Infertility Flashcards
What proportion of couples are affected by infertility at some point in their lives?
1 in 6
What is the World Health Organisation definition of infertility?
inability of couple to achieve clinical pregnancy within 12 months of beginning regular unprotected sexual intercourse
What are 2 types of infertility?
- Primary infertility
- Secondary infertility
What is primary infertility?
No previous pregnancies within the relationship
What is secondary infertility?
Couple has had at least one pregnancy in the past
What proportion of the normal fertile population will conceive within 1 year, and what proportion by the end of 2 years?
84% by end of 1 year, 92% by end of 2 years
What are the terms used to express the chance of conception within a given time interval?
- Cumulative pregnancy rates
- Live birth rates
Chance of realising a family with one child with + without IVF with advancing maternal age in image
What is the definition of fecundability?
percentage of women exposed to the risk of a pregnancy for one menstrual cycle, who will subsequently produce a live-born infant
What is the normal range of fecundability for one menstrual cycle?
15-28%
What is the trend of fecundability over time?
usually diminishes slightly with each passing month of not conceiving
What single factor causes fertility to decline?
age
What is the rough number of oocytes a woman is born with?
1 million
By puberty how many oocytes does the average woman have?
approximately 250 000
How many oocytes does the average woman have by menopause?
below 1000
How many mature oocytes will a woman typically release during her life?
only 500
What happens to the remaining oocytes that are lost throughout a woman’s life, that are not released as a mature oocyte?
undergo atresia or apoptosis
How many functioning oocytes remain at the menopause (average age 51 years)?
no functioning oocytes
What causes the decline in fertility with increasing age?
directly related to declining oocyte population and the eggs’ inherent quality
increased risk of miscarriage with advancing maternal age
From what age does a very steep decline in fecundity occur?
from age 40 (but small declines from 31 and 36 also)
How does the effect of male age on fertility compare with female?
effect of age on men’s fertility is less pronounced
What are 5 groups of causes of infertility?
- Ovuation disorders
- Male factor
- Unexplained
- Tubal factors
- Others including endometriosis
What are 6 things to look for during examination of a woman for infertility and why for each?
- Heigh and weight for BMI: high or low associated with lower fertility
- Body hair distribution: hyperandrogenism
- Galactorrhoea: hyperprolactinaemia
- Uterine structural abnormalities: may be assoc/ w infertility
- Immobile and/or tender uterus: endometriosis or PID, assoc/ w tubal damage
- Visual fields: pituitary adenoma causing hyperprolactinaemia
What is the easiest way to determine uterine structural abnormalities?
most usefully determined by transvaginal ultrasound
What are 4 things to look for in the examination of a man in infertility?
- Scrotum - varicocele/ swellings
- Size (volume) of testes - small testes associated with oligospermia
- Position of the testes - undescended testes
- Prostate - chronic infection
- Outline of epididymis - for presence of vas deferens
What is the range for normal BMI?
19-25
What type of change in weight can cause anovulation/menstrual disturbance leading to infertility?
Change in weight of >10%
What is the commonest cause of hyperandrogenism?
PCOS
When should examination of the man be performed in infertility?
only in presence of any relevant history
or genitalia examination if semen analysis abnormal
What are 5 initial investigations which you might perform to investigate infertility?
- F: early follicular phase (e.g. day 2) luteinising hormone (LH), follicle-stimulating hormone (FSH), oestradiol, anti-Müllerian hormone (AMH)
- F: rubella (offer vaccination if not immune)
- F: Day 21 (7 days before menses) serum progesterone (to assess ovulation)
- F: test of tubal patency (laparoscopic hydrotubation, hysterosalpingo-contrast sonography (HyCoSy) or hysterosalpingography (HSG)
- M: semen analysis x1
What are 4 early follicular phase hormones to measure in the female for initial investigations for infertility?
- LH
- FSH
- Oestradiol
- Anti-Müllerian hormone (AMH)
What are 5 investigations to be selectively performed to investigate female infertility?
- Pelvic ultrasound scan for ovarian morphology and uterine abnormalities
- Laparoscopy for diagnosis of endometriosis, may be combined with tubal patency
- Hysteroscopy for intrauterine anomalies
- Prolactin and thyroid function tests
- Testosterone, androstenedione, 17-hydroyprogesterone and sex hormone-binding globulin (SHBG, to calculate Free Androgen Index, when raised is an indicator of hyperandrogenism)
What are 4 types of hormones which may be selectively measured, and are usually performed together, when investigating female infertility?
- Testosterone
- Androstenedione
- 17-hydroxyprogesterone
- Sex hormone-binding globulin (SHBG)
What are 4 investigations for male infertility to be selectively performed, in addition to semen analysis?
- Sperm function tests if initial test consistently abnormal
- Mixed agglutination reaction test or immunobead test for antisperm antibodies
- FSH, LH, testosterone if low sperm count (oligospermia) (raised FSH if testicular failure, low if central nervous system cause)
- Transrectal ultrasound for suspected abnormalities of the seminal vesicles and prostate
What are 3 ways to classify male factors for infertility?
- Sperm production
- Sperm function
- Sperm delivery
What words are used to desribe absent sperm production?
azoospermia
What is the term for a reduced count of sperm of normal appearance?
oligospermia
What is the word used to describe poor sperm motility, lacking the normal forward progressive movement?
Asthenospermia
What is the word for sperm which appear morphologically defective with abnormalities of head, midpiece or tail?
teratospermia
Overall what are 4 examples of disorders of sperm production?
