Week 3 Flashcards
What can go wrong with the hypothalamo-pituitary-gonadal axis
Central pathology: can be congenital or acquired
-lack of secretion of LH and FSH
-hypothalamic/pituitary disease
Gonadal damage: can be congential or acquired
-failure of germ cell production
-lack of sex steroid production
Polycystic ovary syndrome
Presentation: female
Menstrual history important
-oligoamenorrhoea
—irregular cycle, <9 periods a year or 42 day cycles
-amenorrhoea
—primary: failure of menarche after age 15
—secondary: absent periods for 6 months after menarche
—infertility
Oestrogen deficiency:
-hot flushes, poor libido, dyspareunia
Hirsutism, acne, androgenic alopecia
Weight
Galactorrhoea
Causes of amenorrhoea
Pregnancy- always exclude
Central causes:
-hypothalamic- weight loss (anorexia), excessive exercise, stress
-pituitary-hyperprolactinaemia (lactation), pituitary tumours
-hypogonadotropic hypogonadism (failure of LH, FSH secretion)
Ovarian causes:
-turners syndrome (45XO)
-premature ovarian failure
Polycystic ovary syndrome
Miscellaneous- thyrotoxicosis, chronic disease, local uterine problems
Leptin
Leptin decreases food intake, energy expenditure up and sympathetic activity up to lose weight
Congenital leptin deficiency:
-severe obesity, hyperphagia, hypogonadotropic hypogonadism
Anterior pituitary hormones
ACTH: regulation adrenal cortex
TSH: thyroid hormone regulation
GH: growth (+)
LH/FSH: reproductive control
PRL: breast milk production
Control of PRL secretion
Synthesised in lactotrophs
Regulation of PRL different to other anterior pituitary hormones
-negative regulation by tonic release of inhibiting factor- dopamine
When you disrupt dopamine- lactation
TRH positive effect- hypothyroidism Increase PRL
Physiological hyperprolactinaemia- stress
Physical or psychological
Post seizure
Greater increase in women
Rarely exceeds 850-1000mU/L
PRL does have circadian rhythm with peak during sleep
Clinical features of hyperprolactinaemia
Usually easy to recognise in pre menopausal women
Less apparent in men and post menopausal women
Pre menopausal women:
-hypogonadism: oligo/amenorrhoea, symptoms of oestrogen deficiency (vaginal dryness, lack libido, lack energy)) associated problems
-galactorrhoea- spontaneous/expressible
Post menopausal women:
-due to hypogonadal status- none of above
Pathological hyperprolactinaemia
PRL-secreting pituitary tumours- prolactinomas
-microadenomas (<1cm diameter)
-macroadenomas (>1cm diameter)
Loss of inhibitory effect hypothalamus derived DA
-pituitary stalk compression/pituitary disconnection
Drugs- DA antagonists
-phenothiazines, metoclopramide, TCAs, verapamil
Hypothyroidism- increased TRH
Premature ovarian insufficiency
Amenorrhoea
Oestrogen deficiency
Elevated LH, FSH (>30IU/L) all <45 years of age
Causes:
Congenital- Turner’s syndrome
-1:2500 live births 45XO
-short stature and gonadal dysgenesis (streak ovaries)
-webbed neck, cubitus valgus, congenital heart disease, hypothyroidism, lymphoedema
Autoimmune (nb thyroid, additions, diabetes)
Iatrogenic- chemotherapy and radiotherapy and surgery
Mutations in FSH receptor, galactossaemia, FMR1 gene permutation
Phenotype of tuners syndrome XO
Short stature
Low hairline
Characteristic facial features
Fold of skin
Construction of aorta
Shield shaped thorax
Poor breast development
Widely spaced nipples
Elbow deformity
Shortened metacarpal IV
Small finger nails
Rudimentary ovaries gonadal streak (underdeveloped gonadal structures)
No menstruation
Brown spots (nevi)
Autoimmune POI
POI is often caused by autoimmune diseases such as Graves’ disease, Addison’s, diabetes
2-10% of POI cases are linked with adrenal autoimmunity. POI precedes Addison’s disease by 8-14 years
The mechanism of autoimmune POI is likely to be due to inflammatory infiltration of follicles and production of anti ovarian Ab, apoptosis and atrophy
