Subfertility Flashcards
recall the mode of action, efficacy, indications, contraindications and complications (and their management) of subfertility therapies (incl. intrauterine insemination (IUI), in-vitro fertilisation (IVF), intra-cytoplasmic sperm injection (ICSI) and ovulation induction)
Define subfertility.
No universal definition but usually failure to conceive after 12 months of regular unprotected intercourse
How common is infertility?
Infertility affects around 1 in 7 couples.
What is the difference between primary and secondary infertility?
Primary - have never conceived together
Secondary - previously conceived (either may have conceived in previous relationship)
What are the conception rates for couples who have regular sex for 1year and 2 years?
Of couples who have regular sexual intercourse:
70% will conceive within 6 months
80% within 12 months
90% within 24 months
With regular intercourse, what is the chance of a couple conceiving in a single menstrual cycle?
18-20% i.e we are relatively infertile
What is the most important factor affecting fertility?
Female age - fertility falls sharply after age 36 years and further dips after age 40 years. This is due to decline in quality and quantity of eggs
Both frequency and timing of sexual intercourse also impact strongly on the chance of conceiving naturally.
What is the effect of age on male fertility?
Male age is also an important factor; semen quality
tends to fall in men over the age of 50, while frequency of intercourse tends to fall in men over the age of
40.
What are the most common causes of infertility in a couple?
- male factor 30%
- unexplained 20%
- ovulation failure 20%
- tubal damage 15%
- other causes 15%
What are the female causes of subfertility? Give an example of the aetiology of each.
- Ovulatory disorders e.g. PCOS
- Tubal damage e.g. in PID or endometriosis
- Uterine disorders - e.g. fibroids especially if large (>5cm) + submucosal; endometrial polyps and Asherman’s syndrome
Other:
- Decreased ovarian reserve and age
- Lifestyle and PMH - smoking, DM, epilepsy, thyroid, bowel disease
What are the male causes of subfertility? Give an example of the aetiology of each.
- Compromised sperm number e.g. orchitis or epididymitis where there is damage to spermatogonial cells or stores; pelvic radiotherapy; torsion
- Medical conditions and lifestyle e.g. DM, occupational exposure
- Erectile difficulties or ejaculation problems
- Genetic
What are the genetic aetiologies of male subfertility? What investigation can be done for this?
- Kleinfelter XXY or other aneuploidies of sex chromosomes;
- Structural abnormalities of autosomes like inversions, deletions or balanced translocations;
- Microdeletions of the azoospermic factor (AZF) regions of Y chromosome –> low sperm count and motility
Investigation: Karyotype
How long do sperm vs eggs survive in the female reproductive tract?
Eggs are thought to be fertilizable for about 12–24 hours
postovulation, while sperm can survive in the female reproductive tract for up to 72 hours.
What two basic investigations should be done for couples who are infertile?
- semen analysis
- serum progesterone 7 days prior to expected next period. For a typical 28 day cycle, this is done on day 21.
Only done iafter 12 months of infertility.
What progesterone level indicates that ovulation is occurring in the female?
< 16 nmol/l = Repeat, if consistently low refer to specialist
16 - 30 nmol/l = Repeat
> 30 nmol/l = Indicates ovulation
What day 21 progesterone level would prompt referal to fertility specialist?
< 16 nmol/l
This should be consistent on a repeat
When should sperm analysis be performed? How quickly must the sperm reach the lab? When can it be repeated?
Between 3-5 days of abstinence from sex
Within 1 hour
Can only be repeated after 3 months to allow spermatogenesis to occur (sometimes abnormal initially due to insults such as viral infection)
What are the parameters assessed in sperm analysis? What is the normal sperm number per ml?
- volume > 1.5 ml
- pH > 7.2
- sperm concentration > 15 million / ml
- morphology > 4% normal forms
- motility > 32% progressive motility
- vitality > 58% live spermatozoa
NB: different ranges exist in different guidelines. These represent results at the 5th centile, as done by WHO.
What are some key counselling points to give subfertile couples?
