what is the definition of infertility?
no possibility of conceiving without treatment
what is the definition of subfertility?
if conception has not occurred after a year of regular unprotected intercourse
what % of couples are affected by subfertility?
what is the difference between primary and secondary subfertility?
- primary: female partner has NEVER conceived
- secondary: female partner has previously conceived even if the pregnancy ended in a miscarriage or TOP
what 4 basic conditions are needed for pregnancy? and give % of contribution to infertility
- 1. egg produced: anovulation 30%
- 2. adequate sperm released - 'male factor': 25%
- 3. sperm reach egg to fertilise: tubes damaged 25%; sexual prob 5%; cervical (<5%)
- 4. implantation of embryo: incidence unknown but may account for 30% of unexplained subfertility
who does fertility decrease with increasing female age?
mainly due to reduced genetic QUALITY of the remaining oocytes, rather than ovulatory problem
at the beginning of each cycle describe the levels of oestrogen, FSH and LH
- low oestrogen levels exert POSITIVE FEEDBACK to hypothalamus to causes GnRH pulses
- this stimulates anterior pit to produce FSH and LH which cause growth and maturation of follicles of ovary which contain immature oocyte
what do the maturing follicles of the ovary produce? and how does this affect other hormone levels
- oestradiol (E2) so get NEGATIVE FEEDBACK to hypothalamus and so
- less FSH and LH made
- so the maturing follicles COMPETE for the stimulating hormones and usually one is large enough with enough FSH and LH receptors to survive
what does the dominant follicle also co-regulated by and what does this do?
inhibit B which suppresses FSH
as the follicles matured, what happens to hormone levels?
it releases more oestradiol which causes POSITIVE FEEDBACK so more FSH and LH are released and get LH peak to rupture the ripe follicle and release egg (ovulation) onto ovarian surface where fallopian tube picks it up
what happens to the follicle after ovulation?
follicle becomes a corpus luteum
what does corpus luteum release?
oestrogen and progesterone to maintain a secretory endometrium suitable for embryo implantation
what happes to the CL if no implantation?
- involutes and hormone levels fall
- get menstruation 14 days after ovulation
what happens to hormone levels and how if embryo does implant?
HCG made by trophoblast tissue acts on CL to maintain O+P production until fetoplacental unit takes over at 8-10 weeks gestation
how can you detect ovulation in history alone?
- 1. regular cycles of periods means usually they are ovulatory
- 2. vaginal spotting or more discharge
- 3. pelvic pain = mittelschmertz (means middle pain) around time of ovulation
what happens to body temperature before and after ovulation?
- pre-ovulation: drops 0.2 degrees C
- luteal phase: rises 0.5 degrees C
what is the only proof of ovulation?
when is the luteal phase?
from ovulation to subsequent menstruation
what investigations are done to detect ovulation? (3)
- 1. elevated serum progesterone levels in MID-LUTEAL phase. so if you see low progesterone result - can only be interpreted as showing lack of ovulation if was taken 7 days before next period eg in 28day cycle on day21. if irregular cycle, need repeat prog tests until next period starts.
- 2. USS serially monitor follicular growth and after ovulation show the fall in size and haemorrhagic nature of CL
- 3. urine predictor kit indicates if LH surge has taken place - then ovulation should follow
- 4. temperature charts - not recommended
name common causes of anovulation - think of axis down body
- 1. HYPOTHALAMUS: hypothalamic hypogonadism: anorexia, stress, exercise
- 2. PITUITARY GLAND: hyperprolactinaemia, pituitary damage
- 3. THYROID GLAND: hyper or hyopthyroidism
- 4. ADRENAL GLAND: adrenal hyperplasia
- 5. OVARY: PCOS, POF
what is the most common cause of anovulatory infertility?
what type of USS do you do in suspected PCOS?
what are the features on USS of PCO?
- multiple: 12+
- small 2-8mm follicles
- in an enlarged ovary > 10ml
what % of women have PCO?
