Slides on use of progesterones in Infertility treatments - In vitro fertilization (IVF), Intrauterine Insemination (IUI) and natural cycle treatments

2. ‘PRO – GEST – ER – ONE’
Crucial factor for
 Successful implantation &
 Continuation of early Pregnancy

3. SOURCE OF PROGESTERONE
 Corpus luteum
 In Pregnancy
Corpus luteum- before 7 wks. Gestation
Trophoblast - beyond 9 wks.
Both Sources - bet. 7 – 9 wks. of
gestation (Luteo-placental shift)

4. PROGESTERONE
ADMINISTRATION
 Improves endometrial receptivity -
inducing secretory changes of
endometrium in the luteal phase
 Addition of progesterone in
infertility treatment -
well established clinical practice.

5. PROGESTERONE ADMINISTRATION IN
INFERTILITY TREATMENTS
 Normo-ovulatory women stimulated
with cc
 In PCOS & anovulatory cycles
 In superovulation regimens for IUI
 In IVF – ET Cycles

6. IN NORMO-OVULATORY &
UNEXPLAINED INFERTILITY
Beneficial role of O.I & IUI
has been established
Antiesterogens, cc -
most popular drugs for
stimulation

7. NORMO–OVULATORY WOMEN – CC STIMULATION
CC occupies Hypothalamic ER longer than Estrogens
Greater luteal LH conc. LH pulse frequency
Significant of maintenance of CL
serum E2 & prog
Lengthening of
luteal phase
Routine supplementation with prog. does not seem to
improve PR in Normo-ovulatory stimulated with CC.
(P. Devroey et al, 2010)

8. IN PCOS – PROGESTERONE
SUPPLEMENTATION
 Granulosa cells -
Inherent abnormality to respond to
Gonadotrophins & steroidogenesis
 Luteinised granulosa cells -
Produce decreased amounts of Progesterone
 In PCOS -
Inherent benefit regardless of medication
used for O.I.

9. SUPER OVULATION CYCLES
 FSH/HMG are far more efficient than anti-estrogens
 Objective is to achieve development of multiple follicles
Multiple corpora lutea
Secrete supraphysiological conc.of E2 & Prog. In luteal phase
negative feed back on H-P-axis
Inhibit production of Luteal LH
 Luteal phase support required to improve clinical outcome

11. IVF - ET
 IVF – ET mainstay of infertility treatment
Involves controlled ovarian Hyperstimulation medications
Several mature follicles
Supraphysiological levels of E2 in follicular phase
Premature endogenous LH surge
Premature release of oocytes
 Prevention of premature LH surge -
by adding GnRH-a (agonists / antagonists)

12. INADEQUATE LUTEAL PHASE
– COH FOR IVF - ET
 GnRH-a suppresses endogenous
gonadotrophins, particularly LH
 After Down-regulation-pituitary slow to recover
(approx. 2 – 3 wks.)
 Exogenous Gonadotrophins & multiple follicles
release supraphysiological levels of E2
 Trauma inflicted on ovarian follicles during OR
reduced steroidogenesis of C.L.

13. IN IVF - ET
 Univeral practice of administering large
amounts of exogenous prog. to support
luteal phase
to achieve high & steady levels of prog.
to support implantation & early pregnancy

14. PRACTICES FOR LUTEAL
SUPPORT
 Exogenous administration of progesterones
and/or
 Stimulating Endogenous Prog. Production
by HCG inj

16. VARIOUS ROUTES – PROGESTERONE
ADMINISTRATION
 Oral
 Vaginal
 Parenteral

17. ORAL PROGESTOGENS
 Synthetic Progestins
 Developed to resist degradation by gut & liver
 Dydrogesterone
 10 mg. tabs
 2 – 3 times a day
Main advantage –
simplest route of administration

18. ORAL PROGESTINS -
DISADVANTAGES
 Inadequate circulating conc., even when
provided in micronized form
 Variable plasma concentrations
 First pass metabolism
>90% prog. metabolised during
First - Hepatic - pass
Reduces efficiency &
Results in high levels of metabolites

19. ORAL PROGESTINS – SIDE
EFFECTS
 Gastritis, nausea, Headaches
 Weight gain, Premenstrual symptoms
 Undesirable lipid changes
 Somnolence & Dizziness
Caused by 5 ∞ - reduced compounds
Comparable to Benzodiazepines
 May cause psychological effects

21. ORAL PROGESTINS
Several randomized Trials show
Significantly lower implantation &
pregnancy rates
Higher miscarriage rates
compared to IM/vag.Progesterones.