- Azoospermia
- Oligospermia
- Asthenospermia
- Teratospermia
What can cause azoospermia?
Testicular failure
What is meant by normal sperm function?
ability of sperm to reach, bind and fertilise the oocyte
What methods are available to measure sperm function?
no reliable methods currently available other than monitoring proportion of sperm moving and assessing speed of their progress
What factor can affect sperm motility?
antisperm antibodies
What are 4 causes of problems with sperm delivery?
- Absence or blockage of vas deferens or epididymis
- Impotence
- Premature ejaculation
- Physical inability to have normal sexual intercourse
To summarise what are the 3 types of male factors of infertility and examples of causes?
- Sperm prodcution: azoospermia, oligospermia, asthenospermia, teratospermia
- Sperm function: antisperm antibodies
- Sperm delivery: absent/blocked vas/epididymis, impotence, premature ejaculation
What information does semen analysis provide about sperm?
spermatogenesis (production) and aspect of sperm delivery, but gives little information about sperm function
What are the 6 parameters that are measured by semen analysis?
- Volume
- Concentration
- Total motility
- Progressive motility
- Normal forms
- Vitality
What is the lower limit of reference range for 1. sperm volume 2. concentration 3. total motility 4. progressive motility 5. normal forms 6. vitality?
- Volume: 1.5ml
- Concentration: 15 x 106 / ml
- Total motility: 40%
- Progressive motility: 32%
- Normal forms: 4%
- Vitality: 58%
What should be done when a man’s sperm count is found to be abnormal?
second count should be arranged, as individual man’s result varies considerably- should be at least 3 months apart as spermatogenesis takes approximately 3 months to complete
What time should there be in between sperm samples and why?
3 months, as spermatogenesis takes approximately 3 months to complete
How should sperm samples for semen analysis be taken?
Masturbation or sexual intercourse into non-lubricated condom
What period of abstinence is required prior to obtaining a sperm sample for semen analysis?
between 3 and 5 days prior
How commonly are tests of sperm function performed?
no longer used routinely, more emphasis now placed on identification of number of abnormal/normal sperm
some sperm function tests, such as ability of sperm to swim through culture medium, employed in specialised reproductive medicine units where more complicated treatment may be considered
What are 3 examples of tests of sperm function?
- Ability of sperm to swim through culture medium
- Post-coital test
- Antibodies against sperm
What is the post-coital test of sperm function?
involves asking the couple to have sexual intercourse timed to the woman’s mid-cycle
6-12 hours later sample of endocervical mucus is taken, looking for presence or absence of sperm
Why is the post-coital test sometimes considered for testing sperm function?
some studies show positive correlation between finding of motile sperm in mucus and chance of subsequent pregnancy
Why have most centres abandoned the post-coital test of sperm function?
some studies show finding positive or negative result doesn’t alter chance or timing of pregnancy
What can cause antibodies to develop against sperm and what is the commonest cause?
- injury or infection to the testis and epididymis
- Vasectomy and attempted reversal are commonest
What types of antibodies can form against sperm and how do they attach to them?
- serum IgA or bound IgA
- Attach principally to tail, midpiece or head of sperm
What are 2 examples of the tests used to identify antisperm antibodies?
- Mixed agglutination reaction test
- Immunobead test
What levels of antisperm antibodies detected are thoguht to affect fertility?
- 17-49%: likely to be associated with fall in fertility
- >50%: significantly affect fertility
What are 2 key things which ovarian failure may be associated and what proportion of these conditions are associated with ovarian failure?
- Primary amenorrhoea: 50% have ovarian failure
- Secondary amenorrhoea: 15%
What are 2 examples of causes of primary amenorrhoea, which may be associated with infertility (50% of time)?
- Genetic causes e.g. Turner syndrome (45, XO)
- Autoimmune
What are 3 examples of causes of secondary amenorrhoea, 15% of which may present with infertility?
- Previous ovarian surgery
- Abdominal radiotherapy
- Chemotherapy
What is the term given to ovarian failure with no identifiable cause?
Idiopathic premature menopause
What are 4 key causes of anovulation as a cause of female fertility?
- Weight-related anovulation
- Polcystic ovary syndrome
- Luteinised unruptured follicle syndrome
- Hyperprolactinaemia
What degree of body fat is considered needed to maintain ovulatory cycles?
minimum 22% of body weight
How does substantial weight loss affect ovulation?
- leads to disappearance of normal 24h secretory pattern of gonadotrophin-releasing hormone (GnRH) which reverts to nocturnal pattern seen in pubescent girls
- Ovaries develop multifollicular appearance on ultrasound
What will the appearance of ovaries on ultrasound be in weight-related anovluation due to weight loss?
multifollicular appearance
How can excessive exercise cause anovulation?
increases muscle bulk and decreases body fat
(female athletes or ballerinas can be amenorrhoeic)
How does excess weight gain affect fertility?
profound effect:
reduces chance of conception, increases risk of miscarriage and risk of obstetric complications
What is the effect of distribution of weight on fertility?
central (visceral) fat has bigger impact on fertility than peripheral fat distribution
waist-hip ratio, which more reliably picks up visceral fat distribution, is a more reliable guide to impact of fat on fertility than the BMI
What proportion of women presenting with anovulatory infertility will have PCOS?
50%
What is luteinised unruptured follicle syndrome?
oocyte may be retained following luteinising hormone (LH) surge
What will repeated ultrasound scans show in luteinised unruptured follicle syndrome?
will fail to show expected collapse of follicle at ovulation, and follicle persists into the luteal phase
In what proportion of cases of secondary amenorrhoea is hyperprolactinaemia diagnosed?
