell
Ca-CaM
Myosin
MLCP
MLCK
Myosin-P
+ Actin
Contraction
Excitation-Contraction Coupling (ECC)
We need
Stimulus – Action potential

Depolarization Vm
Signalling messenger – Calcium

Ca2+
Myofilament activation - MLCK

VOCC
Ca2+
Smooth muscle cell
Ca-CaM
Myosin
MLCP
MLCK Communication between
Myosin-P
+ Actin cells - Gap junctions
(Connexin 43)
Contraction
Relaxation We need
De-phosphorylation of Myosin –
MLCP
Depolarization Vm
Ca2+
Ca2+ Ca extrusion/uptake into SR
PMCA (needs ATP)
VOCC
Hyperpolarisation of the Vm
Ca2+ Ca2+
SERCA SR [Ca2+]
Ca-CaM
Myosin Smooth muscle cell

MLCK MLCP
Myosin-P
+ Actin
Relaxation
However…..
- Agonists e.g. hormones can change membrane potential and increase Ca entry
Depolarization Vm
E.g. Oxytocin
GPCR
Ca2+ Gq/11
PLC-β
GPCR
VOCC PIP2 G12/13
IP3 DAG
Ca2+
Ca2+
SR [Ca2+] Effects
Ca-CaM
Myosin
MLCK MLCP
Myosin-P
+ Actin
Contraction
What is oxytocin?
Oxytocin
Maternal Pro-social
behaviour and behaviours
pair bonding
Stress relief
Milk ejection reflex
Oxytocin
Maternal Pro-social
behaviour and behaviours
pair bonding
Stress relief
Milk ejection reflex
Uterine
contraction
Hypothalamus
- supraoptic nuclei
- paraventricular
nuclei
magnocellular
neurons
Anterior Posterior
pituitary pituitary
Prolactin Oxytocin (OT)

FSH, LH, Vasopressin (AVP)
TSH, ACTH, GH
Oxytocin increases [Ca]i in human myometrium
Arrowsmith and Wray 2014, J Neuroendocrinol

Arrowsmith Accepted, Current Opinion in Physiology,
Oxytocin increases [Ca]i in human myometrium: Ca release from the
Sarcoplasmic reticulum
Simultaneous recordings of force and

Ca in myometrial muscle in vitro

Arrowsmith 2020, Current Opinion in Physiology,
Oxytocin increases [Ca]i in human myometrium Ca entry mechanisms?
2mMCaCl2
2 100nM
100nM
Force
(mN) Removing external Ca,
0
1.2
significantly reduces
F 400/500
oxytocin’s action
(Calcium)
0.8 20min

2mMCaCl2
2 100nM
100nM
Force
(mN)
0
1.2
F 400/500
(Calcium)
0.8 20min

Through VOCCs YES!
2mMCaCl2
2 100nM
100nM
Force
(mN)
0
1.2
F 400/500
(Calcium)
0.8 20min

Oxytocin increases [Ca]i in human myometrium
Ca entry mechanisms?
YES!
2mMCaCl2
2 100nM
100nM
Force
(mN)
0
1.2
F 400/500
(Calcium)
0.8 20min
Via Store-
operated Ca entry
YES!
2mMCaCl2
2 100nM
100nM
Force
(mN)
0
1.2
F 400/500
(Calcium)
0.8 20min
Via Store-
operated Ca entry
Oxytocin changes Ca sensitivity in human myometrium
Increases force of contraction

without a change in [Ca]i
Phosphorylation of MLCP,
inactivates it
Myosin is phosphorylated
independently of a change
in Ca
Questions? Arrowsmith and Wray 2014, J Neuroendocrinol

So now we know how the myometrium
contracts….
What’s next?
Uterine contractions are important for multiple
reproductive functions
Menstruation Labour
Pregnancy
Conception Delivery
(Baby Eve)
Removal of menses
Retrograde menstruation / cervico fundal contractions → endometriosis?
Peristalsis mid cycle and trauma induced injury and repair model of
adenomyosis ?
Menstruation
oxytocin
Arch Gynecol Obstet (2009) 280:529–538 DOI 10.1007/s00404-009-1191-0