- nb - majority have regular cycles
how may women with PCO develop features of the syndrome?
if they put on weight
what % of women does PCOS affect?
how do you make a diagnosis of PCOS?
- need 2 out of 3:
- 1. PCO on ultrasound
- 2. irregular periods >35 days apart
- 3. hirsutism: clinical (acne or hairy) and or biochemical (raised serum testosterone)
what creates susceptibility to PCO?
what are the LH and insulin levels like in PCOS?
- disordered LH production, high
- peripheral insulin resistance, so compensatory high insulin levels
what effect does high LH and insulin levels have?
- 1. increased ovarian androgen production
- 2. increase adrenal androgen production
- 3. reduced hepatic production of SHBG leading to high free androgen levels
why do pts get lots of small follicles in PCO?
- increased intraovarian androgens disrupts folliculogenesis leading to small ovarian follicles
- and irregular or absent ovulation
which main environmental factor can modify the phenotype of PCOS and how?
increased weight can increase insulin and consequently androgen levels
what is likely in the FH of PCOS?
name 3 typical presenting symptoms of PCOS
- irregular periods
why do PCOS get more miscarriage?
- related to high LH or insulin levels
- and high BMI
for anovulation, give a diagnosis if the FSH is low, high or normal
- low: hypothalamic disease
- high: ovarian failure
- normal: PCOS
which 5 blood tests do you do in suspected PCOS or to exclude other causes of anovulation?
- LH: high in PCOS
- prolactin: exclude prolactinoma
- serum testosterone if hirsutism: may be androgen secreting tumour or CAH
which investigations do you do in suspected PCOS?
- Bloods: FSH LH TSH prolactin testosterone
- USS: transvaginal
- screening: diabetes, abnormal lipids - fasting lipids and glucose
what are the complications of PCOS?
- 1. DM2: in up to 50%
- 2. gestational diabetes in 30% risk reduced by weight loss
- 3. endometrial cancer: more common in women with many years of amenorrhoea due to UNOPPOSED OESTROGEN action
why are PCOS women not at risk of osteoporosis even though they are amenorrheic?
as have NORMAL oestrogen levels
what general advice is given to PCOS pts?
diet exercise to normalise weight: will result in reduction in insulin levels and improve all PCOS symptoms
if fertility is NOT required, what is treatment in PCOS?
1. COCP: regulate menstruation and treat hirsutism
how many bleeds a year are needed to protect endometrium?
at least 3-4 per year
which 2 anti-androgen drugs are used to treat hirsutism in PCOS and what advice must be given with these
- cyproterone acetate (can be COCP)
- but conception must be avoided
what is eflornithine?
topical antiandrogen used for facial hirsutism
which drug can be used in PCOS which helps all aspects of it?
metformin: reduce insulin levels as it sensitises body to insulin and so reduces androgen levels and hirsutism and promotes ovulation
what causes Kallmanns syndrome?
when GnRH secreting neurones fail to develop]
name 4 symptoms of PROLACTINOMA
- 1. oligo/amenorrhoea
- 2. galactorrhoea
- 3. headaches
- 4. bitemporal hemianopia
what is treatment of prolactinoma?
- 1. DA agonist: bromocriptine or cabergoline - usually restores ovulation
- 2. surgery if 1 fails or neuro symptoms warrant it
what are 4 causes of hyperprolactinaemia?
- 1. benign adenoma
- 2. pit hyperplasia
- 3. associated with PCOS
- 4. psychotropic drug SE
give 2 causes of pituitary damage
- 1. pressure from tumours
- 2. infarction following severe PPH (Sheehans syndrome)
why do you get high FSH and LH levels in premature ovarian failure?
- ovary fails so less oestrogen and inhibin made
- so LESS NEGATIVE FEEDBACK so high FSH and LH levels
why do exogenous gonadotrophins not work in POF?
as no ovarian follicles to respond!
what is only treatment for fertility in POF?
what needs to be protected in POF and how?
- bone protection
- OCP or HRT
what health advice needs to be given in treatment of infertility, especially anovulatory?