10-15%
What proportion of women with hyperprolactinaemia will have galactorrhoea?
one third
What are 2 key symptoms of hyperprolactinaemia?
- Galactorrhoea
- Visual impairment (bitemporal hemianopia) due to pressure on optic chiasm from pituitary adenoma
What are 2 types of investigations of ovarian function that can be performed?
- Tests of ovulation
- Tests of ovarian reserve
What is the only way to categorically confirm ovulation?
pregnancy
What are 3 investigations to perform that can imply that ovulation has taken place?
- History: over 90% of women with regular menstrual cycles will ovulate spontaneously
- Urinary LH kit: picks up mid-cycle surge of LH that start cascade reaction leading to ovulation
- Mid-luteal phase progesterone (7 days prior to first day of period)
What is the most commonly used test of ovulation?
Mid-luteal phase progesterone
What is the level of mid-luteal phase progesterone generally regarded as evidence of satisfactory ovulation?
>28 nmol/L
When should the mid-luteal phase progesterone test be timed for?
between 7 and 10 days before next menstrual period (need knowledge of length of patient’s normal cycle)
What is the definition of ovarian reserve?
number of viable oocytes in the ovary
When is testing ovarian reserve particularly important?
women contemplating more complex fertility treatment - may provide guide to their response to treatment
What are 4 ways to test ovarian reserve?
- FSH at start of menstrual cycle (early follicular phase)
- Antral follicle count on ultrasound - number of small developing follicles seen in ovary
- Measuring ovarian volume
- Measuring concentration of anti-Müllerian homrone (AMH)
When should FSH be measured to determine ovarian reserve?
between days 2 and 5 of menstrual cycle
How is the result of early follicular phase FSH interpreted for ovarian reserve?
raised FSH between days 2-5 indicates impaired ovarian reserve and likely poor response to ovarian stimulation
Why can ovarian volume be measured as a way of determining ovarian reserve?
indication of ovarian activity as ovaries decrease in size with advancing age and decline in oocyte number s
What is AMH and why is it measured for determining ovarian reserve?
- produced in small developing follicles
- unlike FSH can be usefully measured throughout menstrual cycle
What is the key benefit of tests of ovarian reserve?
identifying women who may not respond well to fertility treatment or will have shorter reproductive lifespan (not great for predicting overall natural fertility if woman has regular menstrual cycle and is ovulating)
In addition to tests of ovulation and of ovarian reserve, what are 4 further types of investigations for infertility that may be considered in women?
- Pelvic ultrasound
- Chlamydia serology
- Serum testosterone measurement, 17-hydroxyprogesterone, TFTs
- Progestogen challenge test
Why can pelvic ultrasound be useful for identifying causes of infertility?
useful in defining ovarian morphology, more reliable than pelvic examinatino in identifying potentially relevant pelvic pathology e.g. fibroids, ovarian cysts and endometrial polyps
Why might chlamydia serology be performed for female infertility?
screening test for tubal pathology - if positive antibody titre, more likely to have tubal pathology due to link with salpingitis
When is serum testosterone indicated for women with subfertility and what is it to exclude?
- If evidence of hirsutism
- To exclude sinister disorders such as androgen-secreting tumours of ovary or adrenal gland
What further blood test might you perform in women with elevated serum testosterone and why?
17-hydroxyprogesterone - to exclude late-onset congenital adrenal hyperplasia
Why might you perform thyroid function tests for female subfertility?
approx 7% women will have thyroid disorder, which may have impact on pregnancy if not appropriately treated
In which women with subfertility might you consider a progestogen challenge test?
history of amenorrhoea and normal levels of FSH and prolactin - to determine whether the woman is clinically oestrogenised
What can progestogen challenge tests in subfertile women be used to guide?
what would be most appropriate medication to use to induce ovulation
How can the results of a progestogen challenge test be interpreted?
- if bleeding normal following 5 days or oral progestogen, patient is well-oesotrgenised
- if bleeding absent or scanty, woman is poorly oestrogenised
- presence of withdrawal bleed demonstrates presence of endometrium and patency of genital tract
What further test can be done to further inform the progestogen challenge test and how?
visualise and measure endometrial thickness by transvaginal scanning - as thick and adequately oestrogenised endometrium can be seen on scan
What are 3 places where tubal patency might be lost?
- Fimbrial end
- Cornu (proximal end)
- Tubo-ovarian relationship disrupted by peritubal adhesions
What are the 2 degrees of severity of fimbrial disease leading to disruption of tubal patency?
- Agglutination of fimbria to produce a narrowed opening - known as a phimosis
- Complete agglutination to form a hydrosalpinx (fluid-filled tube)
What are 4 important features of tubal patency/ lack thereof for fertility prognosis?
- Degree of dilatation of fallopian tube
- Extent of fibrosis of wall of tube
- Damage to endosalpinx
- If one or both tubes affected
What effect might there be of loss of tubal patency on the endosalpinx and what implication can this have?
intraluminal adhesions and flattening of mucosal folds; microsurgery to relieve tubal blockage may not restore tubal function
What are 6 types of tests for tubal patency in female subfertility?
- Hysteroslapingography (HSG)
- Hysterosalpingo-contract sonography (HyCoSy)
- Diagnostic laparoscopy with dye hydrotubation
- Selective salpingography
- Salpingoscopy
- Falloposcopy
What 3 things to do before assessing tubal patency more invasively?
