Since the first formal description of LPD in 1949 as a possible cause of infertility and recurrent miscarriage by Jones. Innumerable investigations have been undertaken in an effort to verify its existence or to characterize its pathophysiology, diagnosis, and treatment. The consensus of the literature is that LPD does exist and that its cause is multifactorial like abnormal folliculogenesis, inadequate LH surge,inadequate secretion of progesterone by the corpus luteum, aberrant end-organ response by the endometrium.

1. Dr. Laxmi Shrikhande MD; FICOG; FICMCH;FICMU
▪ Director-Shrikhande Fertility Centre, Nagpur
▪ Senior Vice President FOGSI 2012
▪ Associate member RCOG, London
▪ Member of European Society of Human Reproduction
▪ Received Bharat excellence Award for contribution to women’s health
▪ Chairperson HIV Committee FOGSI 2009-12
▪ Received best FOGSI committee award
▪ National Editor-The Journal of OB / GY of India
▪ Vice Chairperson Elect Indian College of OB/GY
▪ Publications-Thirteen National & seven International
▪ Editor-FOGSI Focus on HIV in women
▪ Editor-FOGSI Focus on SUI- Myths & Facts
▪ Presented Papers at FIGO,SAFOG,AOFOG, IFFS

2. Luteal phase support in IUI
and ART
Dr Laxmi Shrikhande
Director-Shrikhande Hospital &
Research Centre, INDIA

3. “When a thing ceases to be a subject of
controversy, it ceases to be a subject
of interest.”
William Hazlitt (1778–1830), English essayist

4. • Since the first formal description of LPD in 1949 as a
possible cause of infertility and recurrent
miscarriage by Jones,
• innumerable investigations have been undertaken in
an effort to verify its existence or to characterize its
pathophysiology, diagnosis, and treatment.
Jones GES: Some newer aspects of management of infertility. JAMA 141:1123, 1949

5. The consensus of the literature is that LPD does exist
and that its cause is multifactorial-
• abnormal folliculogenesis,
• inadequate LH surge,
• inadequate secretion of progesterone by the
corpus luteum,
• aberrant end-organ response by the
endometrium

6. Scope
• Is there any need for support in natural cycle /
IUI / IVF cycles ?
• What to give ?
• When to give ?
• What dose?
• When to stop ?

7. Luteal phase in a natural cycle
• Between ovulation and either
pregnancy / menses
• LH as the hormone to
support corpus luteum and
stimulate progesterone
production
• In ovulatory women, 92% of
cycles show normal luteal
function, and luteal support is
unnecessary (Rosenberg et al.,
1980).

8. Natural cycle IUI
• Donor Inseminations
• Cervical factor infertility
• Mild/Moderate male factor infertility
Luteal Phase support will unnecessarily increase the cost
of the cycle without increasing the pregnancy rate.Thus
not recommended

9. What happens to Luteal phase in stimulated
cycles
▪ Multiple follicles of different size might ovulate at different
times, expanding the fertilization window.
▪ Thus, both oestradiol and progesterone, after multiple
ovulation is expected to be significantly higher
(Macklon and Fauser, 2000).
▪ These high concentrations may not only influence the
receptivity of the endometrium, but may also cause luteal
insufficiency and early luteolysis
(Erdem et al., 2008).

10. CC - Stimulated Cycles
Some authors reported luteal phase
inadequacy in up to 50% of clomiphene citrate
induced cycles in anovulatory women
[Cook et al.,1984,Keenan et al.,1989]

11. CC - Stimulated Cycles
▪ 400 women analysed
▪ No difference observed in ongoing pregnancy between
patients who did, or did not, receive vaginal
progesterone as luteal support [8.7% (17/196) versus
9.3% (19/204)
▪ Thus routine supplementation of the luteal phase with
vaginal progesterone does not seem to improve
pregnancy rates in normo-ovulatory women stimulated
with clomiphene citrate for IUI
Paul devroy, Human reproduction, vol 25, issue 10. pg 2501-2506

12. Studies favoring the luteal phase support in IUI
• Montville et al -Fertil Steril. 2010
• Erdem et al – Fertil Steril. 2009
• Cohlen review - Reprod Biomed Online.
2009