- Folic acid
- Aim for BMI 20-25
- Advise regular sexual intercourse every 2-3 days (without use of lubricants which are spermicidal)
- Reduce smoking and alcohol
How can stress affect fertility?
Direct influence on the hypothalamic-pituitary-ovarian axis interfering with regular ovulation and may reduce conception by reducing libido and frequency of intercourse.
What further investigations can be done in females for subfertility?
Blood hormone profile
- FSH
- Oestradiol
- LH
- Anti-Mullerian hormone - used as a marker and comparison point as it does not change throughout the menstrual cycle in respose to gonadotrophins. It is produced by granulosa cells of the ovarian follicles
- If cycles are irregular measure: TFTs, prolactin, testosterone
STI screen - HIV, hep B, hep C if assisted reproductive technology (ART) is being considered
TVUSS - assess uterine size and shape, fibroids, ovarian size, position and morphology, antral follicle count (AFC) to assess ovarian reserve.
Hystersalpingiography (HSG) - assess tubal patency using X ray or other methods using USS or synography. Although tubal patency does not indicate function. Only done if there are risk factors for tubal damage.
What antral follicle counts represent a poor vs good response?
Antral follicle count is an important parameter of ovarian reserve
< 4 = poor response
16+ = good response
Summarise the medical and surgical managements for subfertility.
What are the indications for ovulation induction?
Ovulatory problems e.g. in PCOS
What are the methods used for ovulation induction?
Clomiphene citrate (1st line)
If clomiphene reistant consider:
- Adding metformin
- Aromatase inhibitors (not licensed for this use)
- Injectible gonadotrophins
Alternatively:
- Laparoscopic Ovarian Drilling (LOD) - for unknown reasons, passing electrical energy through polycystic ovaries can cause ovulation. But done under GA.
What is the MOA of clomiphene citrate in OI?
- –> binds oestrogen receptors in the hypothalamus and pituitary
- –>blocks normal feedback loops of oestrogens
- –> surge in gonadotrophin release
- –> stimulation of ovary to recruit more follicles for maturation
What is the efficacy of ovulation induction for subfertility?
70% of those on clomiphene will oculate and ~50% of these will be pregnant within 6 months of trying
What are the complications of ovulation induction and how are these managed?
12% risk of multiple pregnancy
Management:
- Monitor with USS to track growth of follicles, identify time of ovulation and reduce risk of multiple pregnancy
What surgeries may be performed to help subfertility?
- Ablation of endometriosis
- Tubal potency testing
- Removal of hydrosalpinges (associated with improvement in IVF)
- Myomectomy
What are the indications for intrauterine insemination (IUI)?
- Mild endometriosis
- Mild male factor subfertility
- Couples who do not have intercourse, single women or same sex couples using donor sperm
What is the efficacy or IUI?
Success rate of IUI is 10-20% per treatment cycle
What are the steps invovled in IUI?
- May begin with SC injections of exogenous FSH to stimulate the ovaries to produce 2-3 mature follicles (stimulated IUI)
- US tracking of follicles to avoid over- or understimulation
- SC injection of hCG triggers ovulation and timing of insemination (NB: hCG mimic LH surge due to cross-over of their alpha-subunits)
What are the complications of IUI and their management?
Over or understimulation of follicles by daily exogenous FSH injections.
Managed by monitoring with USS.
What are the indications for in-vitro fertilisations in subfertility?
- Tubal factor subfertility (original indication when IVF was designed)
- Endometriosis
- Failed ovulation induction and IUI
- If donor eggs are needed
What are the steps carried out in IVF?
- Pituitary down-regulation using GnRH - blocks LH surges and premature ovulation.
- Controlled ovarian stimulation - daily SC gonadotrophin injections to cause follicle recruitment. Monitor with TVUSS for timing of egg collection. Ideally 15 follicles should be recruited. Measure endometrial thickness.