Recent data suggests adenomyosis is linked to
infertility in mice via aberrant Ca signalling and
uterine peristalsis
Removal of menses:
Retrograde menstruation / cervico fundal contractions → endometriosis?
Peristalsis mid cycle and trauma induced injury and repair model of
adenomyosis ?
Menstruation
Sperm transport towards the fallopian tubes:
Cervico-fundal contractions (peristalsis)
Overactive peristalsis and poor implantation?
Conception
Menstruation Labour
Pregnancy
Conception Delivery
(Baby Eve)
The myometrium in pregnancy
Role:
• To house and support the growing fetus, placenta and membranes
• To grow and stretch to accommodate the growing fetus (hypertrophy
and hyperplasia)
• To stay quiescent
Until……
The myometrium and parturition*
* Expulsion of the fetus from the uterus through the cervix and vagina
1.
3 Stages:
1. Dilation stage – onset of labour, cervical dilation

and thinning, membranes rupture? (waters break)
2.
2. Expulsion stage – cervix dilates to 10cm,

contractions reach max intensity, baby is delivered
3. Placental stage (afterbirth)– uterine contractions

3.
detach the placenta from the endometrium and
placenta is expelled
The challenges:
~300,000 women die each year from complications of pregnancy /childbirth1
>50% uterine contractility problems
10% of births (15M) are preterm → neonatal death and disability

~75% spontaneous labour onset (contractions occur too early)
10 babies stillborn every day in UK (4 in 1000 births)2

- contractions are too strong, cause fetal distress
100,000 unplanned operations (EmCS) carried out p.a (16%)3

for dysfunctional labour/poor contractions
10% incidence of obstetric haemorrhage – leading cause of maternal death4

~70% due to poor contractility/uterine atony
(1) WH0, 2019; (2) ONS, Births in E&W 2020; (3, 4) Maternity services, NHS digital;
Pre-term labour Prolonged/
dysfunctional labour
Neonatal death,
Exhaustion,
Neurological sequalae
Need for CS
Caesarean section
delivery
Fetal distress Infection

Repeat CS
Still birth,
Hypoxic damage
Need for Caesarean section Post-partum complications
Post-partum haemorrhage,
Maternal death,
➢ All involve uterine muscular activity Hysterectomy
➢ Aberrant timing or strength of contractions
What initiates labour…?
?
Initiation of labour and delivery…..a complex story!
Placental factors Fetal factors

Estrogen Relaxin Cervical Fetal growth
CRH dilatation Fetal pituitary
Stretch of the
myometrium
+
Maternal oxytocin Prostaglandin production
release
+
+ Increased excitability of the myometrium
Labour contractions
Initiation of labour
CRH (Corticotrophin releasing hormone)
• Produced in placenta and released into CRH

mothers circulation
• CRH levels exponentially rise towards
term…placental clock?
• In fetus, acts on fetal adrenal gland to
release DHEA, the precursor for
placental estrogen
Estrogen
• Estrogen promotes increased sensitivity

of the myometrium to oxytocin and
increases its excitability via gap
junctions
Progesterone (P4)
• Despite being the pro-gestational

hormone, there is NO decrease in P4
levels in humans
• ‘Functional’ progesterone withdrawal

involving changes in P4 receptor
isoform expression
Plasma P4 levels in mice decrease significantly
prior to labour onset
Labour and uterine contractions
 Estrogen
1. Dilatation of cervix
2. Powerful, co-ordinated uterine contractions  Oxytocin receptors in  Uterine responsiveness to
myometrium low levels of oxytocin
START : ~30 secs, every 30 mins.
END: ~1-2mins, every 2-3 mins.  Uterine
contractions
POSITIVE feedback involving oxytocin
NEUROENDOCRINE REFLEX (Ferguson reflex)  Pressure/stretch