13. Studies not favoring luteal phase support in IUI
• Ebrahimy M.- 12th International Congress of
Gynecology and Obstetrics 2010.
• Kyrou D - Hum Reprod. 2010
• Bibi Shahnaz Aali, Iran J Reprod Med. Apr 2013
• Romero Nieto MI , Gynecol Endocrinol.2014

14. Luteal phase support after IUI
Conclusion
➢ Progesterone luteal phase support may be of benefit to
patients undergoing ovulation induction with gonadotropins
in IUIcycles.
➢ Progesterone support did not benefit patients undergoing
ovulation induction with CC, suggesting a potential
difference in endogenous luteal phase function depending
on the method of ovulation induction.
Hill MJ Fertil Steril. 2013- a systematic review and meta-analysis.

15. LPS in IUI cycles
• Shortened luteal phase in 20% of stimulated cycles for
ovulation induction using FSH (Olson et al., 1983).
• In a recent meta-analysis (Hill et al., FS, 2013) of 5 trials
involving 1,938 cycles in 1,298 patients, LPS with P
improves success.
• Improvement seen in FSH cycles only but not in CC-
induced cycles.
OR (95% CI)
Clinincal pregnancy 1.47 (1.15-1.98)
Live birth 2.11 (1.21-3.67)

16. Luteal phase defect in IVF
Reasons
1.Supra-physiological steroid concentrations
secreted by multiple corpora lutea directly inhibit
LH release (Fauser and Devroey, 2003)
2.HCG for the final oocyte maturation suppresses
LH production (Miyake et al., 1979)

17. Luteal phase defect in IVF
3. GnRH agonist or antagonist for downregulation
prevents LH rise in the luteal phase
4. Removal of large quantities of granulosa cells
during oocyte retrieval

18. • hCG or progesterone improved pregnancy rates IVF
cycles using GnRH agonist
• OHSS in 5% of cycles with hCG
• Conclusion: Routine use of luteal phase support in
IVF cycles using GnRH agonist
Meta-analysis of 18 trials

19. • 385 women were randomized into 3 groups
hCG TUGOR ET (D3)
No. of patients 130 128 127
Ongoing
pregnancy rate
20.8% 22.7% 23.6%

20. IVF
Period
Egg
retrieva
l
Embryo
transfer Pregnancy tes
Ovarian stimulation
Antagonist
GnRH agonist
LUTEAL PHASE SUPPORT
What? How long? When?

21. LPS in ART
1. Human chorionic gonadotrophin (hCG)
2. Progesterone: oral, intramuscular, vaginal
3. Progesterone and oestradiol
4. hCG and progesterone
5. Progesterone and GnRH agonist

22. hCG Vs Progesterone
• No significant difference found between P and
hCG or between P and P plus hCG in terms of
pregnancy or miscarriage rates
• Risk of OHSS significantly higher with treatments
involving hCG than with P alone

23. Progesterone Vs HCG
• Consensus opinion in favor of
Progesterone
❖Once pregnancy is established
– Supplemental hCG is not beneficial

24. Progesterone
• Different routes of administration
❑Oral, intramuscular or vaginal

25. Oral progesterone
• Reduced implantation rates when compared with
hCG, IM and vaginal progesterone
▪ Poor bioavailability due to rapid hepatic metabolism
(Maxson et al., 1984)
▪ Failure to induce uniform secretory changes in
endometrium (Devroey et al., 1989; Critchley et al., 1990)
• Metabolites induce significant sedative and hypnotic
effects (Arafat et al., 1988)

26. Vaginal progesterone
• Easy to administer
• Avoids liver first-pass metabolism
• No systemic side-effects
• Higher endometrial tissue level despite low serum
level due to ‘first uterine pass effect’
• Similar pregnancy rate as intramuscular
progesterone

27. Vaginal progesterone
• Associated with vaginal discharge and perineal
irritation
▪ tablets: 6%
▪ gelatin capsules: 0-14%
▪ suppositories: 25-30%
▪ bioadhesive gel: 17%
• Affect patients’ comfort and compliance during
the IVF treatment