The sharing of auto antigens between the ovary and adrenals may explain the link with POI and addisons
Fragile X permutation and POI
1 in 200 females has the genetic change that leads to FXPOI. FXPOI accounts for about 4-6% of all cases of POI in women
Mutations in the FMR1 gene increase a women’s risk of developing FXPOI
FXPOI is inherited in an Xlinked dominant pattern therefore one copy leads to the condition
Management of POI
Diagnosis on serial FSH and E2 levels
Karyotyping and FMR-1 permutation analysis
Screening for autoimmune diseases:
-anti adrenal, TPO, ovarian Abs
Anti mullerian hormone (AMH) produced by gonadal cells
DEXA scan: POI carries 50% risk of osteopaenia. Bone density
Manage with oestrogen replacement- need progesterone added if still has uterus
Polycystic ovary syndrome
Commonest endocrine condition affecting 10% of all pre-menopausal women
-oligomenorrhoea 80%
-hirsutism 30%
-obesity 40%
-infertility 30%- anovulation
-polycystic ovaries on ultrasound
Hyperandrogenism:
-increased testosterone, androstenedione, DHEA
-increased LH/FSH ratio
-not oestrogen deficient (progesterone withdrawal bleed)
Aetiology unknown
Rotterdam diagnostic criteria for PCOS
European society for human reproduction and embryology/american society for reproductive medicine (ESHRE/ASRM)
2 out of 3
-oligo/amenorrhea
-clinical or biochemical signs of hyperandrogenaemia
-polycystic ovaries
Exclusion of other causes of androgen excess/oligo-amenorrhoea (Cushing’s, androgen producing tumours, CAH etc)
Clinical features in PCOS
Anovulation
Insulin resistance
Androgen excess
Obesity- can break cycle
Polycystic ovaries
PCO does not = PCOS
Cysts often peripherally, 2-9mm follicles
>/=20 follicles in at least one ovary
PCO: 20-25% of female population
Acanthosis nigricans
Marker insulin resistance
Darker skin patches: back of neck, armpit etc
Hirsutism
Male hormone dependent hair growth
Upper lip, chin
Anterior neck
Sideburn
Breast
Pubic hair
Ferriman gallwey score of hirsutism
Androgenic alopecia
Male pattern baldness
PCOS and pregnancy
Oligo/amenorrhoea and infertility: commenest clinical problem
Risk of gestational diabetes and pregnancy related hypertension is ten times increased
IVF: increased risk of ovarian hyperstimulation syndrome OHSS although this can be avoided by using an antagonist OVF protocol with a GnRH trigger injection for egg maturation
A pregnant PCOS woman is always a risk patient
PCOS- what to treat and how
Obesity, oligo/amenorrhoea: metformin, lifestyle
-modification (diet, exercise); MPA 10mg od for 10 days every month if no spontaneous bleed, weight loss pharmacotherapy (avoid prganancy); Bariatric surgery (avoid pregnancy 2 years)
Anovulatory infertility: clomiphene or letrozole-> metformin +IVF. Ongoing trial comparing these treatments. Inositol also insulin sensitiser and can be brought OTC
Hirsutism: Yasmin (pill), vaniqua cream (eflornithine 11.5%), cosmetic removal, spironolactone (antiandrogen)
Anti androgenic oral contraceptives
Dianette: 35microg ethinyl estradiol, cyproteterone acetate, high risk venous thrombosis in leg
Zoely: 2.5mg nomegestrol acetate, 1.5mg estradiol
Yasmin: 30microg ethinyl estradiol, drospirenone
21-hydroxylase deficiency
Mimics PCOS
Classical form- neonatal/infancy presentation “simple-virilising”
—adrenal androgen excess (virilised female)
-“salt wasting”: co existing aldosterone deficiency 75%
Non classical form: childhood/adult presentation
-“cryptic”
-premature puberty, hirsutism, PCOS
Can’t make cortisol, sometimes aldosterone
Too much testosterone, masculinisation mild-severe, 17-OHP when diagnosing PCOS if high not converted into aldosterone or cortisol rule out 12-hydroxylase deficiency
Androgen insensitivity syndrome
Spectrum of disorders due to mutations in the androgen receptor
Complete, incomplete, reifensteins, poorly virilised infertile male