- Inihibition of premature ovulation - GnRH agonist to blcok oocyte maturation and ovulation so that scheduled egg collection can take place
- hCG trigger - replicates LH surge to allow for eggs to be collected
- Egg collection - at 37 hours post hCG trigger; done under anaesthesia where needle is inserted into ovaries under TVUSS control and follicular flui aspirated from each follicle that contains an oocyte
- Fertlisation - insemination of 100,000 sperm in petri dish with an egg or isolation of specific sperm prior and their injection into the cytoplasm (intracytoplasmic sperm injection ICSI)
- Embryo culture - incubation iundr strict condition of temp, pH, humidity and oxygen.
- Embryo transfer - occurs at days 2, 3, or 5 of development. Most successsful when at the blastocyst stage at time of implantation. Transferred using a soft plastic catheter into the uterus under USS. Choice of how many are transferred depends on couple and clinician.
- Embryo cryopreservation - for future use
- Luteal phase support by progesterone supplementation- prevents premature LH surge which would reduce ability of corpus luteum to produce progesterone.
- Pregnancy test done at 14 days post embryo transfer
Where can patients get information on statistics on IVF and clinic success rates?
HFEA website - they provide guidelines and statistics for patients and clinicians , and inspect clinics to ensure they adhere to mutually agreed quality standards
What is the fertilisation success rate of intracytoplasmic sperm injection (ICSI) vs IVF?
IVF = 60%
ICSI = 70%
This is checked the next day after fertilisation to confirm.
What is the success rate of IVF in achieving pregnancy?
Female <35 years = 40-45% from a single cycle
Female >40 years = <15%
…and remember that IVF does not preclude patients from normal complications of pregnancy like miscarriage and ectopic pregnancy.
What is the most significant complication of IVF treatment?
Ovarian hyperstimulation syndrome (OHSS) - occurs in 1-3% of cases
How do patients with OHSS present?
If severe:
- ascites,
- enlarged multifollicular ovaries,
- pulmonary oedema
- coagulopathy.
What is the RCOG classification for severity of OHSS?
Mild
- Abdominal pain
- Abdominal bloating
Moderate
- Mild +
- Nausea and vomiting
- Ultrasound evidence of ascites
Severe
- Moderate +
- Clinical evidence of ascites
- Oliguria
- Haematocrit > 45%
- Hypoproteinaemia
Critical
- Severe +
- Thromboembolism
- Acute respiratory distress syndrome
- Anuria
- Tense ascites
What treatments is OHSS likely to occur after?
- gonadotropin or hCG treatment.
- rarely after clomifene
What is the pathophysiology of OHSS?
It is thought that…
- The presence of multiple luteinized cysts within the ovaries
- –> high levels of not only oestrogens and progesterone but also vasoactive substances such as VEGF.
- –> increased membrane permeability and loss of fluid from the intravascular compartment
What is the management of OHSS?
- Admission to hospital
- Manage under specialist tem
NB: use of low-dose stimulation, ultrasound monitoring, GnRH antagonist protocols, GnRH agonist triggers, and a more liberal freezing policy have significantly reduced the incidence of OHSS,
In the case of azoospermia (e.g. due to blockage of the vas deferens or testicular problems) what can be done?
Surgical sperm retrieval - fine needle is inserted
into the epididymis or the testicular tissue to obtain sperm or testicular tissue with sperm respectively. These can then be used in IVF/ICSI
What are the indications for preimplantation genetic testing?
Couples who carry a genetic disease (but who are fertile) may choose to use IVF and preimplantation genetic diagnosis (PGD) to avoid an affected pregnancy
. These patients may previously have had affected children or terminations for an affected fetus.
How is preimplantation genetic testing carried out?
IVF will create multiple embryos.
These embryos can then be genetically tested for the relevant disease, by the removal of several cells at the blastocyst stage that are tested and taken to reflect the genotype of the remaining embryo.
Only embryos free of the disease are transferred into the uterus.
Can PGD be used for sex selection?
No this is illegal in the UK but available controversially in many other countries
What types of mutations is PGD used to diagnose?
- most monogenic diseases
- translocations
Some testing has also been done to detect chromosomal aneuploidy in embryos in patients having IVF, to select the embryos with the greatest implantation potential. This remains controversial and subject to research trials
