It is about recent evidences in Luteal Phase Support medications in IVF cycles. It will help to define individualized guidelines for the same.

1. Evidence Based Approach to
Luteal Phase Support in IVF
Cycles
Dr. Snehal Dhobale Kohale
M.S.,D.N.B.(OBGY)
Fellowship in Reproductive Medicine
Consultant Reproductive Medicine

2. Basic Definitions
Luteal Phase
• Is defined as the period from occurrence of ovulation until the establishment of a
pregnancy or the resumption of menses 2 weeks later.
Luteal Phase Defect
• Indicates an inadequate secretory transformation of the endometrium due to deficient
ovarian progesterone secretion or an intrinsic uterine defect
• The incidence of luteal-phase deficiency has been reported to be in the range of 3.5–
20% of infertile patients

3. Luteal Phase Support
• Is the term used to describe the administration of medications with the
aim to support the process of implantation

4. Hormones in the Luteal Phase

5. • It is well established that the ovarian stimulation regimens used in
assisted reproduction cycles alter the luteal phase.
Edwards et al 1980, Kolibianakis et al 2003
• Ovarian stimulation causes
- an inadequate development of the endometrium
- an asynchrony between the endometrium and the transferred embryo
and
- adverse effects on endometrial receptivity
Macklon & Fraser 2000, Devroey et al 2004

6. Luteal Phase in COS cycles
• Supraphysiological E2/P4 in early luteal phase  negative feedback  LH  --
Premature Luteolysis
• Agonist cycles : LH suppression
• Antagonist cycles: Excessive negative steroid feedback results in suppressed
pituitary LH release
• Removal of granulosa cells at OPU may lead to corpus luteum insufficiency

7. Short Luteal phase in COS

8. Need for LPS
• Pregnancy rates are significantly reduced GnRHa ovarian stimulation
without luteal phase support

9. • Luteal phase support remains mandatory for ovarian stimulation with
GnRHant co treatment in ART cycles. (J. Clin. Endocrinol. Metab., 2003)

10. When to Start???
• From day of OR or ET
• Not be later than day 3 after OR
Early Start - premature secretory changes in the endometrium therefore
decreased implantation rate
Late Start - lead to luteal insufficiency and decreased implantation rate
Williams SC et al., Delaying the initiation of progesterone supplementation results in decreased pregnancy rates after in vitro fertilization: a
randomized, prospective study. Fertil Steril. 2001 Dec;76(6):1140-3.

11. When to Stop ???
P support from CL until around 7 wks of pregnancy – Luteo-Placental shift
at 8wks.
Currently available evidence, however, does not support the use of
progesterone beyond obtaining a positive pregnancy test result (2 weeks
after the transfer).
At that stage the rising HCG rescues the corpus luteum that will support the
implanted embryo.
Shah D, Nagarajan N. Luteal insufficiency in first trimester. Indian J Endocr Metab 2013;17:44-9

12. Andersen et al. conducted a prospective study in which 303 patients enrolled in
stimulated IVF cycles(GnRH agonist long protocol) and receiving micronized
progesterone 600 mg in the luteal phase were randomized to
Stopping P support after first diagnosis of pregnancy vs. continuing for 3 more
weeks (n = 303)
No differences found in miscarriage rates and P supplementation can be safely
withdrawn after the first positive beta-hCG result
Andersen NA et al. Progesterone supplementation during early gestations after IVF or ICSI has no effect on the
delivery rates: a randomized controlled trial. Hum. Reprod. 2002; 17 (2): 357-361.

13. Luteal Phase Support
I. Endometrial support – complements production by CL
(i) Progesterone preparation
(ii) Estrogen preparation
II. Agents which support CL
(i) hCG
(ii) GnRH-analogue
(iii) LH
III. Newer agents which promote angiogenesis and vascular supply

14. Progesterone Preparations
(i) Micronized
(a) Oral / vaginal - 200-400 mg BD
(b) Vaginal Gel (8%) - 90 mg daily
(c) Vaginal Pessary - 100-400 mg daily
(ii) Intramuscular (oil based) - 100-400 mg daily
(iii) Subcutaneous (aqueous preparation) - 25 mg daily
(iv) Synthetic – Dydrogesterone - 10 mg BD or TDS

16. First Uterine Pass Effect

17. • 1hr after insertion • 4hrs after insertion
1. Cicinelli E et al., Transvaginal progesterone: evidence for a new functional ‘portal system’ flowing from the vagina
to the uterus. Human Reproduction Update .1999; 5(4): 365–372 .
2. Bulleti HR et al ., Targeted drug delivery in gynaecology: the first uterine pass effect. Human Reproduction. 1997;
12 (5): 1073–1079.