Complete (testicular feminisation)-46XY “females”:
-female external genitalia
-short, blind ending vagina
-no uterus, abdominal/inguinal testes
-absent prostate, axillary pubic hair
-gynaecomastia- impressive breast development
Androgen insensitivity syndrome presentation
“Inguinal hernia”- inguinal testes
Primary amenorrhoea- no uterus
Elevated LH, testosterone and E2
Oestrogen from aromatisation of testosterone and LH-driven gonad secretion
T secretion 50% increased vs normal
5a-reductase deficiency
Hard to differentiate from androgen insensitivity
Females but 46XY
Unable to convert T to DHT
Lack of virilisation external genitalia
Appear ‘female’
Abdominal testes
Primary amenorrhoea
Virilisation at puberty
Gender change in some cultures
Negative feedback LH and FSH
Testosterone- leydig cells, LH
Sertoli cells - sperm inhibin
If spermatic failure not producing lots sperm no negative feedback increases FSH and LH
Testosterone falls with age
Physiological vs pathological
Hypogonadism presentation male
Delayed puberty
Psychological effects
-loss of libido and reduced sexual behaviour
-lack of sex drive versus erectile impotence
Gynaecomastia
Loss of body hair, reduced shaving frequency, thin skin
Decreased muscle mass, female fat distribution
Oesteoporosis
Infertility +/- reduced testicular volume
Testicular volume
Orchidometer measures testicular volume in ml
Pre pubertal= 1-3ml
Normal adult male= 15-25ml
Causes: male hypogonadism I
Primary gonadal failure
-trauma- surgery and torsion
-chemotherapy and radiotherapy
-undescended testes (cryptorchidism) (10% at birth)
-infection, inflammation and infiltration
-orchitis (mumps)
-iron overload
-(varicocele)
Chromosomal abnormalities
-Klinefelters syndrome
Systemic diseases:
-liver cirrhosis
-renal failure
-thyroid dysfunction
-myotonic dystrophy
Causes: male hypogonadism II
Secondary gonadal failure
-pituitary tumours
-hyperprolactinaemia
-hypothalamic disorders
—craniopharyngioma
—kallmans syndrome
—GnRH therapy
Systemic disease
Obesity
Androgen use and abuse
Investigation of hypogonadism
Clinical examination
LH, FSH, testosterone
-is testosterone low (remember age)
-negative feedback
-high LH, FSH indicates primary gonadal failure
-low LH, FSH suggests secondary cause
Further investigations to establish cause accordingly
-eg liver function, prolactin, karyotype, imaging etc
Klinefelters syndrome
Affects 1:1000 males
47XXY
Primary hypogonadism- “firm pea-sized” testes
Feminisation - azoospermia, gynaecomastia
Reduced secondary sexual hair
Oesteoporosis
Eunuchs- tall stature
Reduced IQ in 40%
20 fold increased risk of breast cancer
Myotonic dystrophy
Autosomal dominant
Progressive muscular weakness
Myotonia
Mental retardation
Frontal baldness
Cataracts
Primary gonadal failure
Kallmans syndrome
Idiopathic hypogonadotropic hypogonadism
1:10000 - M:F 4:1
Anosmia in 75%
Failure of migration of GnRH neurones
Genetics revealing
-X linked, autosomal recessive or autosomal dominant
-mutation in Kal-1, FGF23 receptor 1, prokineticin
-GnRH-Rec and G protein coupled receptor 54 (normosomic)
Genetic causes of hypogonadotropic hypogonadism
Genetic defects:
-GnRH neuron migration: KAL1, FGFR1, NELF, PROK2, PROKR2
-GnRH synthesis and release: GPR54, LEP, LEPR, SF1, DAX1
GnRH action: GNRHR
Gonadotropin synthesis: LHB, FSHB, SF1, DAX1
Testosterone replacement
Tablets- testosterone undecanoate
Buccal mucosa
Injection- intramuscular testosterone esters monthly or 3 monthly
Transdermal- patches and gels (testogel)
Subdermal implants every 6 months
Safety issues:
-behaviour
-annual PSA, FBC, lipids, BP over 50 years of age
Androgen abuse- designer drugs
100s compounds freely available via internet, gyms
Androgen abuse causes “hypogonadism”
And testosterone injections
Real hazards of androgen abuse
Psychological changes
Prostate cancer
Atrophy of testes