- Rule out history suggestive of pelvic pathology
- Negative physical examination
- Negative chlamydia antibody titre
What should determine the method for assessing tubal patency?
least invasive method should be employed
What does hysterosalpingography involve?
inserting cannula into cervix and passing radio-opaque fluid into the uterine cavity and fallopian tubes, demonstrating their outline
performed under X-ray in outpatients
How reliable is hysterosalpingography to assess tubal patency?
if normal, 97% likely to be right
if abnormal, can only be relied upon in 34% of cases (66% false positive rate)
If an abnormality is found on hysterosalpingography with the tubal system, what is the next step?
low reliablility, need laparosopy to confirm abnormality and its nature
What does hysterosalpingo-contrast sonography (HyCoSy) involve?
pelvic ultrasound scan at which galactose-containing ultrasound contrast medium inserted into uterine cavity, outlining any abnormalities such as submucosal fibroids and endometrial polyps, before passing down fallopian tubes to confirm tubal patency
How does the diagnostic accuracy of HyCoSy compare with HSG (hysterosalpingraphy)?
similar
What does diagnostic laparoscopy with dye hydrotubation involve?
- provides direct view of pelvic organs and offers possibility to treat minor pathology discovered
- methylthioninium chloride (methylene blue) dye inserted through cannula in cervix to demonstrate tubal patency
- hysteroscopy often carried out at same time to examine uterine cavity
- diagnostic laparoscopy requires admission to hospital, usually day case, and GA
What is the gold standard investigation for tubal patency, and what else is often used as the first-line?
Diagnostic laparoscopy with dye hydrotubation (lap and dye)
but this is invasive and expensive so most specialists do HSG or HyCoSy first
When would selective salpingography be performed?
if HSG or laparoscopy detects a proximal blockage - further inestigation may be considered
What 2 things might cause blockage of the fallopian tubes on HSG or laparoscopy?
spasm of muscle of uterine cornua, or genuine pathology
What does selective salpingography involve?
fine guidewire inserted into internal tubal ostium under direct fluoroscopic control or by direct vision using a hysteroscope
this may dislodge small plug of amorphous debris, restoring patency - this technique appears to increase likelihood of pregnancy in women with proximal tube damage
When is salpingoscopy considered?
if question of pursuing tubal surgery raised
What does salpingoscopy involve?
fine telescope called salpingoscope passed down operating laparoscope and inserted into ampullary portion of fallopian tube
What proportion of patients with macroscopically damaged fallopian tubes will ahve fine intratubal adhesions and what does their presence indicate?
50%
adversely affect outcome of subsequent tubal surgery
What is Falloposcopy?
fine instrument, falloposcope, with diameter <1mm, inserted into fallopian tube via uterine cavity
performed on outpatient basis
What is the disadvantage of falloposcopy?
equipment fragile and expensive and limited to small number of centres
What proportion of couples with infertility conceive spontaneously during investigation or while awaiting treatment?
20%
What are 5 factors that influence whether a couple is likely to conceive spontaneously while awaiting investigation or treatment for infertility?
- Age of woman
- How long couple has been trying to conceive
- Whether they have been pregnant before
- Tubal patency
- Sperm motility
When is referral to assisted conception services generally appropriate?
for most couples after initial investigations have been completed - early referral best
What are 4 general health measures to counsel a subfertile couple about?
- Smoking
- Alcohol intake
- Diet
- Recommend folic acid to woman as routine prevention of neural tube defects
What is the approach to management of subfertility when the cause is anovulation?
inducing ovulation - various ways, depending on the cause
How long should ovulation induction be continued for and why?
long enough to give optimum chance for conception - generally 12 months
What is the treatment for anovulation caused by hyperprolactinaemia?
Dopamine agonist - bromocriptine or cabergoline
How can women with excess or decreased body weight be managed to induce ovulation?
- should be managed with dietary adjustments
- Can use exogenous gonadotrophins but should avoid generally as increased risk of pregnancy complications
- Women with moderate obesity often show resistance to treatment with clomifene citrate and gonadotrophins, requiring much higher doses to induce ovulation
What class of drug is clomifene?
Selective oestrogen receptor modulator (SERM) - ovulatory stimulatant
What do most women who have anovulation but are oestrogenised suffer from?
PCOS - 85% of patients with oligomenorrhoea and 25% of those with amenorrhoea
What is the first line treatment for anovulation in PCOS?
- oral anti-oestrogen therapy: clomifene citrate or letrozole
What is the mode of action of clomifene to stimulate ovulation in oestrogenised patients (e.g. PCOS)?
increases plasma FSH concentration by competitively blocking the negative feedback effects of andogenous oestradiol on the hypothalamus (FSH is principal hormone responsible for follicular recruitment and development)
What is the mode of action of letrozole to treat anovulation in oestrogenised patients e.g. PCOS?
suppresses oestrogen negative feedback centrally and does not have the anti-oestrogenic effects on the endometrium that are observed with clomifene
How is clomifene given to induce ovulation in oestrogenised patients with anovulation e.g. PCOS?
initially dose of 50mg daily for 5 days given at beginning of a cycle - days 2-6 inclusive
if no response (judged by luteal phase progesterone estimations), dose increased to usual maximum of 100mg daily for 5 days
rarely in obese patients, dose may be increased to 150mg daily for 5 days
What is there a risk of when using clomifene for oestrogenised patients with anovulation e.g. PCOS and why?
multiple pregnancy - 10% chance
may induce multiple follicles
How is letrozole given to treat patients who are oestrogenised with anovulation e.g. PCOS?
