IVF cycles and medications Flashcards
Describe GnRH hormone
Decapeptide protein neurohormone containing 10 amino acids.
Half life is only 2-4minutes
Control of reproductive cycles requires constant release in a pulsatile fashion
Pathway for GnRH stimulation
Neurohormone synthesised in the ribosomes of the cytoplasm of a GnRH neuron in the arcuate nucleus then transported to the neuronal terminal (along the hypothalamic nerve tract).
Secreted from here into the blood vessel (hypophyseal portal system) to travel to the anterior pituitary where it binds to GnRH receptors on the gonadotrophs to produce FSH and LH.
Pulsatile secretion high frequency lower amplitude in follicular phase.
Lower frequency and higher amplitude in the luteal phase.
GnRH agonists name
- Leuprolide Acetate (Brand names: Lupron)
- Goserelin Acetate (Brand name: Zoladex)
- Nafarelin Acetate (Brand name: Synarel)
- Buserelin (Brand names: Suprefact, Suprecur, Buserecur)
- Triptorelin (Brand names: Decapeptyl, Gonapeptyl)
- Histrelin (Brand names: Supprelin LA, Vantas)
- Deslorelin (Brand name: Ovuplant)
- Gonadorelin (Brand names: Factrel, Gonadorelin, Lutrepulse)
GnRH antagonist names
- Ganirelix Acetate (Brand names: Ganirelix, Fyremadel, Antagon, Orgalutran)
- Cetrorelix Acetate (Brand name: Cetrotide)
- Relugolix (oral)
- Elagolix (oral)
- Linzagolix (oral)
Types of IVF cycles
Ultra-long GnRHa
Long GnRHa (follicular start or midluteal start)
Short GnRHa
Ultrashort GnRHa
Microdose flare
Antagonist (fixed or flexible)
Agonist cycles - types, pros and cons
Cochrane review found clinical pregnancy rate per cycle started was higher for the long protocol over the short and ultrashort protocols for GnRH agonist use in IVF.
So short and ultrashort (also issue of not always suppressing premature LH surge) not used.
Have moved away from the use of these cycles routinely.
Advantages: More coordinated antral follicle growth during ovarian stimulation. More flexibility of the long GnRH agonist protocol allows a more controlled organisation of egg retrievals, in such a way that a significant decrease and even avoidance of oocyte retrievals over the weekend, GnRH antagonist cycles relies on
the random occurrence of spontaneous menses
Can cause: functional ovarian cysts (particularly if long agonist commenced in early follicular phase), vasomotor symptoms, longer burdern of treatment and increased risk of OHSS compared to Antagonist cycles.
Pretreatment with COCP
With antagonist cycles the rate of live birth or ongoing pregnancy was lower in the pretreatment group (OR 0.74, 95% CI 0.58to 0.95; 6 RCTs; 1335 women; I2 = 0%; moderate quality evidence). Cochrane 2017 (Farquhar).
Try to avoid use as above review demonstrated reduction in LBR.
Was/is used as
- Helpful for scheduling and timing.
- Synchronise follicular development.
- Lowers cyst formation rates in agonist cycles.
Dose adjustment of FSH to improve outcomes in IVF cycles
Cochrane review 2024 looked at this:
Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI)
Findings:
We did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT) affected live birth/ongoing pregnancy rates, but we could not rule out differences, due to sample size limitations. Low‐certainty evidence suggests that it is unclear if ORT‐based individualisation leads to an increase in live birth/ongoing pregnancy rates compared to a policy of giving all women 150 IU. The confidence interval is consistent with an increase of up to around six percentage points with ORT‐based dosing (e.g. from 25% to 31%) or a very small decrease (< 1%). A difference of this magnitude could be important to many women. It is unclear if this is driven by improved outcomes in a particular subgroup. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU. However, the size of the effect is also unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates. It is likely that different ORT algorithms differ in their effectiveness.
Current evidence does not provide a clear justification for adjusting the dose of 150 IU in poor or normal responders, especially as increased dose is associated with greater total FSH dose and cost. It is unclear whether a decreased dose in predicted high responders reduces OHSS, although this would appear to be the most likely explanation for the results.
Adjuvant medication and IVF cycles the evidence (ESHRE guideline)
1. Metformin
2. Growth hormone
3. Testosterone
4. DHEA (dehydroepiandrostenerone)
5. Aspirin
6. Sildenafil
7. Indomethacin
- Routine use of adjuvant metformin before or during OS is not recommended with the GnRH antagonist protocol for women with PCOS. (Strong ++)
- Use of GH before and/or during OS is probably not recommended in poor responders (conditional ++)
- Use of testosterone before OS is probably not recommended for poor responders (conditional ++)
- Use of DHEA before and/or during OS is probably not recommended for poor responders (conditional ++)
- Use of aspirin before and/or during OS is not recommended in the general population or in poor responders. (strong +++)
- Use of sildenafil before and/or during OS is not recommended for poor responders (strong +)
- There is no evidence addressing the efficacy and safety of indomethacin use. This should not be used outside a research setting.