Azoospermia- infertility
Polycythaemia
???cardiovascular death
Male infertility
Assessment- history and examination
Seminal fluid analysis
LH FSH testosterone
Increased FSH- germ cell failure- numbers game, IVF, ICSI etc (may need endocrine input if primary gonadal failure)
Normal FSH, normal sized testes- think of obstructive uropathy
Low FSH, LH, testosterone- endocrine causes
-pituitary/hypothalamic disease
-replace with LH (HCG 2000 units/twice weekly and FSH 75 IU x3week- injections)
-spermatogenesis may take >12 months
Requirements for fertilisation
A sperm- maturation, capacitation
An egg- arrested at metaphase II
In same place at same time
Synchronise with receptive endometrium
Ovulation
Cumulus-oocyte complex is picked up by ciliated fimbriae on the infundibulum at the end of the uterine tube
Chemoattraction to ovulation site- follicular fluid
Muscular contractions to uterine tube
Sperm in the female tract
As the sperm move through the female tract their numbers decrease rapidly
~200 million sperm are deposited in the upper vagina
Seminal plasma- short term buffering- coagulates within a minute- semenogelin- PSA- flow back
Cervical mucus is least viscous during days 9-16 of the menstrual cycle- OCP- sperm selection
~100000 sperm enter the uterus
Pro ovarian contractions of myometrium- inc in late follicular phase
~1000 sperm enter each uterine tube- uterotubal junction
Chemotaxis in humans- P4 - follicular fluid/cumulus cells
Fertilisation occurs in the ampulla region of uterine tube 10s-100s of sperm
Sperm remain capable of fertilisation for ~5days within the female tract
Oocyte remains viable for ~24hours
OPKs- widely available- LH-not recommended
Sperm interaction with egg vestments
Remote detection of oocyte- cumulus complex
Penetration of cumulus
Zona binding
Acrosome reaction
Zona penetration
Penetration of cumulus
Approx 3000 cells embedded in gelatinous matrix (hyaluronic acid)
Closely apposed cells form tight organised layer
Others less organised
Sperm penetrate and can disperse the cumulus (enzyme hyaluronidase to break down hyaluronic acid0
After penetrating cumulus sperm bind zona- induces AR
AR is vital
Permits zona penetration
Exposes new membrane for oocyte fusion
Hydrolytic proteolytic enzymes, exposes inner acrosomal membrane that has receptor potential for sperm to bind to egg
The zona pellucida
Extracellular protein matrix which surrounds all mammalian eggs
4 glycoproteins in human- ZP1, ZP2, ZP3, ZP4
Important for sperm-egg binding and induction of AR
Persists post fertilisation
Fusion
Sperm penetrates the ZP and occupies the perevitelline space —between ZP and plasma membrane
Equatorial segment of sperm head fuses with oocyte plasma membrane
Sperm nucleus is encased by a vesicle composed of internalised oocyte membrane
Large increase in the free [Ca2+]i-sweeps across egg from point of sperm fusion
Izumo
Named for Japanese shrine dedicated to marriage
Sperm membrane receptor for fusion
Detectable on sperm surface only after acrosome reaction
KO completely abolishes fusion
Juno and Maia
Receptors for izumo on the oocyte plasma membrane
Juno-roman goddess of marriage and fertility
KO abolishes fusion
Maia- goddess of growth
Binds izumo after juno induced conformational change Maia follows
Oocyte activation
Within 1-3 minutes of fusion- large rise in [Ca2+]i which sweeps across egg from point of sperm entry- lasts 2-3 mins
Followed by Ca2+ oscillations every 3-15 mins which may last for several hours
Triggered by phospholipase C zeta- sperm specific PLC- release of IP3 and DAG- PKC
Release of Meiotic block
M-phase promoting factor MPF= cyclin dependent kinase cdk1 plus cyclin b
Blocks metaphase to anaphase transition
MPF is stabilised by cytostatic factor CSF
Raised calcium levels suppressed CSF activity and destroy cyclin B by activating anaphase promoting complex/cyclosome (APC/C)- ubiquitin E3 ligase
