ART Flashcards
Define infertility
Infertility defined as the failure to conceive after 1 year of regular unprotected intercourse.
Describe the causes of the infertility
- Mechanical blockage to egg and sperm meeting
- Failure of gamete production or release
- Failure of fertilisation/implantation & miscarraige
- Unknown/unexplained
Mechanical blockage to egg and sperm meeting- examples
Infection/occlusion of vas deferens or uterine tubes.
- Previous ligation for sterilisation.
- Endometriosis. (Endometriosis in the uterine tubes will block them. Chlamydia can also cause blockage of the uterine tubes)
- Congenital defects (congenital absence of the vas deferens)
Failure of gamete production or release- examples
Anovulation, maternal age, PCOS.
Azoospermia, asthenozoospermia, teratozoospermia.
Failure of fertilisation/implantation & miscarraige
Genetic factors.
Endometrial receptivity, maternal age.
What is vasectomy?
Ligation of the vas deferens
What is endometrioisis?
cell from the lining of the uterus find their way into other places in the pelvis. They will implant and respond the high E2 levels and proliferate.
Process of ART- assisted reproductive technology?
Start by Inducing ovulation with exogenous hormones.
By-passing the uterine tube (IVF).
Can make the egg and the sperm meet in a dish
Direct collection of sperm from the testis/epididymis.
Aspirate sperm
Direct insertion of the sperm into the egg (ICSI).
Donor gametes.
Donor eggs and donor sperm
Usually is a combination of the above.
What are the ways of inducing ovultion?
- Administering gonadotrophins (hormones)
- Removing negative feedback
Exogenous gonadotrophins are used to do what?
Used to treat women who are anovulatory or who have oligo/amenorrhoea.
The aim is to induce single dominant follicle.
Daily injections…monitor by ultrasound during the cycle.
How do exogenous gonadotrophins induce ovulation?
In the normal menstrual cycle there are oocytes that are recruited into the cycle by the inter cycle rise in FHS.
As they start to grow they produce estrogen. As they produce estrogen, there is negative feedback on the hypothalamus and pituitary, reducing FSH.
The reduction in FSH causes most of the oocytes to undergo apoptosis as they are FSH dependant. But the most advanced which has the most FSH receptors and started to induce LH receptors survives the fall in FSH and will go onto become the dominant follicle.
BUT sometimes the follicles are not producing enough estrogen to cause ovulation. If you were to administer exogenous gonadotrophins (mainly FSH) you can kickstart the follicle development, causing the selection of the dominant follicle.
You need to monitor this by ultrasound as if you give too much FSH you don’t get the dominant follicle selection as FSH will remain high.
Can be made via recombinant technology but also by collection from old woman’s urine and purifying. Post menopausal women have more FSH in their urine as they have low estrogen levels, so less negative feedback.
Why does removing negative feedback do?
Normally at the end of the cycle there is the death of CL and progesterone levels fall. This fall in progesterone levels results in a rise in FSH, starting the new cycle.
So if you remove the feedback estrogen is placing on the cycle you will get a natural rise in FSH
Gonadotrophin levels may be normal, but are not cyclical.
Inter-cycle rise in FSH relies on death of the corpus luteum.
ie. fall in levels of progesterone and estradiol.
There is no corpus luteum in the absence of ovulation
Cannot reduce progesterone as there has not been a corpus luteum to make any.
There are follicles in the ovary making estradiol so we can remove the negative feedback of this.
In what situations would it be good to induce ovulation by removing negative feedback?
You have a bit of FSH production, but not enough to stimulate the gonads
A few follicles producing estrogen, but not enough to cause ovulation.
So if you can remove the feedback from estrogen, we will release the negative feedback on the hypothalamus and pituitary and endogenous FHS will therefore rise.
What are the 2 ways to remove oestrogen feedback and what drugs are used?
1) Block the E2 receptor on the pituitary gonadotroph cells with SERM (selective estrogen receptor modulator) : Clomid/Clomiphene.
2) Stop E2 being made by the gonads using an aromatase inhibitor.
Drugs ending in ‘zole’ eg. Letrozole.
Testosterone -> (via aromatase) Estradiol
Outline the IVF cycle
Hypothalamic-pituitary down regulation (GnRH)
Administer exogenous GnRH
To prevent an LH surge and loss of follicles (premature ovulation)
Ovarian stimulation (monitoring follicles)
To obtain as many follicles as possible
hCG trigger
Oocyte retrieval
Fertilisation in vitro
Mix with sperm in a dish
Embryo culture 3 – 5 days
Embryo or Blastocyst Transfer
Pregnancy confirmation
Luteal phase support - Cyclogest (progesterone)
As failure will occur at each stage, we require as many eggs as possible and so hyper-stimulate the ovaries to increase follicle numbers.
Outline the IVF cycle
At the beginning of the cycle the CL has died, progesterone levels fall, this has removed the negative feedback on the pituitary and hypothalamus.
There is an intercycle rise of FSH
In the ovaries there will normally be two dozen small antral follicles. These are follicles that 3 months ago left the primordial pool and started to grow independent of LH and FSH.
When they get to the small antral stage, and start to have a fluid filled space inside, they start to express FSH receptors.
Then as soon as the next menstrual cycle starts and FSH rises, they all get recruited into the cycle and start growing.
As they grow they produce estrogen, this estrogen will act via negative feedback to reduce FSH.
The lack of FSH will kill most, but the most advanced one will have the most FSH receptors and also have some LH receptors, it will become the dominant follicle.
It will continue to produce estrogen and this will have a negative affect on FSH, which will lead to atresia.
How is a single follicle selected in each cycle- IVF?
IVF is different. Exogenous FSH is given every day
Endogenous FSH is switched off with GnRH – it is given at a constant level, shutting down the axis.
No matter how much estrogen the follicles produce, it has no effect as we are giving FSH exogenously. So all the follicles are selected, we want 10-15. Any more is dangerous. This is monitored via ultrasound.
Why do we down-regulate HPG axis using GnRH antagonist or agonist?
prevent an LH surge
Downregulate Hypothamo-pituitary gonadal axis using GnRH antagonist or agonist.
Prevents the LH spike and potential loss of the follicles- what is the significance of this?
LH surge causes resumption of meiosis 1 and initiation of meiosis 2.
Why do we require a lot of eggs?
As failure will occur at each stage, we require as many eggs as possible and so hyper-stimulate the ovaries to increase follicle numbers.
Give FSH by subcutaneous injection every day. Growth of multiple follicles.
Monitor follicle growth with ultrasound until most follicles 12–19mm.
At this point hCG trigger given (GnRH agonist or Kisspeptin may be used).
Why is LH not used?
LH is not used as it has a short half life, hCG is used as it binds to the LH receptor
Will cause meiosis 1 resumption and initiation of meiosis 2
Timing of ovarian stimulation?
36 hours allowed for completion of meiosis I and initiation of meiosis II before egg collection.
There is a window of opportunity where the eggs are fertile but they WONT be ovulated, so we can go in and collect them
Describe the process of oocyte retrieval
Transvaginal needle goes through the wall of the vagina.
Under ultrasound guidance with a trans vaginal ultrasound probe, we can take the needle right to the follicle and aspirate the follicular fluid inside, and the egg will come out with it.
Collect mature eggs from ovary using transvaginal needle aspiration under ultrasound guidance.
IVF vs IUI
