How do we choose the best progesterone to support the luteal phase Prof. Dr. Herman Tournaye MSD Fertility Regional Stand Alone Scientific Symposium Lisbon
In the last 3 years the speaker or the speaker s s institution received educational, consulting and/or research grants from Flanders Fund for Scientific Research, Research Fund Willy Gepts Ferring, MSD, Besins, Roche,Gedeon- Richter, Cook, Teva, Origio, ObsEva, Merck and Abbott
The window of implantation trmbaby.com
Progesterone in hyperstimulated fresh-et IVF Jones H Hum Reprod 1996
Need for luteal phase support (LPS) in IVF
Online survey on LPS (2009 and 2012)
Why do we refrain from using hcg? Ongoing Pregnancy Rate
Why do we refrain from using hcg? OHSS Rate
Low-dose hcg for LPS
All progesterones are derived from diosgenin (discorea root or yam ) 10 tons of yam tubers to synthesize 3 kilograms of progesterone via Marker degradation chemically identical to progesterone of ovarian origin (empiric formula, C21H30O2; molecular weight 314.47)
Best dose of progesterone? No agreement on standard dose to be used even after more than 40 years IM route: 12,5-100 mg/day oral route: 600-1200 mg /day (micronized P4) 20-40 mg /day (dydrogesterone) vaginal route: pessaries: 400 mg /day (e.g. Ellios ) tablets: 200-900 mg /day (e.g. Endometrin ) suppositories: 200-400 mg /day (e.g. Cyclogest ) capsules: 200-900 mg /day (e.g. Utrogestan ) gel: 90-180 mg /day (e.g. Crinone )
How much progesterone?
Parenteral progesterone IM route: SC route: difficult to self-administer painful (warm up oil solution) occasional sterile abscess (oil vehicle) occasional allergic reaction (oil vehicle) daily injections new kid on the block more easy to self-administer daily injections
Other parenteral options for LPS
Goodlife Pharma promotional leaflet Subcutaneous progesterone Water-soluble formulation of progesterone (25 mg/d SC): molecular complex of progesterone and starch permits solubility in water of the otherwise only lipid-soluble progesterone Zoppetti et al., 2007
Subcutaneous progesterone SC P4 Vaginal P4 Study events total events total weight risk difference M-H, Fixed, 95% CI Lockwood 2014 93 319 100 321 45,0% -0,02 [-0,09, 0,05] Baker 2014 163 392 174 390 55,0% -0,03 [-0,10, 0,04] Total (95% CI) 711 711 100% -0,03 [-0,08, 0,02] Total events 256 274 Heterogenity: Chi 2 = 0,04, df = 1 (P = 0,84); I 2 = 0%, Test overall effect: Z = 1,01 (P = 0,31) -0,2-0,1 0 0,1 0,2 Favors IV P4 Favors SC P4
GnRH agonists as LPS
GnRH agonists as LPS
Non-parenteral routes vaginal route: oral route: vaginal discharge perineal irritation and itching higher risk fungal infection better patient comfort (compliance?) fewer side effects better compliance? culturally better accepted
aaainjurycenters.com
Why doctors prefer intravaginal progesterone PNAS 1997 Model: extra-corporal utero-vaginal perfusion model with radiolabeled drugs Conclusion: Our experiments show that a fraction of the vaginally administered progesterone reaches the uterus before being transported elsewhere in the body
Why doctors prefer intravaginal progesterone www.medscape.org
Oral progesterone: want it flat or curved? Micronisation produces micronised progesteron light exposure creates a curved retrosteroid structure: dydrogesterone or synthetic P4
Oral progesterone: want it flat or curved? Dydrogesterone: light-exposed curved or synthetic progesterone has ~5.6 times higher oral bioavailability than micronized flat natural P4 requires a 10 20 times lower oral dose (less side effects) Bioavailability Dose 28% oral dydrogesterone <5% oral micronized progesterone 4 8% vaginal micronized progesterone 10 mg oral dydrogesterone 100 200 mg oral micronized progesterone 200 mg vaginal micronized progesterone 1. Stanczyk FZ, et al. Endocr Rev 2013;34(2):171 208; 2. Paulson RJ, et al. J Clin Endocrinol Metab 2014;99(11):4241 4249; 3. Schindler AE, et al. Maturitas 2008;61(1 2):171 180;
'Synthetic or curved oral vs flat micronised progesterone Ongoing Pregnancy Rate
Oral dydrogesterone is non-inferior to micronized vaginal progesterone Fertil Steril! 2018;109:756 62
Oral dydrogesterone is non-inferior to micronized vaginal progesterone
'Synthetic' oral vs micronised P4: Patient dissatisfaction
What about FRET? * *mnc-fet : modified natural cycle FET (hcg trigger) tnc-fet: true natural cycle FET
What about FRET?
Conclusions (1) Luteal supplementation is (probably) necessary in hyperstimulated fresh-et IVF Luteal supplementation in natural cycle FRET probably not indicated Progesterone to be preferred over standard hcg regimens Dose? One cannot see the forest for the trees... Administration route? Doctors do not trust oral administration Patients seem not to like intravaginal P4
Conclusions (2) Vaginal route is the current gold standard Evidence shows synthetic oral route is at least equally effective Oral route may imply better patient comfort and less adverse effects (?) Oral dydrogesterone may become the gold standard