Stretching of the cervix causes nerve impulses sent to + at cervix from fetus
brain stimulating posterior pituitary production of

oxytocin, further stimulating contraction and enabling Neuroendocrine
reflex
labour to progress.
 Oxytocin 
secretion Prostaglandin
Posterior pituitary production
Labour progression: A positive feedback loop
of
NEUROENDOCRINE REFLEX
Bringing it all together…
Placental factors Fetal factors

Estrogen Relaxin Cervical Fetal growth
CRH dilatation Fetal pituitary
Stretch of the
cervix/myometrium
+
Maternal oxytocin Prostaglandin production
release
+
+ Increased excitability of the myometrium
Labour contractions
So what can (and does) go wrong….?
Preterm birth:
• Delivery of the fetus before 37 weeks gestation
• Sub-categories of preterm birth, based on gestational age:
• extremely preterm (less than 28 weeks)
• very preterm (28 to 32 weeks)
• moderate to late preterm (32 to 37 weeks)

The toll of preterm birth
www.who.int/mediacentre/factsheets/fs363
The toll of preterm birth
• 75% are ‘spontaneous’ preterm birth

• Premature rupture of membranes (PPROM)
• Preterm labour onset
• Increased neonatal morbidity and mortality

• sepsis,
• intraventricular hemorrhage,
• necrotizing enterocolitis
• respiratory distress syndrome
• Reduced lifelong achievement in survivors

Aetiology of preterm labour onset?
Uterine
contraction
Fetal
Cervical membrane
ripening rupture
Aetiology of preterm labour onset?
Uterine
contraction
Fetal
Cervical membrane
ripening rupture
Aetiology of ‘normal’ labour onset- role of inflammation
Uterine quiescence Uterine activation
Progesterone
Inflammatory signalling
PR-A/B ratio
Cytokines, chemokines
Oxytocin receptor
Gap junctions
Cervical ripening
Membrane rupture
Uterine contraction

macrophages
Progesterone
neutrophils Inflammatory signalling
PR-A/B ratio
Oxytocin receptor
Gap junctions
Cervical ripening
Membrane rupture
Uterine contraction

macrophages
Progesterone
PR-A/B ratio
Oxytocin receptor
Fetus/placenta Gap junctions
CRH
Surfactant
Stretch
Cervical ripening
Membrane rupture
Uterine contraction
Aetiology of preterm labour onset – aberrant inflammation?

macrophages
Progesterone
PR-A/B ratio
Oxytocin receptor
Fetus/placenta Gap junctions
CRH
Surfactant
Stretch
Cervical ripening
Membrane rupture
PRETERM uterine contraction

The aetiology of preterm birth
?
Preterm birth: Treatment
Knowing what you know about myometrial

contractions,
how could you inhibit them?

Dysfunctional labour - dystocia
Dysfunctional labour - dystocia
Knowing what you know about myometrial

contractions,
how could you augment them?

‘Womens’ problems’
Heart failure or CVD Labour dystocia

(uterine failure)
~ 50 drugs 1 ‘drug’
Pharmacopeia
‘Womens’ problems’
Preterm
Heart failure or CVD
contractions
Nifedipine
Ritodrine (β2-AR)
~ 50 drugs ~5 drugs MgSO4
Indomethacin
Atosiban
Pharmacopeia
Post-Partum Haemorrhage (PPH)
• The most common form of major obstetric haemorrhage
• The second leading direct cause of maternal deaths in the UK and the leading cause of
maternal mortality in the world
• Traditional definition:
‘the loss of 500 ml or more of blood from the genital tract after the delivery of the
fetus’ (or 1000 ml following Caesarean delivery)
• Primary postpartum haemorrhage occurs within the first 24 hours of delivery
• Secondary postpartum haemorrhage occurs between 24 hours and 12 weeks after delivery
RCOG 2016, BMJ 2017