Cohesin protein complexes- ring like structures that hold sister chromatids together
Oppose pulling force of microtubules
Scc1 subunit of cohesin is cleaved by separase
Securin- inhibits separase activity until ubiquitinated by APC/C
Resumption of cell cycle in the oocyte and completion of meiosis II
Block to polyspermy
Fast block- electrical- membrane depolarisation
Slow block- cortical reaction- triggered by increase [Ca2+] 1 hr plus
Disperse contents through zona pellucida, cortical granules- proteases etc, zona pellucida reaction
The cortical reaction
Cortical granules contain a mixture of enzymes, including several proteases which diffuse into the zona pellucida following exocytosis from the egg
Induces the zona reaction
The zona reaction
The alteration in the structure of the zona pellucida catalysed by proteases from cortical granules
Cleavage of ZP2 by ovastacin protease
Sperm can no longer bind or penetrate
Loss of juno
Juno protein is shed from oocyte plasma membrane with the cortical granules
Undetectable within 40 minutes of fusion
No further sperm can fuse
Sperm contribution
Haploid male genome- sex of the baby
Centriole- the oocyte has none- forms spindle for first cell division
Oocyte contribution
Haploid female genome
Cytoplasm
All organelles
Mitochondria- maternally inherited
Zygotic/pronucleate (2PN) stage
Decondensation of sperm DNA- protamine/histone exchange
Male and female pronuclei replicate their DNA
Pronuclei migrate towards each other
Guided by sperm aster- microtubules radiating from centrosome
Syngamy
18-24 hours
Pronuclear membranes break down
Chromatin intermixes
Nuclear envelope reforms around zygote nucleus
Cleavage begins- end of fertilisation/beginning of embryogenesis
Transport embryo to the uterus
Increased progesterone: oestrogen ratio relaxes musculature of female reproductive tract- isthmic sphincter- UTJ
Mostly transported under action of cilia
Cleavage stages
Zygote cleaves to form two blastomeres
4-8- cell stages, preimplantation genetic testing (PGT), embryo transfer
Morula- 16-32 cells- solid ball (mulberry) near end of uterine tube
No cytoplasmic synthesis so blastomere size decreases with each division
ZP
Control of development
Up to 2 cell stage- dependent on oocyte cytoplasm
4-8 cell stage- major burst of transcription
Many maternally derived proteins persist until blastocysts stage- poor oocyte maturation
Embryo metabolism and growth is stimulated by a number of growth factors- both autocrine and paracrine- embryo development in vitro
Compaction
8 cell stage onwards- inside outside polarity starts to develop
Outer cells- trophoblast- placenta
Inner cells- inner cell mass- embryoblast
Late morula- fluid absorption- formation of intracellular junctions between trophoblasts cells- Na+/K+ ATPase
Blastocyst formation
Day 5
Blastocoel
Distinct ICM and single layered epithelial trophoblast layer hCG
Embryonic and abembryonic pole
IVF- embryo transfer- embryonic genome activated, past stage of totipotency
Hatching
Late day 6 onwards
Blastocyst expands out of hole in ZP- abembryonic pole
Implantation
Twins
1 in 67
Monozygotic vs dizygotic
Increased risk of dizygotic twins- maternal age, fertility treatment (ovulation induction, multiple embryos)
Increase risk of monozygotic twins- in vitro embryo culture
Monochorionic- twin-twin transfusion syndrome- imbalance of blood flow
Monoamniotic- umbilical cord entangled, compressed
Baby-premature birth, LBW, cerebral palsy
Mother- Preeclampsia, hypertension, GD, mortality
NHS- cost not buy one get one free
Endometrial structure
Underlying muscular myometrial layer
Lining- endometrium- two layers
Upper functional layer (functionalis/stratum functionale)- undergoes proliferation then shedding (menstruation)
Lower basal layer (basalis/stratum basale)- attached to myometrium; remains intact during menstruation