5mg daily for 5 days, from day 2 of cycle
How effective is letrozole at inducing ovulation for oestrogenised patients with anovulation e.g. PCOS compared with clomifene citrate, and why is it not used more frequently?
more efective, but not licensed for ovulation induction
Why are clomifene and gonadotrophins meant to be avoided for ovulation induction in underweight or obese women?
increased risk of pregnancy complications
In what proportion of cycles can ovulation be achieved successfully using clomifene/letrozole?
80% of cycles
(cumulative prengnayc rates: up to 30% after 6 months treatment)
What are 6 possible side effects of the use of clomifene citrate?
- Vasomotor symptoms (hot flushes)
- Pelvic discomfort
- Nausea
- Breast discomfort
- Visual disturbances
- Cholestatic jaundice
In what 2 situations should clomifene be discontinued and not used again?
- Visual disturbance
- Choelstatic jaundice
What are 2 sources from which exogenous gonadotrophins are dervied?
- Extracted from postmenopausal women’s urine
- Created in vitro by genetically engineered mammalian cells
What are gonadotrophins, which may be used to treat fertility?
mainly FSH in initial therapy given - >99%, and small mount of LH
hCG given to induce ovulation once the follicle reaches maturity
How are gonadotrophins administered for the purposes of treating fertility?
subcutaneous injection
What are 2 risks associated with the use of gonadotrophins to induce ovulation in oestrogenised anovulating women (e.g. PCOS)?
- Ovarian hyperstimulation syndrome (OHSS)
- Multiple pregnancy - 20% incidence
How can the risk of multiple pregnancy associated with gonadotrophin treatment for anovulation in oestrogenised women be reduced?
careful monitoring and step up of the dose - can be reduced from 20% to <5%
How are gonadotrophins given to induce ovulation in anovulating, oestrogenised women e.g. PCOS?
- low dose regime: 1 ampoule daily for 10 days
- increase dose if necessary by small increments until satisfactory follicular growth occurs
- when follicle reaches maturity, hCG given to induce ovulation to replace physiological LH surge
How is response to gonadotrophin treatment of anovulatory oestrogenised women monitored?
ovarian ultrasound, sometimes combined with serum oestradiol measurement
What are 2 types of causes of infertility that gonadotrophin therapy is successful at treating?
- Hypothalamic amenorrhoea
- PCOS
What treatment can be offered to treat PCOS (oestrogenised form of anovulation) if standard ovulation-induction e.g. clomifene/letrozole/gonadotrophins fail?
Laparoscopic ovarian diathermy
What does laparosopic ovarian diathermy do to treat subfertility caused by PCOS involve?
ovarian capsule is pierced 4 times for 5 seconds with a needle point diathermy
either stimulates spontaneous ovulation or women become more responsive to clomifene or gonadotrophin therapy
How long do the effects of laparoscopic ovarian diathermy remain effective for?
chronic anovulation returns in 50% within 2 years
What are 2 risks of laparoscopic ovarian diathermy to treat anovulation in oestrogenised women?
- risk of iatrogenic adhesion formation
- reduction in ovarian reserve, leading to premature menopause if diathermy used excessively
What is another drug option to treat anovulation specific to the oestrogenised state of PCOS in obese women?
Metformin, used alone or in combo with clomifene
How does the effectiveness of metformin + clomifene compare with letrozole in treating anovulation in PCOS?
less effective
To summarise what are 4 ways to treat anovulation in oestrogenised patients (most of whom have PCOS)?
- Oral anti-oestrogen therapy (first line) - usually clomifene citrate or letrozole
- Exogenous gonadotrophins - mainly FSH, then hCG to stimulate ovulation
- Laparoscopic ovarian diathermy
- Metformin - if obese
What are 3 typical biochemical findings in anovulation in oestrogen-deficient women? What is the name of this condition?
- Low FSH
- Normal prolactin
- Either low serum oestradiol or negative progestogen withdrawal test
= hypogonadotrophic hypogonadism
What is the management to stimulate ovulation in hypogonadotrophic hypogonadism (low FSH, anovulation)?
Exogenous gonadotrophins
What are the 2 broad treatment options for tubal disease causing infertility?
- Surgery
- IVF
How commonly is tubal surgery performed for tubal causes of infertility?
rarely now as IVF has improved
What are 3 factors to consider when deciding whether to treat tubal disease with surgery?
- Woman’s age
- Site and extent of tubal damage
- Other factors that might influence fertility
Why should you consider age as an important factor when deciding whether to perform tubal surgery to treat infertility?
IVF may be better option for women in late 30s or their 40s
How does the prognosis of tubal disease vary depending on location?
distal tubal occlusion carries poorer prognosis than proximal disease
When should surgery be considered for tubal damage?
when damage is relatively minor, especially proximal - better success rate
if moderate-to-severe distal abnormality / multiple sites in same tube - poor prognosis, IVF more appropriate
What techniques are used to perform tubal surgery to repair damage causing infertility?
-
laparoscopically most common now (rather than laparotomy)
- using either CO2 laser or electrodiathermy
- Selective salpingography - passing gine catheter through uterus and along fallopian tube under x-ray screening - used sometimes for proximal obstruction caused by plug of amorphous debris
What key risk is associated with tubal surgery to treat infertility and what is done as a result?
- 10x increased risk of ectopic pregnancy
- advised to undergo USS at 6 weeks’ gestation to confirm site of subsequent pregnancy
What 3 types of endometriosis treatment are thought to be effective when this is the cause of infertility?