Management of thin endometrium
Thin endometrium may not impact pregnancy outcomes in ovarian stimulation treatment cycles. ⊕○○○
Most observational studies do not show a difference in pregnancy rates with thin endometrium at different cut-offs. A systematic review did not find a difference in endometrial thickness in patients who were pregnant versus not pregnant.
Canadian guideline doesn’t recommend any adjuvants as limited evidence (G-CSF may have some side effects).
Conventional options:
1. Oestradiol
2. Combined hormonal therapies
3. Growth hormone
4. Granulocyte colony stimulating factor (G-CSF)
5. Slidenafil citrate
6. Vasoactive substances - aspirin, pentoxifylline, tocopherol, L-Ariginine
Novel options:
1. Platelet-Rich plasma
2. Stem cell therapies
– BMDSCs (bone marrow derived stem cells)
– ADSCs (adipose derived stem cells)
– UCMSCs (umbilical cord mesenchymal stem cells)
3. Tissue bioengineering (Hydrogels)
Yujie Shang, Minghua Wu, Ruohan He, Yuanyuan Ye, Xiumei Sun, Administration of growth hormone improves endometrial function in women undergoing in vitro fertilization: a systematic review and meta-analysis, Human Reproduction Update, Volume 28, Issue 6, November-December 2022, Pages 838–857, https://doi.org/10.1093/humupd/dmac028
(Shang, Y.; Wu, M.; He, R.; Ye, Y.; Sun, X. Administration of growth hormone improves endometrial function in women undergoing in vitro fertilization: A systematic review and meta-analysis. Hum. Reprod. Update 2022, 28, 838–857)
(Zhang Y, Chen X, Chen S, Wei C, Li B, Wang Z, Shen X, Lin X. Intrauterine administration of G-CSF for promoting endometrial growth after hysteroscopic adhesiolysis: a randomized controlled trial. Hum Reprod. 2022 Apr 1;37(4):725-733. doi: 10.1093/humrep/deac023. PMID: 35147195).
All show limited and inconsistant efficacy.
Sildenafil
selective phosphodiesterase type 5 enzyme inhibitor
?use in thin endometrium
No benefit in standard IVF cycle.
Erectile dysfunction
Semen sample if difficult with producing a sample
GnRH antagonists MoA
Rapid competitive inhibitors of the binding of GnRH to its receptors.
Causes rapid drop in LH then FSH levels.
Produced by the significant substitution of 4-6 amino acids for unnatural “D” amino acids.
New generation antagonists are much better tolerated as they are devoid of the histamine releasing properties of early products.
GnRH agonist MoA
Reversibly block pituitary gonadotrophin secretion
Initial flare up phase (drains pituitary of FSH/LH) followed by pituitary desensitisation through GnRH receptor internalisation in pituitary.
Down regulation - not easily reversed and longer term.
Matters less if a patient misses a dose cf antagonists.
GnRH antagonist versus agonist cycles
Cochrane review (73 RCTs 12 200 women)
No difference in LBR (OR: 1.02, 95% CI: 0.85-1.23).
Reduction in incidence of severe OHSS with antagonist protocol (0.61, 95% CI: 0.51-0.72).
Cycle cancellation to prevent OHSS was used less frequently in the antagonist group (OR: 0.47, 95% CI: 0.32-0.69).
Cycle cancellation due to poor ovarian response was more frequent in women who received antagonist as compared to those who received the agonist (OR: 1.32, 95% CI: 1.06- 1.65).
4 phases of IVF cycle
Manipulation of the HPO axis
Controlled ovarian hyperstimulation
Gamete maturation
Luteal phase support
LH
Short half life
Similar regulation to FSH but more reliant on GnRH pulsatility than sex steroid feedback.
In males very important in Leydig cell function of T production
Different triggers
SERMs
Selective estrogen receptor modulators are a class of drugs that act on estrogen receptors.
Actions are different in various tissues, allowing them to selectively inhibit or stimulate oestrogen-like action in various tissues.
First gen –
Clomiphene, used as OI, Anti-oestrogenic – breast, uterus. Oestrogenic – bone, lipids, SHBG, IGF1
Tamoxifen, used for breast cancer as endocrine therapy - anti-oestrogenic – breast, vagina. Oestrogenic – bone, lipids, SHBG, IGF-1, uterus.
Second gen –
Raloxifene - Anti-oestrogenic – breast, vagina. Oestrogenic – bone, lipids, SHBG, IGF1. Variable uterine effects.
Third gen –
Bazedoxifene - Anti-oestrogenic – breast, uterus. Oestrogenic – bone, lipids, SHGB, IGF1, variable vaginal effects.