Functional layer is reconstituted out of the underlying basal layer
Stromal matrix covered with luminal epithelium
Glandular epithelial extensions penetrate into stroma
Stroma contains a rich supply of blood vessels- the spiral arteries
Proliferative (follicular) phase
After menstruation, endometrium is very thin and consists only few layers of cells (basal layer)
In the first ~14 days of menstrual cycle, endometrial cells proliferate- oestrogen increases
Thickening due to stromal cell proliferation and stromal oedema
Surface epithelium increases in surface area and metabolic activity
Increase in number and size of glandular invaginations of the stroma
Expression of intracellular PR
Secretory (luteal) phase
After ovulation, ovaries begin to produce progesterone
Progesterone stimulates synthesis of secretory material by the glands - rich in glycogen, glycoproteins and amino acids- provides nutrition for blastocyst
Stromal cells becoming larger and plumper
Spiral arteries become fully developed
Cellular secretions are released into the glandular lumen
Must be oestrogen-primed= receptive endometrium
Window of implantation
Lasts 4 days (days 20-24)
Characterised by the appearance of small elevations at the apical pole of the epithelial endometrium cells= pinopodes.
Pinopodes are involved in the absorption of the uterine fluid
Brings the blastocyst closer to the endometrium
Also immobilises it
Menstruation
Spiral arteries of the functional layer are hormone sensitive- constrict when the progesterone concentration falls
Collapse and necrosis of the functional layer
Blood and necrotic tissue is lost (menstruation)
Clinical relevance
Infertility
Miscarriage- 1 in 4, 60% chromosomal problems- 25% embryos are aneuploid (20% eggs and 3-4% sperm) lost before or during implantation
Ectopic pregnancy: 1 in 100 pregnancies, not just tubal, epithelium can support early development, rupture of blood vessels- life threatening to mother
Risk factors: history of PID, tubal surgery, failed sterilisation, IUD in place
Requirements for fertility
Production of normal sperm
Production of normal eggs
Sperm traverse the female tract to reach the egg- capacitation- time constraints
Sperm penetrate and fertilise the oocyte
Implantation of the embryo into the uterus
Normal pregnancy
Fertility
Measure of the actual outcome of the reproductive process- number of children born to an individual/couple
Fecundability
Probability of conceiving each month- the monthly chance of pregnancy or monthly fertility rate, either for an individual (measured over time) or for a population (the number of conceptions occurring in one month)
Fecundity
Measure of the ability to conceive and produce a live birth
Infertility
The inability to conceive after a period of unprotected intercourse or the inability to carry a pregnancy to term
The National institute for clinical excellence (NICE) define infertility as failing to get pregnant after a two years of regular unprotected sex
Subfertility
A state of reduced fertility
Generally people seek medical advice after one year of subfertility
How big a problem is infertility
Its estimated that 1 in 6 couples
Most couples unaware of fertility status until they wish to reproduce
Though the majority of these may become pregnant naturally given time a significant minority will not
Infertility is the commonest reason for women aged 20-45 to see their GP after pregnancy itself
Only 20% of these cases arise through sterility
Perceptions are not always correct but
Avoid self inflicted factors that reduce fertility
Age
Smoking
Obesity
History
How long trying
Family history- genetics suspicions
Current sexual history- awkward questions
Past sexual history- really awkward questions
Female factors
Ovulatory disorders
Tubal damage
Endometriosis
Uterine abnormalities
