Week 3 Flashcards

1
Q

What can go wrong with the hypothalamo-pituitary-gonadal axis

A

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

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2
Q

Presentation: female

A

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

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3
Q

Causes of amenorrhoea

A

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

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4
Q

Leptin

A

Leptin decreases food intake, energy expenditure up and sympathetic activity up to lose weight
Congenital leptin deficiency:
-severe obesity, hyperphagia, hypogonadotropic hypogonadism

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5
Q

Anterior pituitary hormones

A

ACTH: regulation adrenal cortex
TSH: thyroid hormone regulation
GH: growth (+)
LH/FSH: reproductive control
PRL: breast milk production

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6
Q

Control of PRL secretion

A

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

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7
Q

Physiological hyperprolactinaemia- stress

A

Physical or psychological
Post seizure
Greater increase in women
Rarely exceeds 850-1000mU/L
PRL does have circadian rhythm with peak during sleep

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8
Q

Clinical features of hyperprolactinaemia

A

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

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9
Q

Pathological hyperprolactinaemia

A

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

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10
Q

Premature ovarian insufficiency

A

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

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11
Q

Phenotype of tuners syndrome XO

A

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)

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12
Q

Autoimmune POI

A

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

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13
Q

Fragile X permutation and POI

A

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

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14
Q

Management of POI

A

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

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15
Q

Polycystic ovary syndrome

A

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

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16
Q

Rotterdam diagnostic criteria for PCOS

A

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)

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17
Q

Clinical features in PCOS

A

Anovulation
Insulin resistance
Androgen excess
Obesity- can break cycle

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18
Q

Polycystic ovaries

A

PCO does not = PCOS
Cysts often peripherally, 2-9mm follicles
>/=20 follicles in at least one ovary
PCO: 20-25% of female population

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19
Q

Acanthosis nigricans

A

Marker insulin resistance
Darker skin patches: back of neck, armpit etc

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20
Q

Hirsutism

A

Male hormone dependent hair growth
Upper lip, chin
Anterior neck
Sideburn
Breast
Pubic hair
Ferriman gallwey score of hirsutism

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21
Q

Androgenic alopecia

A

Male pattern baldness

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22
Q

PCOS and pregnancy

A

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

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23
Q

PCOS- what to treat and how

A

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)

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24
Q

Anti androgenic oral contraceptives

A

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

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25
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
26
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
27
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
28
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
29
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
30
Testosterone falls with age
Physiological vs pathological
31
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
32
Testicular volume
Orchidometer measures testicular volume in ml Pre pubertal= 1-3ml Normal adult male= 15-25ml
33
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
34
Causes: male hypogonadism II
Secondary gonadal failure -pituitary tumours -hyperprolactinaemia -hypothalamic disorders —craniopharyngioma —kallmans syndrome —GnRH therapy Systemic disease Obesity Androgen use and abuse
35
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
36
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
37
Myotonic dystrophy
Autosomal dominant Progressive muscular weakness Myotonia Mental retardation Frontal baldness Cataracts Primary gonadal failure
38
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)
39
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
40
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
41
Androgen abuse- designer drugs
100s compounds freely available via internet, gyms Androgen abuse causes “hypogonadism” And testosterone injections
42
Real hazards of androgen abuse
Psychological changes Prostate cancer Atrophy of testes Azoospermia- infertility Polycythaemia ???cardiovascular death
43
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
44
Requirements for fertilisation
A sperm- maturation, capacitation An egg- arrested at metaphase II In same place at same time Synchronise with receptive endometrium
45
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
46
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
47
Sperm interaction with egg vestments
Remote detection of oocyte- cumulus complex Penetration of cumulus Zona binding Acrosome reaction Zona penetration
48
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
49
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
50
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
51
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
52
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
53
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
54
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
55
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
56
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
57
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
58
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
59
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
60
Sperm contribution
Haploid male genome- sex of the baby Centriole- the oocyte has none- forms spindle for first cell division
61
Oocyte contribution
Haploid female genome Cytoplasm All organelles Mitochondria- maternally inherited
62
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
63
Syngamy
18-24 hours Pronuclear membranes break down Chromatin intermixes Nuclear envelope reforms around zygote nucleus Cleavage begins- end of fertilisation/beginning of embryogenesis
64
Transport embryo to the uterus
Increased progesterone: oestrogen ratio relaxes musculature of female reproductive tract- isthmic sphincter- UTJ Mostly transported under action of cilia
65
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
66
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
67
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
68
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
69
Hatching
Late day 6 onwards Blastocyst expands out of hole in ZP- abembryonic pole Implantation
70
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
71
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
72
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
73
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
74
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
75
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)
76
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
77
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
78
Fertility
Measure of the actual outcome of the reproductive process- number of children born to an individual/couple
79
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)
80
Fecundity
Measure of the ability to conceive and produce a live birth
81
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
82
Subfertility
A state of reduced fertility Generally people seek medical advice after one year of subfertility
83
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
84
Perceptions are not always correct but
Avoid self inflicted factors that reduce fertility Age Smoking Obesity
85
History
How long trying Family history- genetics suspicions Current sexual history- awkward questions Past sexual history- really awkward questions
86
Female factors
Ovulatory disorders Tubal damage Endometriosis Uterine abnormalities Implantation, growth and development
87
Female diagnosis
Some causes can be diagnosed by blood analyses (hormonal) Some causes diagnosed by surgery (laparoscopy) or radiography- HSG (hysterosalpingogram)
88
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
89
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
90
Maternal problems 40-50%
Cervical incompetence Implantation defects (ectopic) Autoimmune eg lupus Immunological incompatibility- ABO or rhesus blood group loci
91
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
92
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
93
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
94
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
95
Male disorders
Production of spermatozoa Transport of spermatozoa Transmission of spermatozoa Sperm function in the female tract Fertilisation and events after
96
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
97
Initial screening/ diagnosis
Reproductive history 2 semen analyses- one month apart Later may do additional blood analyses Many we cannot diagnose
98
Examination of the male
General- weight, BP, urinalysis Secondary sexual characteristics Signs of endocrine disease Gynaecomastia Abdominal examination Genital examination Digital PR
99
Endocrine evaluation
If abnormally low sperm concentration especially <5million/ml Impaired sexual function Other clinical findings suggestive of a specific endocrinopathy
100
Production of spermatozoa
An ejaculate is graded as: -normozoospermic >15 million spermatozoa/ml -oligozoospermic -asthenozoospermic -teratozoospermic -combinations of above Azoospermic- no sperm
101
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
102
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
103
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
104
Failure in transmission
Erectile dysfunction Ejaculatory dysfunction -retrograde -defects of accessory sex glands
105
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
106
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
107
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
108
Total failure in transport
Post infectious: bilateral epididymal/vas occlusion Congenital bilateral absence of vas deferens- CBAVD Azoospermic semen samples- obstructive azoospermia
109
Indications for genetic testing
Genetic abnormalities may cause infertility by affecting sperm production or sperm transport Men with non-obstructive azoospermia or oligozoospermia
110
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
111
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
112
Fertilisation and after
Post fertilisation processes -centriole function (spindle formation) -chromatin decondensation -protamine exchange -pronuclear fusion -activation of genes for placenta formation
113
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