PPOS

Question 1

Mechanism of pituitary suppression by progestin

Answer 1

High dose or prolonged exposure to progestins slows the GnRH pulse frequency via the KNDy neurons by negative feedback and reduction in kisspeptin. This then causes a drop in the LH pulse frequency, reduces mean LH plasma concentration and prevent the LH surge

Question 2

Different regimens of PPOS

Answer 2

Fixed progestin regimen - started simultaneously with the gonadotrophins.
Flexible progestin regimen - started when leading follicle reaches 13-14mm.
Most commonly studied is MPA 10mg once daily.
All cycles are freeze only as endometrium will be dysfunctional/not synced

Question 3

Evidence for oocyte donors

Answer 3

cheaper
Not planning fresh transfer
Oral versus injectable

Question 3

Physiology of benefit of PPOS in PCOS and evidence

Answer 3

-High tonic secretion of LH during the follicular phase
- Hyperandrogenemia
- Increased intrafollicular androgens
(can all lead to poor oocyte quality)

Progestin suppresses LH secretion from early follicular phase.
OHSS, Freeze all cycle- well suits PPOS.

A meta-analysis of RCTs from Frontiers of Endocrinology in 2021 showed no difference to premature LH surge, OHSS, clinical pregnancy rates and live birth rates in PCOS between PPOS and GNRH antagonist cycles

Question 3

People who might benefit from PPOS

Answer 3

Oocyte donors,
fertility preservation (elective or oncology),
those needing freeze only cycle (PGT-A, PCOS)
Those self funding IVF (must cheaper)
Some research showing benefit in DOR group as it prevents early LH surge which can occur in 8% of cycles (but not ideal candidates for freeze only regimens)

Question 4

Evidence and physiology of potential benefit of PPOS in DOR

Answer 4

premature LH surge occurs in 8% of antagonist cycles - more common in those with DOR, advanced age, reduced response to gonadotrophins.

Meta-analysis showed lower rates of premature LH surge and similar live birth rates between the two cycle types.

Question 5

Benefits of MPA as progestin in PPOS

Answer 5

Use 10mg per day
Moderate-strong progestin action
Small androgenic effect
Does not interfere with the measurement of endogenous progesterone

Question 6

Long term safety of PPOS

Answer 6

Still under investigation
Does not appear to be an increased risk of aneuploidy
?longer time to cleavage and blastocyst development
Potential concerns around developing follicles being exposed to high levels of progesterone.
Similar congenital anomaly rates to Antagonist protocol, no difference in neonatal outcomes reported

Question 7

Is PPOS cost-effective

Answer 7

Lower cost of progestin compared to GnRH analogues, especially GnRH antagonist.
Cost of cryopreservation and thawing, monitoring ET cycles
Evans et al, 2019 RBMO- “PPOS would only be more cost effective when a fresh ET would not be attempted”.

Question 8

Cochrane review 2023

Answer 8

Little or no differences in LBR may exist when comparing MPA 4 mg with GnRH agonists in normo‐responders. Oocyte Pick-up Cancellation Rate (OPCR) may be slightly increased in the MPA 4 mg group, but MPA 4 mg reduces the doses of gonadotropins in comparison to GnRH agonists.

Little or no differences in OPCR may exist between progestogens and GnRH antagonists in normo‐responders and donors. However, micronised progesterone could improve by 2 to 6 MII oocytes.

When comparing one progestogen to another, dydrogesterone suggested slightly lower OPCR than MPA and micronised progesterone, and MPA suggested slightly lower OPCR than the micronised progesterone 100 mg. Finally, MPA 10 mg suggests a lower OPCR than MPA 4 mg.

There is uncertainty regarding the rest of the outcomes due to imprecision and no solid conclusions can be drawn.