PPH Cause
• Poor uterine tone (failure to contract) accounts for about 80% of all cases of primary
postpartum haemorrhage*,
Stage 3: Placental stage (afterbirth)– uterine

contractions detach the placenta from the
endometrium and placenta is expelled
• The blood flow to the uterus at term (>37 weeks of gestation) is approximately 1000 mL of
blood every minute, and a fetus at term receives about 200 mL/kg/minute from the
placenta**
• Endometritis is the commonest cause of secondary postpartum haemorrhage presenting

up to 12 weeks after delivery
*Arulkumaran S.. Curr Obstet Gynaecol1999;9:101-5.
**Ferrazzi E, Placenta2011;32:487-92
PPH management
Serious maternal morbidities include multiorgan failure, multiple blood transfusion, and peripartum hysterectomy
• Active management of the third stage of labour

• Expulsion of the placenta and membranes after delivery by uterine massage
• Controlled cord traction
• Use of drugs to aid uterine contraction WHICH DRUGS?
Oxytocin is the most commonly used drug in the medical management of postpartum haemorrhage
Ergometrine (ergot alkaloid) - First line drug in developing countries - Arterial vasoconstriction and myometrial contraction
Tranexamic acid - Antifibrinolytic (stabilises clotting)
Prostaglandins F2α OR Misoprostol (prostaglandin analogue) – myometrial contraction
Carbetocin (synthetic oxytocin analogue)
Syntometrine (combination of oxytocin and ergometrine)

Summary- uterine contractions
• Physiological pathways responsible for uterine contraction and its relaxation

including Excitation contraction coupling
• Disorders of contraction including

• Adenomyosis,
• Preterm birth,
• Labour dystocia and PPH
• Causes of Preterm birth and potential treatment strategies

• Dysfunctional labour, PPH and treatment strategies
Further Reading
Papers on Moodle
For physiology of contractions:
‘Insights into the Uterus’ by Wray 2007
‘Physiological pathways and molecular mechanisms regulating uterine contractility by Aguilar and
Mitchell 2010

Reproductive Health and Disease - Lecture 2 Infertility 02.02.23 For Moodle

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Reproductive health and

Phone 0161 247 1177

• Disorders of uterine function in pregnancy

1. Describe the physiological principles of male reproduction

Semen disorders idiopathic

• Diminished Sperm Count & Quality

• Tubal problems (Ductus deferens)

1st meiotic division

Section through the seminiferous tubules of the testes

• Controlled by hormones from the

• Controlled by hormones from the

• Controlled by hormones from the

• Follicle Stimulating Hormone

• Diminished Sperm Count & Quality

• Tubal problems (Ductus deferens)

Men whose partners had a time-to-pregnancy (TTP) of Progressive

Provided reference distributions for semen parameters Morphology

*lower reference limits,

Oligozoospermia: Low sperm concentration Most common

Teratozoospermia: Reduced percentage of morphologically normal sperm

Normozoospermia: Normal semen parameters

Azoospermia: No spermatozoa found in semen

Necrozoospermia: No live sperm in semen

Globozoospermia: Round headed acrosome-less sperm

Sperm Conc. 15 million /

Sperm motility (progressive)

A global 50% decline

Carlsen et al, 1992 https://doi.org/10.1136/bmj.305.6854.609

Male development and

• Mono-[2-(carboxymethyl) hexyl] phthalate (MCMHP)

Covalent attachment of sugar to a protein or lipid

Advanced glycation end product

1. Amino group of a protein

2. Production of Schiff base

Zhu, Life Sciences 2020

Infections and injury

• Diagnosed by physical examination and

• Found in ~15% of all males

• Most common cause of male infertility

• Present with oligoasthenoteratozoospermia

....is related to semen abnormalities,

Exacerbated by smoking and by infection or inflammation of the

Candida spp Neisseria gonorrhoeae

An inflammation of the epididymis and/or testicle (testis)

• Changes in functional capacity of sperm –

• Changes in semen biochemistry

BTB : highly specialized tight junctions

Restricts the passage of larger

Exists to prevent reactions against

Antisperm antibodies (ASA) significantly

Klinefelter syndrome is the most common

1 in 600 new born males

Affected males carry an additional X

Abnormal body proportions Testosterone replacement therapy

Low testosterone levels Breast reduction surgery

Prolonged use of anabolic steroids induces

Decreased serum testosterone, testicular

Negative feedback of androgens on