Implantation, growth and development
Female diagnosis
Some causes can be diagnosed by blood analyses (hormonal)
Some causes diagnosed by surgery (laparoscopy) or radiography- HSG (hysterosalpingogram)
Ovulation disorders (~40%)
Absent cycles: primary amenorrhoea, secondary amenorrhoea, irregular cycles- oligomenorrhoea, anovulatory cycles
Associated with stress, obesity, strenuous exercises, anorexia nervosa and drug use- placebo treatment >30% pregnancy
Possible failure of maturation of neuroendocrine system at puberty
Idiopathic ovarian failure; polycystic ovarian syndrome PCOS; anovulatory cycles- endocrinologically normal; abbreviated luteal phase
Idiopathic ovarian failure: gonadotrophin secretion is normal but is insufficient to support a normal cycle <— end organ insensitivity, oestrogen levels fail to rise and follicles fail to mature (many small follicles)
Polycystic ovarian syndrome PCOS: associated with increased LH and androgens (mild increase in follicular phase)
Anovulatory cycles- endocrinologically normal: luteinised unruptured follicle syndrome LUF- eggs ‘deficient’
Abbreviated luteal phase: decreased progesterone -> poor luteinisation
Disorders of female tract
Tubal obstruction:
-usually secondary consequence of pelvic infection
-increase incidence after STDs eg gonorrhoea, chlamydia, and tuberculosis
-post abortal or post pregnancy sepsis
-infection-> impaired oocyte and sperm transport due to loss of cilia on intraluminal cells and scarring -> adhesions
Endometriosis:
-endometrial tissue growth escalates in ectopic sites- oviduct, ovary or peritoneal cavity-> scarring/adhesions
Maternal problems 40-50%
Cervical incompetence
Implantation defects (ectopic)
Autoimmune eg lupus
Immunological incompatibility- ABO or rhesus blood group loci
Spontaneous pregnancy loss
Biochemical pregnancy= tested by presence of hCG in blood and urine 18-30 days after the initiation of the last period
Clinical pregnancy: US at 5 weeks, foetal heart at 7 weeks
Losses:
-4/5 cycles involving unprotected intercourse do not result in pregnancy
-flushing of human uterus revealed that at day 4/5 only 20% of embryos recovered were blastocysts- rest abnormal slow developing
-15-25% of clinical pregnancies fail (usually 1st trimester)
Total 15-20% conceptions-> live birth
Abnormal conceptus (50-60% losses)
Genetic abnormalities in clinical pregnancies
-0.5% live births
-5% still births
-50-60% spontaneous abortion
10% recognised pregnancies are chromosomally abnormal
Chromosomal abnormalities
Translocations
Errors of ploidy: deletions or duplications of a complete set of haploid chromosomes
Errors of chromosome number or ’somy’: loss or gain of a single chromosome
Effect of delayed reproduction- ageing
Bigger factor for female- declines after 20s sharp decline after 35
In males caused by other age related factors eg diabetes, hypertension
Male disorders
Production of spermatozoa
Transport of spermatozoa
Transmission of spermatozoa
Sperm function in the female tract
Fertilisation and events after
Goals of evaluation of the infertile male
Identify potentially correctable conditions. Eg. Ductal obstruction or hypogonadotrophic hypogonadism
Identify potentially irreversible conditions requiring assisted reproductive technique using sperm of the male partner
Identify irreversible conditions for which donor insemination or adoption are the possible options
Identify life threatening conditions that may underlie the infertility eg. Testicular cancer, pituitary tumours
Identify genetic abnormalities that may affect the health of the offspring if assisted reproductive techniques are to be employed
Initial screening/ diagnosis
Reproductive history
2 semen analyses- one month apart
Later may do additional blood analyses
Many we cannot diagnose
Examination of the male
General- weight, BP, urinalysis