18. Vaginal progesterone increases endometrial tissue levels (Fert.Steril, 2012)

19. IM progesterone is associated with the highest serum levels (Fert.Steril, 2012)

20. Which Is Better???
• Oral or I.M. progesterone ?
Definitely I.M. progesterone (Daya & Grundy, 2004)
• Oral or vaginal progesterone ?
Definitely vaginal progesterone (Daya & Grundy, 2004)
• I.M. or vaginal progesterone ?
Both are equally effective No difference in CPR
(Daya & Grundy, 2004; MA: Zarutiski & Philips, 2009)

21. • The meta analysis showed a comparable effect between vaginal progesterone as
an oil-in-capsule or as a bio adhesive gel and IM P administration on the
endpoints of clinical pregnancy (OR = 0.91, 95% [CI 0.74, 1.13]) and ongoing
pregnancy (OR = 0.94, 95% [CI 0.71, 1.26]). A nominally significantly lower rate
of miscarriage was observed with vaginal P compared with IM P (OR = 0.54, 95%
[CI 0.29, 1.02]).
Zarutskie PW and Phillips JA. A meta-analysis of the route of administration of luteal phase support in assisted
reproductive technology: vaginal versus intramuscular progesterone. Fertility and Sterility. 2009; 92(1): 163–169.

23. Dydrogesterone – Duphaston
A retroprogesterone with good oral bioavailability, has an anti-estrogenic effect on the endometrium
causing a secretory transformation (Whitehead, 1980). Properties closest to native progesterone. Only
synthetic progesterone used for LPS
Dose
• 10 - 20 mg per day, orally
• Peak plasma levels in 20 mins
• No effect on Body weight, blood pressure, blood clotting factors, cholesterol, LDL, HDL, triglycerides
• Diuretic - prevents water & sodium retention, decreased incidence of HT, mastalgia, irritability, bloating
• Adrenal & liver function not affected.
• Results in decidualization of endometrium with no glandular asynchrony.

24. Dydrogesterone as Immunomodulator
• Progressive increase in PIBF cells with increasing concentrations of dydrogesterone.
J Szekeres Bartho 9th World Congress of Gynecological Endocrinology,
Hong Kong, December 2001
• Dydrogesterone inhibits the production of the Th1 cytokines IFN-g and TNF-a from
lymphocytes and up-regulates the production of the Th2 cytokines IL-4 and IL-6,
inducing a Th1 to Th2 cytokine shift.
Raj Raghupathy et al. BJOG 2005;112:1-6
• Dydrogesterone has an immunomodulatory capability and appears to induce a maternal
cytokine shift from Th1 cytokine dominance towards a Th2 bias.
Raj Raghupathy et al. BJOG 2005;112:1-6

26. Estrogen for LPS
The addition of E2 to progesterone in the luteal phase does not enhance
the probability of pregnancy (except FET and OD cycles)

28. Low Dose Aspirin
• Low dose aspirin   TXA2/PGI2  vasodilatation and decreased
platelet aggregation  increased ovarian and endometrial blood flow 
 ovarian responsiveness,  endometrial thickness,  implantation rate
• It may decrease uterine contraction at the time of ET
• The results of randomized controlled trials are controversial

29. Low Molecular Weight Heparin
• Anticoagulation effect of heparin prevents placental thrombosis and
infarction and promotes establishment and continuation of pregnancy
especially in RPL and thrombophilia cases
• Recently, heparin has been shown to be effective in improving
implantation rates (IRs) without the presence of thrombophilia
(Urman et al., 2009).

30. • There is emerging evidence that heparin modulates endometrial
receptivity and decidualization of endometrial stromal cells and improves
implantation. Fluhr et al. (2010) have shown that heparin increases the
production of prolactin and insulin-like growth factor (IGF-1) and inhibits
the production of insulin-like growth-factor-binding protein (IGFBP-1).
The expression of these proteins plays an important role in endometrial
development and receptivity during the ‘implantation window’ (Wilcox et
al., 1999; Fluhr et al., 2007, 2008).

31. • Additionally, heparin regulates heparin-binding epidermal growth factor
(EGF), which is expressed maximally at the time of implantation, thus
enhancing implantation, trophoblast invasion and promoting the early
stages of embryo development (Tamada et al., 1999; Constancia et al.,
2002; Stevenson et al., 2005).

32. Corticosteroids
• As immunosuppressive
• Controversial evidences

33. GnRH agonist
• GnRH receptor is expressed in the human preimplantation embryos,
endometrium, and corpus luteum, implicating a direct effect of GnRHa
on the these targets
• GnRHa has been shown to stimulate trophoblast production of hCG.
• Luteal-phase GnRHa (Triptorelin 0.1 mg 6 d after ICSI) enhances embryo
implantation and live birth rates.
Hum. Reprod., 2006

34. Cochrane Review 2011
• Cochrane review 2011 showed a significant effect in favour of progesterone for
luteal phase support, favouring synthetic progesterone over micronized
progesterone. Overall, the addition of other substances such as estrogen or hCG
did not seem to improve outcomes.
• They found no evidence favouring a specific route or duration of administration
of progesterone.
• It was found that hCG, or hCG plus progesterone, was associated with a higher
risk of OHSS.
• The use of hCG should therefore be avoided.

35. Cochrane Review 2011
• There were significant results showing a benefit from addition of GnRH
agonist to progesterone for the outcomes of live birth, clinical pregnancy
and on-going pregnancy.
• For now, progesterone seems to be the best option as luteal phase
support, with better pregnancy results when synthetic progesterone is
used.

37. THANK
YOU