22. LUTEAL SUPPORT –
PARENTERAL ROUTE
IM HCG Inj.
IM Progesterone in Oil

23. IM - HCG
 Doses of 1,500 – 2,000 U
from ET with 2 days gap
Advantage –
 Better compliance
 Less painful

24. IM–HCG – ‘COCHRANE REVIEW’
 HCG vs. No treatment –
significantly higher PR in HCG
treated compared to no Rx
 HCG vs. IM – P4
Similar PR in both groups

25. IM PROGESTERONE IN OIL
Given as deep IM (Gluteal) inj
In a dose of 50 – 100 mg/d
Rapidly absorbed & produces
measurable serum levels with in
2 – 8 hrs.

26. DISADVANTAGES OF IM – P4
 Uncomfortable & Painful
 Injury to sciatic nerve
 Allergic reactions to oil in vehicle
 Inflammatory reaction & abscess
 Reported cases of ac, Eosinophilic
pneumonia
 No established dosing standard
 Requires aid

27. VAGINAL PROGESTERONES
 Micronized progesterone vaginal inserts
100 – 600 mg/d
 Bioadhesive gel – 90 mg/d
Comparable to 50 mg/d IM
Endometrial prog. conc. reaches steady
with in 5 hrs.

28. VAGINAL PROGESTERONES –
MECHANISM OF ACTION
 First – Uterine – pass effect :-
Prog. Reaches Uterus directly, without first
passing through the liver, by
i. passive diffusion
ii. Passage through cervical lumen
iii. Transport via venous & lymphatic circulation
iv. ‘counter-current’ vagina to Uterus transport –
exchange between Utero-vaginal veins &
arteries
 More Physiological form
 High conc. of prog. In Ut. Tissue
 Associated with synchronous endometrial
transformation

29. IM VS. VAG. PROGESTERONES
 Serum P levels following
IM dosing –
 Typically supra
physiological &
 Easily maintained
 Serum levels do not
predict –
subsequent P levels
in endometrial tissue
 Reliable ‘Uterine –
Targeting’
 Nearly 10-fold higher
endometrial conc. of
prog. after vag.
administration as
compared to IM
 ‘First – Uterine – Pass’
effect
 Minimal systemic
absorption &
negligible circulating
levels of P.

30. COMPARISON OF EFFICACY
OF VAG. PROG./IM – P4
 Treatment outcomes no different
 Serum progesterone levels during luteal
phase - higher with IM - P4
 Significantly higher levels with vag.
Progest. after implantation & in
early wks. of preg.

32. Mean serum progesterone levels during the luteal phase
before & after pregnancy test day (day 18 following OR)
0.00
20.00
40.00
60.00
80.00
100.00
120.00
Progesterone
levels
(ng/ml
)
Vaginal prog., Endometrin
Intramuscular Prog.
Mean prog. Levels between
Day 3 to day 18 after OR
Mean progesterone levels
Following day 18 after OR
I I
I
I

33. VAGINAL PROGESTOGENS -
ADVANTAGES
 Patient convenience & Tolerability
 Easier to use
 Less painful
 Less time consuming &
 Associated with few discomforts
 Mainly self administration

34. DISADVANTAGES – OF –
VAGINAL PROGESTERONES
 Messy vaginal discharge
May lead to candidal infections
 May result in significant vaginal
build up –
Causing vaginal irritation

35. COST EFFECTIVENESS

36. CONCLUSION
 Recent cochrane – systematic Review
P. supplementation (vag./IM) associated
with significantly higher ongoing PR
when compared with placebo or no P –
supplementation
Vaginal - P & IM - P4 are comparable
in promoting clinical & ongoing PR

37. CONCLUSION (cont.)
 Vaginal route clearly associated with
several advantages
Reduced local adverse effects
Better complaince
Anticipated high - P in Uterine
environment
Lower systemic absorption
More physiologicallly functioning
corpora lutea

38. CONCLUSION (cont.)
 First choice luteal support regimen world –
wide
 Most studies provide data necessary to
change the paradigm of LPS to vaginal