LECTURE 30 - infertility Flashcards
What are the requirements for fertility?
- production of normal sperm (maturation)
- production of normal eggs
- sperm traverse the female tract to reach egg - capacitation must occur within time constraints
- sperm penetrate and fertilise the oocyte
- implantation of embryo into uterus
What is the clinical definition of infertility?
Failure to conceive after regular unprotected sexual intercourse for 2 years in the absence of known reproductive pathology
What are the main female factors that cause infertility?
- Ovulatory disorders (~60%)
- Disorders of the female tract
- Implantation, growth and development (during pregnancy)
What is tubal obstruction?
- one of the most common disorders of the female tract
- usually secondary consequence of pelvic infection (blocks uterine tubes)
- increased incidence after STIs
- scarring and adhesions in uterine tubes –> impaired oocyte and sperm transport
- diagnosed by HysteroSalpingoGram (HSG), Hystero Contrast Sonogarphy (HyCoSy) or laparoscopy
What is endometriosis?
- endometrial tissue growth in ectopic sites; uterine tubes, ovary or peritoneal cavity –> scarring/ adhesions
What is a separate or bicornuate uterus?
- type of uterine abnormality
- congenital anomaly
- divided uterus
- uterus may be partial or incomplete
- can cause miscarriage, pre-term birth, malpresentation
- can be surgically removed or wait and have C-section
What are uterine leiomyomas (fibroids)?
- affects 1/3 people
- benign smooth muscle tumours driven by oestrogen (as more common in obese people and during menopause they normally leave)
- develop within uterine wall
- can lead to menorrhagia, subfertility, miscarriage
- treated with hormone therapy or surgery
What can occur in males to cause infertility?
- Production of spermatozoa
- Transport of spermatozoa through male tract
- Transmission of sperm to the female
- Sperm function in the female tract
How are male problems with infertility diagnosed?
- most through semen analysis
- a few violent bloody analysis (testosterone, FSH/LH)
- genetic screening
- many cannot be diagnosed
What can be deduced from semen analysis?
- Normozoospermic = >15 million spermatozoa/ml, >32% rapid forward progressive motility, >4% normal morphology
- Oligozoospermic = <15 million spermatozoa/ml
- Asthenozoospermic = <32% progressive motility
- Teratozoospermic = <4% spermatozoa with normal morphology
- Azoospermic = no sperm in ejaculate
How can issues with production of spermatozoa arise?
Genetic = Y chromosome deletions (10% of men presenting with severe oligozoospermic or azoospermic)
Cryptorchidism (1/100) = failure of testes to descend, reduced spermatogenesis and increased risk of testicular cancer
Acquired = trauma, orchitis (mumps), lifestyle (e.g. alcohol/smoking)
How can failure in transport in male tract occur?
- Azoospermic semen can have 2 causes, obstructive (something stopping sperm going from testes to ejaculate) or non-obstructive (doesn’t produce any sperm)
Can occur from
- post infection (bilateral epididymal/ vas occlusion)
- congenital bilateral absence of vas deferens (CBAVD)
What is CBAVD?
Congenital Bilateral Absence of Vas Deferens
- improper development of vas deferens
- linked to CFTR gene mutations
- > 95% of men with CF have CBAVD
- 85% of men with CBAVD are heterozygous for CFTR mutation - no or mild symptoms of CF
What issues can arise in failure in transmission in males?
- erectile dysfunction (1/10 men)
- ejaculatory dysfunction (retrograde ejaculation or defects of accessory sex glands that produce seminal plasma)
What happens in normal ejaculation and what is retrograde ejaculation?
Normally
- contraction of musculature of prostate, seminal vesicles and vas deferens –> seminal fluid and sperm –> urethra = emission
- contraction of urethral and pelvic floor musculature –> ejaculation
- urethral sphincter closes bladder neck
Retrograde
- incompetence of urethral sphincter
- ejaculation into bladder
- ejaculate volume nil or low
- confirmation in urine
What is unexplained infertility?
- 15% of cases
- normal frequency and timing of unprotected intercourse
- no obstructions or malformations in male or female genital tracts
- ovulation confirmed
- normozoospermic
What is slight assistance?
- for anovulation (when ovaries do not release oocyte during menstruation)
- ovulation induced with timed intercourse
- clomiphene: oral anti-oestrogen, take for 5 days at start of cycle, removes inhibitions –> increase of FSH
- need to monitor number of follicles
What is IUI?
Intrauterine insemination
- injection of prepared sperm into the uterine cavity
- important sperm are washed away from seminal plasma as they are rich in prostaglandins which induce uterine contractions
Who might use IUI?
- people unable to have sexual intercourse
- people who need sperm washing e.g. HIV patients
- same-sex relationships
- not for unexplained infertility
Should work because - bypasses cervical mucus
- timed perfectly
- fairly non-invasive
Success rate = 5-10%
- ~10% multiple pregnancy rate
What is IVF?
In vitro fertilisation
- 50-100,000 capacitated, motile sperm added to an oocyte and left to fertilise
What is intracytoplasmic sperm injection (ICSI)?
- used when IVF fails and male factor infertility
- very invasive
- sperm injected into cytoplasm of egg
- 1 sperm per egg
- epididymal or testicular sperm
What is ovarian stimulation?
Used to increase numbers of egg to increase chance of fertilisation for IVF of ICSI
- aim for 10-15 eggs
1. Pituitary suppression (GnRH agonist/ antagonist) - agonist: initially stimulatory flare followed by down regulation of GnRHR - suppression of Gn release
- antagonist: immediate suppression of gonadotrophin release
2. Ovarian stimulation (FSH). Aim = multi-follicular development
3. Monitoring of follicular growth
4. hCG triggering (cf LH surge). Aim = final egg maturation
5. Egg collection
6. Insemination/injection
7. Embryo culture (day 2/3 or day 5/6)
8. Embryo transfer (1 or 2 embryos)
9. Luteal support from artificial progesterone (cf. corpus luteum function in natural pregnancy)
What is blastocyst culture and why is it used?
- culture of embryos in vitro for 5-6 days
- development of the blastocyst passes significant hurdles
- switching on of embryonic genome
- past stages of totipotency to first differentiation
- the ones that make it to blastocyst will lead to higher pregnancy rates
What are the risks of IVF/ICSI?
- multiple pregnancies
- very invasive for women
- ovarian hyperstimulation syndrome (OHSS)
- excessive response to fertility drugs
- multiple follicles produce VEGF - vascular permeability –> fluid accumulation in the peritoneal/thoracic cavity
- occasionally fatal
- risk of congenital abnormalities/long-term maternal risks, imprinting disorders
- inheritance of male infertility (morals?)
What is Preimplantation genetic testing (PGT)?
- removal or one or two cells from the early embryo for genetic analysis
- sex-linked diseases, translocations, single gene disorders e.g. Huntington’s, CF
- only healthy embryos are transferred