- 1. health advice regarding pregnancy
- 2. risks of multiple pregnancy
- 3. use of folic acid
- 4. weight normalisation may restore ovulation: reduce wt in PCOS; increase in anorexia
- 5. treat specific causes eg thyroid or prolactin problems may restore ovulation
what is the first line drug for ovulation induction in PCOS? and how long can you use it for?
- 6 months use limited
what is MOA of clomifene?
- blocks oestrogen receptors in hypothalamus and pituitary
- as FSH/LH release is normally inhibited by oestrogen, the effect of clomigene is to increase the release of FSH and LH as it fools the pituitary into believing there is no oestrogen
which part of cycle is clomifene given and why?
- begninning- day 2-6
- as it can INITIATE process of follicular maturation which is thereafter self perpetuating for that cycle
how should clomifene cycles be monitored?
by ultrasound to reduce risk of multiple follicle maturation and multiple pregnancy
what Rx is given if ovulation does not occur with clomifene for fertility in PCOS? and its MOA
- MOA: oral insulin sensitising drug - aim to restore ovulation
what is the advantage of metformin in terms of ovulation induction?
it does not promote multiple ovulation so there is no increase in multiple pregnancies and therefore no need for scan monitoring
when would metformin be the first line fertility treatment for anovulatory women?
- if they want HIRSUTISM treated
- avoid multiple pregnancies
name 2 additional unproven benefits of metformin in pregnancy in PCOS
- 1. reduce miscarriage rate
- 2. reduce GDM rate
name a surgical way of treating anovulation in PCOS
laparoscopic ovarian diathermy: each ovary is monopolar diathermied at a few points for a few seconds
what are the advantages of LOD (2)
- at same operation check tubal potency using methylene blue insufflation and treat comorbidities eg endometriosis
- lower multiple pregnancy rate
what is the treatment when clomifene has failed or if there is hypogonadotriphic hypogonadism?
- recombinant FSH +/- LH daily subcut injection to stimulate follicular growth
- monitor follicular development with USS
- once a follicle is of a size adequate for ovulation eg 17mm then the process can be artificially stimulated by injection of HCG (which is structurally similar to LH) or use recombinant LH
name 3 main SE of ovulation induction
- 1. multiple pregnancy
- 2. ovarian hyperstimulation syndrome
- 3. ovarian and breast carcinoma
which fertility drugs are likely to cause multiple pregnancy and which is not? and why?
- clomifene and gonadotrophins are: as >1 follicle may mature
- metformin no increased risk
what is the problem with multiple pregnancy?
increases perinatal complications
which drug is more likely to cause OHSS?
- rarely clomifene
what happens in OHSS? when is it more common?
- overstimulation of follicles which can get VERY LARGE and PAINFUL
- more common in IVF than standard ovulation induction
what are the complications of severe OHSS?
- electrolyte disturbance
- pulmonary oedema
name 4 ways of preventing OHSS
- 1. use lowest effective dose of gonadotrophin
- 2. USS monitoring of follicular growth
- 3. coasting: withdraw gonadotrophins but continue pituitary downregulation
- 4. cancellation of IVF cycle - withold HCG injection
what is the treatment of severe OHSS?
- resotre intravascular volume
- electrolyte monitoring and correction
- drainage of ascitic fluid to increase comfort and breathing
where does spermatogenesis occur? and what does it depend on?
- dependent on pituitary LH FSH
what action does LH have in men?
LH - testosterone production in Leydig cells
what does FSH and testosterone do?
control sertoli cells which are involved in SYNTHESIS AND TRANSPORT of sperm
how many days does it take for sperm to develop fully?
what inhibits release of more LH?
testosterone and other steroids
how should a semen sample be produced? when in relation to last ejaculation? when analysed?
- 2-7 days after the last ejaculation
- sample analysed within 1-2hours of production
if you see an abnormal semen analysis, what must be done?
- 1. semen analysis repeated after 70 days (as it takes 70 days to make new sperm)
- 2. examine scrotum
name the 3 parameters and their values of normal semen analysis
- volume > 2ml
- sperm count > 20million/ml
- progressive motility > 50%
what is azoopspermia?
no sperm present
what is oligospermia?