Secondary sexual characteristics
Signs of endocrine disease
Gynaecomastia
Abdominal examination
Genital examination
Digital PR
Endocrine evaluation
If abnormally low sperm concentration especially <5million/ml
Impaired sexual function
Other clinical findings suggestive of a specific endocrinopathy
Production of spermatozoa
An ejaculate is graded as:
-normozoospermic >15 million spermatozoa/ml
-oligozoospermic
-asthenozoospermic
-teratozoospermic
-combinations of above
Azoospermic- no sperm
Failure of production
Congenital testicular deficiency
-Klinefelter (47, XXY)
-Y chromosome deletions
Maldescended testes- cryptorchidism
-reduced spermatogenesis
-increased risk for testicular cancer
Acquired
-trauma- testis torsion
-orchitis (mumps)
Endocrine disorders
Clinical tests on semen and sperm
Leukocytes in semen>1million/ml needs investigation and maybe treatment
Sperm viability tests (HOS test)
Sperm vitality tests (EN tests)
Anti sperm antibodies
Computer aided sperm analysis CASA
Non standard tests of sperm function
DNA damage (TUNEL, SCSA, SDFA, comet assays)
Aneuploidy (usually chromosomes 13,18,21,X and Y)
Oxidative stress tests (MiOxsys, luminol, TOS, TAC)
Cervical mucus penetration CMT and the post coital test (PCT)
Hemizona assay
Acrosome reaction (AR)
Zona free hamster egg sperm penetration SPA
Failure in transmission
Erectile dysfunction
Ejaculatory dysfunction
-retrograde
-defects of accessory sex glands
Normal ejaculation (reminder)
Contraction of musculature of prostate, seminal vesicles and vascular deferens-> seminal fluid and sperm- urethra
Under sympathetic nerve control
Contraction of urethral and pelvic floor musculature -> ejaculation
Vesicular urethral sphincter closes bladder neck
Retrograde ejaculation
Incompetence of urethral sphincter
Ejaculation into the bladder (retrograde) the path of least resistance
Associated conditions:
-diabetes, post traumatic paraplegia, post bladder neck surgery
Ejaculate volume nil or low
Confirmation in urine
Post ejaculatory urine analysis
Indications: low volume ejaculate, absent ejaculate (aspermia), avoid is CBAVD/hypogonadism features
Causes of low volume/ no ejaculate:
-retrograde ejaculation
-lack of emission
-ejaculatory duct obstruction
Total failure in transport
Post infectious: bilateral epididymal/vas occlusion
Congenital bilateral absence of vas deferens- CBAVD
Azoospermic semen samples- obstructive azoospermia
Indications for genetic testing
Genetic abnormalities may cause infertility by affecting sperm production or sperm transport
Men with non-obstructive azoospermia or oligozoospermia
Male chromosomal disorders
Abnormal karyotypes -2.2% in 2373 men attending an infertility clinic
-15.4% were Azoospermic
-6% oligozoospermia
-chromosomal abnormalities resulting in impaired testicular function. Klinefelters or translocations or inversions
Y chromosomes micro deletion in 10-15% of men with severe oligo or azoospermia
Men with <5 million sperms/ml or azoo prior to performing ICSI
CBAVD
Linked to CFTR gene (cystic fibrosis)
-CFTR gene mutation on chromosome 7
-CF associated with CBAVD
Improper development of vas deferens (cf vasectomy)
>95% of men with CF have CBAVD
85% of men with CBAVD have only one severely mutated allele-> no other CF symptoms
Check female partner when relevant
Fertilisation and after
Post fertilisation processes
-centriole function (spindle formation)
-chromatin decondensation
-protamine exchange
-pronuclear fusion
-activation of genes for placenta formation
Unexplained infertility
Normal frequency and distribution of unprotected intercourse
No obstructions of malformations in female or male genital tracts
Normal follicle growth, maturation and ovulation; no signs of ongoing inflammatory reactions
Normal concentration of motile spermatozoa, no anti sperm antibodies or other signs of ongoing inflammatory reaction