- surgery to ablate endometriotic lesions and divide adhesions that may have formed from endometriosis
- evidence this increases chance of conception
- surgery to correct anatomical defect if involves ovary or fallopian tube - beneficial
- treatment with GnRH analogues for 3 months may significantly improve likelihood of pregnancy
- [medical treatment often involves creating anovulation - delays pregnancy]
After treating endometriosis with surgery/ GnRH analogues, if pregnancy does not occur what should be considered next?
- if pregnancy does not occur within 6 months IVF should be considered
What are 5 types of male factor problems that can cause infertility?
- Azoospermia and raised serum FSH - suggests spermatogenic failure
- Azoospermia and normal FSH - vas deferens or epididymal blockage (e.g. vasectomy)
- Hypogonadotrophic hypogonadism
- Idiopathic oligospermia
- Varicocele
What can male azoospermia and raised serum FSH signifiy?
spermatogenic failure - non-obstructive azoospermia
How can azoospermia + raised serum FSH suggesting non-obstructive azoopspermia be confirmed?
testicular biopsy
What are 2 options for the manaagement of azoospermia with raised serum FSH, indicating spermatogenic failure?
- Occasionally islands of spermatogenesis can be identified and sperm extracted from testicular biopsy and used for intracytoplasmic sperm injection (ICSI) as part of IVF treatment
- If no sperm identified at surgical sperm retrieval, use of donor sperm
What screening is performed for sperm donation?
- sperm donors no longer anonymous
- all potential donors screened for family history of medical and genetic conditions and for infection
- HIV, hepatitis B and C
What 3 infections are sperm donors screened for and how?
- HIV, hepatitis B and C
- Semen frozen in straws and quarantined for minimum of 6 months
- donor then screened again for infection at end of period
- only if second screen negative is sperm used for treatment
How is donor insemination performed?
- donor semen inserted into woman’s uterus at time of ovulation
- ovulation predicted by serial pelvic ultrasound scans or detection of LH surge using urinary assay
What are 2 ways of predicting ovulation when carrying out donor insemination?
- serial pelvic ultrasound scans
- detection of LH surge using urinary assay
What is the chance of conception when using donor insemination for male factor fertility problems e.g. spermatogenic failure?
- in first cycle of treatment is 18.8%
- falls rapidly to 6% per cycle for next 12 months
What does azoospermia in the presence of normal FSH signify?
block of vas deferens or epididymis - most commonly caused by vasectomy
What are 2 examples of causes of blockage of the vas deferens or epididymis leading to azoospermia with normal FSH?
- most commonly vasectomy
- if congenital absence of vas - often found to have variant of cystic fibrosis
What are 2 types of treatments for azoospermia with normal FSH i.e. vas or epididymal block?
- Microsurgical techniques:
- re-anastamosis (vasovasostomy)
- attached to epididymis (vasoepididymostomy)
- Epididymal sperm aspiration in combination with IVF and ICSI
What does the type of microsurgical technique to treat vas deferens or epididymal blockage depend upon?
vasovasostomy or vasoepididymostomy depend son site of obstruction
What are the results like of microsurgery to treat epididymal or vas deferens blockage and why?
good anatomical results but poor pregnancy rates
partly because build-up of pressure distal to obstruction may have damaged delicate epididymis, and partly because antisperm antibodies may have formed
What is a useful guide to prognosis for microsurgical treatment of vas deferens of epididymal blockage?
time from original vasectomy (if cause of block) and reversal procedure
poorer pregnancy rates if >10 years
What does IVF with ICSI to treat epididymal or vas deferens blockage involve?
local anaesthetic applied and needle placed percutaneously into epididymis, or microsurgical techniques under anaesthetic
as sperm sample usually of poor quality, direct ICSI into oocytes necessary
What should you screen for if azoospermia with normal FSH is associated with congenital absence of the vas and why?
screen for common cystic fibrosis mutations, as often carry a variant of CF
usually have compound heterogeneicity where each chromosome 7 carries different mutation at site of transmembrane conductance regulator gene, which is responsible for cystic fibrosis
if partner carrier of one of the mutations, 25% chance of child having CF
If male factor infertility is caused by hypogonadotrophic hypogonadism, what is the management? 2 options
- successfully treated with exogenous gonadotrophins (FSH and hCG), or
- using GnRH infusion pump
What is the most common diagnosis in male factor infertility?
idiopathic oligospermia
What are 2 aspects of treatment of idiopathic oligospermia in male factor infertility?
- Mainstay - ICSI using sperm prepared in culture medium
- Multivitamins associated with improvement in sperm parameters, recommended when partner trying to conceive
In what proportion of the male population is there ultrasound evidence of a varicocele?
15%
When would you treat varicocele and how?
- surgeyr to correct is not justified in absence of symptoms and in presence of normal semen analysis
- even in presence of oligospermia, no evidence sperm count or conception rate can be improved with surgery
What is the mainstay of treatment of unexplained infertility?
IVF
What is meant by assisted conception techniques?
those in which gametes, either sperm or eggs, are manipulated to improve the chance of conception
What are 7 assisted conception techniques to be aware of?
- Intra-uterine insemination (IUI)
- In-vitro fertilisation (IVF)
- Gamete intrafallopian tube transfer (GIFT)
- Intracytoplasmic sperm injection (ICSI)
- Egg donation
- Host surrogacy
- Pre-implantation genetic diagnosis (PG)
How is intra-uterine insemination (IUI) performed? 2 methods
- sperm prepared in culture medium, separating seminal fluid, poorly motile sperm and other cellular debris in ejaculate, and producing clean sample of highly motile sperm
- placed into uterine cavity via fine plastic catheter
- either:
- IUI timed to natural ovulation
- Used in conjunction with controlled ovarian stimulation with clomifene or gonadotrophins to recruit up to 2 mature follicles; when follicles reach appropriate size (17mm) ovulation induced with hCG and sperm inserted to uterine cavity
What are 3 situations when the intrauterine insemination (IUI) technique may be used?