< 20 million/ml
what is severe oligospermia?
what is asthenospermia?
absent or low motility
name common causes of abnormal or absent sperm release
- 1. idiopathic
- 2. drug exposure
- 3. varicocoele
- 4. antisperm Abs
- 5. infections
- 6. testicular abnormalities
- 7. obstruction to delivery
- 8. hypothalamic problems
- 9. retrograde ejaculation
which drug exposure can affect male fertility
- drugs: sulfasalazine, anabolic steroids
- industrial chemicals: solvents
which side does varicocoele usually occur?
who is antisperm Abs more common in?
after vasectomy reversal
what % of infertile men have antisperm Abs?
what is evident on semen analysis of men with antisperm Abs?
- poor motility
- clumping together of sperm
which infections can affect sperm?
- mumps orchitis
what other testicular abnormalities can affect male fertility?
- Klinefelter's XXY
- obstruction: congenital absence of vas
which problems not in testicle can affect male fertility?
- hypothalamic problems
- Kallmann's syndrome
what general advice can be given to men for subfertility?
- 1. drug exposure
- 2. testicles should be below body temperature - wear loose clothing, testicular cooling
if there is hypopituitary disease, what is Rx?
if a man is oligospermic what is Rx?
IUI: intrauterine insemination
if moderate-sever oligospermia, what is Rx?
if very severe oligo what is Rx?
ICSI: intra cytoplasmic sperm injection is used as part of an IVF cycle
what is management of azoospermia? 1 examination, 3 Ix, Rx
- examine for presence of vas deferens
- Ix: check karyotype (in case XXY), cystic fibrosis, hormone profile
- Rx: surgical sperm retrieval - extracted direct from testis and then used for ICSI-IVF
if there are no sperm to extract what is final Rx?
DI: donar insemination
what helps sperm get through the cervix?
what are the 3 main causes of problems with fertilisation?
- 1. tubal damage
- 2. cervical problems
- 3. sexual problems
what are the causes of tubal damage?
- 1. infection
- 2. endometriosis
- 3. surgery/adhesions
which infection causes tubal damage and how?
PID - STI chlamydia causes adhesions to form within and around the fallopian tubes
what is the main cause of tubal damage?
what % of women will be infertile after one episode of chlamydia infection?
apart from STI, what are other causes of infection causing tubal damage?
- 1. insertion of intrauterine contraceptive device
- 2. ruptured appendix
what are the symptoms of PID/infection causing tubal damage?
- pelvic pain
- vaginal discharge
- abnormal menstruation
if there are peritubal adhesions or closed fimbrial ends of otherwise normal looking tubes then what is Rx?
laparoscopic adhesiolysis and salpingostomy
what is the Rx of endometriosis in terms of fertility?
laparoscopic surgery to remove endometriotic deposits
why is medical treatment not used to treat fertility in endometriosis?
as it suppresses ovulation
what are the cervical problems which cause failure to fertilise?
- 1. antibody production: Ab agglutinate or kill the sperm
- 2. infection in vagina or cervix that prevents adequate mucus production
- 3. cone biopsy for microinvasive cervical carcinoma
what is often the treatment for cervical problems leading to infertility?
what are the sexual problems leading to infertility?
impotence can be psychological or organic
what is required for sexual problems after exclusion of organic disease?
what are 2 investigations for detection of tubal damage?
- 1. laparoscopy and dye test: allow visualisation and assessment of fallopian tubes, then hysteroscopy to assess uterine cavity
- 2. hysterosalpingogram
- 3. HyCoSy: transvaginal USS & an ultrasound opaque liquid
how is lap and dye test done?
- methylene blue dye is injected through the cervix from the outside
- whether it enters or spills from the tubes can be seen, showing whether tubes are patent
who can a HSG be done in?
women with no history of pelvic damage or infection
when is an HSG usually done in terms of time of menstrual cycle? why?
- during the follicular phase of the menstrual cycle prior to ovulation
- 1. in order to avoid the risk of inducing an ectopic pregnancy
- 2. to avoid risk of exposing an early embryo to radiation
how is an HSG done?
- instillation of a radio-opaque dye through a small catheter placed in cervical canal into uterine cavity
- x-ray image obtained shows the uterine cavity, outline of fallopian tubes and presence or absence of dye in abdominal cavity
- when dye is seen to flow freely into the abdominal cavity, tubal potency is confirmed
what can you see on HSG if there are peri-tubal adhesions?
dye spill appears to be loculated or the tube appears to be in an abnormal position
if you see filling defects on the Xray image when may you see on HSG?
- uterine adhesions
- submucous fibroids
- filling defects
what is the advantage of HyCoSy?
avoids exposure to x-rays
what does the technique of HyCoSy involve?
use of USS to image the uterus and fallopian tubes
how is IUI done?
at the time of gonadotrophin superovulation, washes sperm are injected directly into the cavity of the uterus
what is the criteria for IUI?
1. tubes must be patent: as oocyte still needs to travel from ovary to sperm
which types of infertility can IUI be used in?
- unexplained subfertility
- cervical problems
- sexual problems
- some male factors
what is the success rate of IUI? how many live births
live birth rate is 10% per stimulated cycle
what is the method of IVF?
- 1. during the long protocol IVF, the pituitary gonadotrophins are suppressed using 2-3 weeks of GnRH agonist: to prevent endogenous LH surge and premature ovulation before oocyte collection
- 2. multiple follicular development then achieved with 2 weeks of daily subcut gonadotophin injections FSH, LH
- 3. eggs collected under sedation by aspirating follicles transvaginally under US control
- 4. eggs incubated with washed sperm and transferred to a growth medium
- 5. trans cervical replacement of embryos into uterus 2-5 days later
how many embryos are transferred?
no more than 2 in women < 40years to reduce obstetrics and paediatric complications associated with high order multiples
what can be done with spare, good quality embryos?
- frozen for future thawing
- FER: frozen embryo replacement
in IVF, what extra support is given? and when?
luteal phase support using progesterone or HCG is given until 4-8 weeks gestation
do the tubes need to be patent in IVF?
what is the criteria for IVF?
normal ovarian reserve: FSH < 12 so sufficient oocytes collected for fertilisation and transfer
what is the live birth rate per cycle in women < 36 for IVF?
35% per stimulated cycle
when there is severe male factor infertility when there are not enough motile sperm available to incubate with egg, what method is used?
before ICSI was avaiblae, what method was used for severe male factor infertility?
when is oocyte donation used?
- 1. ovarian failure
- 2. older age >43 yrs
- 3. genetic disease
how does oocyte donation work?
- 1. donor, goes through a full stimulated IVF cycle,
- 2. her retrieved eggs are fertilised with sperm of woman's partner
- 3. recipient receives oestrogen and progesterone to prepare her endometrium for transfer of fresh embryos
what is now done due to shortage of anonyous oocyte donors?
egg sharing - women who need IVF share eggs
when is PGD done?
- day 3 embryos are 8 cells
- 1/2 cells removed from embryo and DNA examined using PCR or FISH to look for genetic abnormality
- unaffected embryos replaced 2 days later
who is PGD indicated in?
- 1. couples who are carriers of single gene defects eg cystic fibrosis
- 2. chromosome translocaitons so high risk child with aneuploidy (chr abn eg downs)
- 3. check sex to avoid replacement of male embryos that ay be affected by haemophilia (not for social reasons in UK)
- 4. over 37yrs needing IVF can have embryos screened and only replace normal embryos to overcome age related decline in IVF success rates
what is the difference between straight surrogacy and host surrogacy?
- straight: surrogates own eggs
- host: patients eggs go through IVF then transfer embryo into surrogate
name 3 complications of assisted conception
- 1. superovulation: multiple pregnancy and OHSS
- 2. egg collection: intraperitoneal bleed, pelvic infection
- 3. pregnancy: multiple, ectopics