- Coital difficulties
- Couples requiring donor sperm (DI)
- IU + superovulation: for women not ovulating
What are the live birth rates for IUI?
11.2% per cycle, increasing to 14.6% for stimulated DI
What is a risk of IUI with ovulation stimulation, and what should be done due to this risk?
risk of multiple pregnancy
careful dosing, monitoring and willingness to cancel cycle due to excessive response of oaries are required
What is meant by in vitra fertilisation (IVF)?
mixing of sperm and egg outside the body
What are 7 indications for IVF?
- Male factor infertility
- Severe endometriosis
- Failed ovulation induction
- Unexplaned infertility
- Preimplantation diagnosis for genetic disease
- Surrogacy
- Egg donation
What are 5 stages of IVF treatment?
- Hormonal regimen: exogenous FSH (IM or SC) and pituitary suppression with GnRH agonist or antagonist, to block inappropriate LH surge; hCG given 36h before oocyte recovery
- Oocyte collection: needle passed through vaginal vault, guided by vaginal ultrasound probe, while woman sedated. Placed in incubator
- Fertilisation and incubation: on morning of oocyte retrieval, man collects sperm sample by masturbation. Prepared in culture medium then added to test tubes with oocytes. Inspected 16h later for signs of fertilisation. Embryos returned to incubator for 24-48h. Surplus embryos frozen
- Embryo transfer: transferred to uterus at 48 or 72h after oocyte collection (4 or 8 cell stage) or on day 5 at blastocyst stage
- Luteal support: luteal phase supported with progesterone suppositories for 14 days until pregnancy result known
What are the 3 aspects of the hormonal regimen stage (stage 1) of IVF?
- Administration of exogenous FSH, by IM or SC injection
- GnRH agonist or antagonist to lock inappropriate LH surge
- As release of LH blocked, hCG used as substitute, 36h before oocyte recovery
What does stage 2, oocyte collection, of IVF involve?
during superovulation treatment, each ovary enlarges to size of tennis ball and lie within 1cm of posterior vaginal fornix
therefore oocytes collected using needle passed through vaginal vault, guided by vaginal ultrasound probe, whilst woman sedated
oocytes identified easily with cumulus cell mass
placed in incubator after removal
What does stage 3 of IVF, fertilisation and incubation, involve?
- man collects sperm sample by masturbation on morning of oocyte retrieval
- sperm prepared in culture and added to test tubes with oocytes
- tubes inspected 16h later for signs of fertilisation: presence of male and female pronucleus
- pronucleate embryos returned to incubator for 24-48h with surplus embryos being frozen
What does stage 4 of IVF, embryo transfer, involve?
- embryos transferred to uterus at 48h (4 cell stage) or 72h (8 cell stage) or on day 5 at blastocyst stage
- transferring at blastocyst stage gives best chance of pregnancy
What are the current rules regarding the number of embryos transferred into the uterus in IVF and how are they likely to change?
- max 2 in <40y, up to 3 if >40y as more likely to have aneuploid embryos
- move in UK to select out women most at risk of twin pregnancy and electively transfer single embryo (eSET - elective single embryo transfer)
What does stage 5 of IVF, the luteal support stage, involve?
pituitary gland has been desensitised + not producing LH, so luteal phase supported with progesterone suppositories for 14 days until pregnancy test result known
What is the live birth rate of IVF?
24.5% per cycle
What is the most significant factor influencing success rate of IVF?
woman’s age - success rates gradually decline from 34 years old
What are 6 main factors negatively affecting IVF success?
- Increasing age of woman
- Increasing duration of infertility
- Number of previous unsuccessful treatments
- Absence of previous pregnancies
- Low ovarian reserve
- Hydrosalpinges - fallopian tube distended with fluid - ideally surgically treated before IVF
What is the cumulative pregnncy rate in women under 40 of IVF after 6 attempts?
68.4%
What proportion of couples have ‘spare’ embryos left over after the initial IVF treatment and what can be done with them?
- 25%
- can be frozen in liquid nitrogen and replaced during a subsequent natural or artificial cycle to give further chance of pregnancy
What does gamete intrafallopian tube transfer (GIFT) involve, as a method of artificial conception?
- superovulation protocol, oocyte collection by vaginal ultrasond-guided needle aspiration
- best 3 oocytes selected and laparoscopy performed
- fallopian tube cannulated and oocytes plus 100 000 sperm, returns to tube
- fertilisation occurs in fallopian tube
How commonly is gamete intrafallopain tube transfer (GIFT) performed?
few centres offer this technique due to poor success rate compared with IVF
What are 3 disadvantages of IVF?
- Risk of superovulation (OHSS) and multiple pregnancy
- Small increase in incidence of congenital anomalies amongst offspring
- Expensive
What is the key indication for ICSI?
used to treat majority of male factor infertility
What are 3 specific indications for ICSI?
- Requirement for sperm aspiration
- congenital absence of vas deferens
- obstructive azoospermia: post-infeciton or iatrogenic
- Semen analysis below reference ranges for any parameter
- Repeated failed fertilisation with IVF
What does the technique of ICSI involve?
- oocytes collected then surrounding cumulus cells removed
- smooth-ended glass pipette holds ooocyte still while sharp ultrafine pipette pieces egg and deposits one sperm + tiny amount of culture medium
- prior to injection sperm is immobilised to avoid damaging delicate structure of oocyte
- subsequent embryo transferred to uterus or frozen as per IVF
What is the success rate like of ICSI?
comparable to conventional IVF: 26.5% live birth rate per cycle
What are 5 disadvantages of ICSI?
- OHSS and multiple birth pregnancy risk
- Increased risk of genetic and developmental defects in post-ICSI pregnancies
- Proportion of male factor infertility has a genetic basis - abnormality may be passed on to next generation
- Increased risk of imprinting disorders in offspring
- Expensive
What are 5 indications for egg donation?
- Premature ovarian failure
- Gonadal dysgenesis
- Iatrogenic - surgery, radiation and chemotherapy
- Carriers of genetic disease
- Failed IVF - poor response, inaccessible ovaries, repeated failure to fertilise (with woman’s own eggs)
How does the process of egg donation compare with donor insemination?
more complicated as donors have to undergo IVF treatment to the stage of oocyte collection
What programme is available for egg donation for couples who cannot afford treatment?
egg sharing programme: infertile couple who cannot afford treatment agree to go through IVF cycle but donate half harvested eggs to recipient who funds both (raies ethical/moral issues)
What is the success rate of egg donation and why?
good success rates: higher than conventional IVF, maintained in women over age of 40 (due to young age of egg donors; on average 25y/o)
What is host surrogacy?
woman undergoes IVF treatment with embryos being transferred to another woman (‘host surrogate’) whose uterus has been suitably prepared by hormone treatment
host carries pregnancy then returns baby to commissioning couple after delivery
When might host surrogacy be used as a method of assisted conception?
functional ovaries but no uterus - due to congenital abnormality or previous hysterectomy
What does English law dictate about host surrogacy?
according to the law the mother is the one who delivers the child, therefore the commissioning couple is required to adopt the child or have a parental order, even though it may be genetically theirs
What is pre-implantation genetic diagnosis (PGD)?
- couples undergo conventional IVF treatment cycle, generally using ICSI as means of fertilisation
- embryos left until day 5 - blastocyst stage - and 5 trophectoderm cells out of approx 250-cell blastocyst are removed and analysed for specific chromosomal abnormalities using next-generation sequencing
- unaffected embryos replaced by embryo transfer in usual member
For which couples can pre-implantation genetic diagnosis (PGD) be useful?
couples who have history of repeated pregnancy failure due to genetic disese or who have had a child with a specific genetic abnormality
What is the success rate of PGD (pre-implantation genetic diagnosis)?
overall chance of success slightly lower than conventional IVF, but greater than 25% per treatment cycle
What proportion of all IVF pregnancies are twin pregnancies?
25%
What is OHSS (ovarian hyper-stimulation syndrome)?
- ovaries over-respond to the gonadotrophin injections
- more than 300 follicles may start to mature
- produces symptosm (abdominal discomfort, nausea, protein-rich ascites, pleural effusion, hypovolaemia, renal and thrombotic problems)
What are 8 symptoms/ problems associted with OHSS?
- ovarian enlargement and abdominal discomfort
- very high concentrations of oestradiol and progesterone make the woman feel nauseated
- if severe, protein-rich ascites can accumulate
- more rarely, pleural effusion may result
- sudden shift in fluid can result in hypovolaemia
- hypovolaemia may result in renal problems
- and thrombotic problems
- untreated, can be fatal
When is the only time OHSS occurs?
only if hCG injection given during superovulation
What condition increases the incidence of OHSS?
PCOS - from <1% incidence to 5%
What is the management of OHSS? 3 aspects
- fluid replacement with protein-rich fluids rather than simple crystalloid solutions
- serum electrolytes monitored as hyperkalaemia and/or hyponatraemia can develop
- thromboprophylaxs is required because of risk of VTE
How does OHSS play out depending on whether pregnancy is succesful vs not?
- usually occurs in women who conceive; can last throughout the early first semester
- if woman does not conceive, condition is self-limiting and resolves spontaneously
How much does the risk of major congenital anomalies increase with IVF?
30-40%
How is IVF thought to cause an increased risk of major congenital anomalies?
due to the underlying infertility or its determinants - couples who take longer than 12 months to coceive also show increased risk of anomalies
What are 4 types of major congenital anomalies that the use of IVF increases the risk of?
- Cleft lip
- Septal heart defects
- Oesophageal atresia
- Anorectal atresia
What is the role of the HFEA - Human Fertilisation and Embryology Act?
regulates research on human embryos, storage of gametes and embryos, and the use in infertility treament of donated gametes and embryos produced outside the body
aim that infertile couples are not exploited
What does the HFEA dictate about assisted conception treatment?
can only be legally performed in a centre licensed by the HFEA, license is renewed on an annual basis
What is the rule regarding the HFEA and all women and men who donate gametes or receive assisted conception treament?
they all have to be registered with the HFEA
What must all couples considering assisted conception be offered?
HFEA requires all couples are offered counselling by a trained counsellor
What are the NICE guidelines for offering cycles of IVF dependent on age?
- if aged <40 years and have not conceived after 2 years of regular unprotected intercourse or 12 cycles of artificial insemination (6 or more by IUI), offer 3 full cycles of IVF
- if aged 40-42 who have not conceived after 2 years of regular UPSI, offer 1 full cycle of IVF providing:
- no previous IVF
- no evidence of low ovarian reserve
- has been discussion of additional implications of IVF and pregnancy at this age