28. Intramuscular progesterone
• Uncomfortable daily injections
• Trained medical personnel
• Allergic reactions to the oil vehicle and marked
inflammation at the injection site, resulting in
redness, pain and even sterile abscess formation

29. Dydrogesterone
• It is structurally and pharmacologically
similar to natural progesterone, has
good oral bioavailability
• has a good safety and tolerability profile
• has no androgenic effects on the fetus,

30. • 1,373 infertile women undergoing IVF randomized
into micronized P gel (Crinone 90mg daily), P capsule
(Utrogestan 200mg tds), and oral dydrogesterone
(Duphason 10mg bd)
• Comparable PR and miscarriage rates
Oral Vaginal gel Vaginal capsule
Clinical PR
at 7 weeks
121/422 (28.7%) 138/482 (28.6%) 104/459 (22.7%)
Miscarriage
rate
14/121 (11.6%) 18/138 (13.0%) 19/104 (18.3%)

31. Dydrogesterone / vaginal progesterone
Comparison of oral dydrogesterone with suppository
vaginal progesterone for luteal-phase support in in
vitro fertilization (IVF): A randomized clinical trial.
Salehpour S, Iran J Reprod Med. 2013
Conclusion - Oral dydrogesterone is as effective as
vaginal progesterone for luteal-phase support in
women undergoing IVF.

32. GnRH agonist in luteal phase -IUI
▪ GnRH agonist was recently suggested as a novel luteal-
phase support that may act at different levels, including
the pituitary gonadotrophs, the endometrium and the
embryo itself
▪ Regimens for IUI :
▪ single dose triptorelin 0.1 mg 6 days after ovulation
▪ Three doses of lupride 1 mg sc 6 days after ovualation

33. GnRH agonist in luteal phase-IVF
Evaluation of the impact of gonadotropin-releasing
hormone agonist as an adjuvant in luteal-phase support
on IVF outcome.
Conclusion - Three 1 mg doses of Lupride administration 6
days after oocyte retrieval in the long protocol cycles does not
result in an increase in ongoing pregnancy rates.
Inamdar and A Majumdar.J Hum Reprod Sci. 2012.

34. GnRH agonist as luteal phase support in IVF

35. • GnRH-a can collaborate in the corpus luteum
function, acting directly on the endometrium via local
receptors, a direct effect on the embryos or
combination.
• GnRH-a administration can improve clinical outcomes
after ICSI.
• Premature to recommend the use of GnRH-a in the
luteal phase because of heterogeneity among trials

36. Role of oestrogen in IUI for luteal support
• The role of oestrogen along with
progesterone in the luteal phase appears to
be only in those cases where GnRH agonist
was used instead of hCG to trigger ovulation

37. Estradiol as luteal phase support-IVF
1. The use of estradiol for luteal phase support in IVF /
ICSI cycles: a systematic review and meta-analysis.
Gelbaya TA, Fertil Steril. 2008
conclusion - The addition of E(2) to P4 for luteal phase support in
IVF/ICSI cycles has no beneficial effect on pregnancy rates
2. Luteal phase support with estrogen in addition to
progesterone increases pregnancy rates in IVF cycles with
poor response to gonadotropins.Kutlusoy F , Gynecol
Endocrinol. 2014

38. LPS in natural cycle FET
• Controversial
1. Retrospective study: no effect on pregnancy rate
following vaginal P in hCG-induced natural FET
cycles (Kyrou et al., 2010)
2. RCT: significantly higher live birth rate when vaginal
P was given in natural FET cycles (30% Vs 20%); no
difference in clinical PR and miscarriage rate
(Bjuresten et al., 2011)

39. • Before 1st July 2009, 2 doses of 1500 IU hCG given on
the day of FET and 6 days after the transfer.
• Such practice was stopped after 1st July 2009.
With hCG Without hCG
Clinical PR 53/205 (25.9%) 59/203 (21.1%)
Miscarriage rate 12/66 (18.2%) 12/75 (16.0%)

40. When to stop ?

41. 600 mg of progesterone starting on the day
of ET for 14 days after ET
150 women did NOT receive P
for another 3 weeks (Study
group)
150 women received P for another 3
weeks (Control group)
Delivery rate
+ve hCG

42. • Prolongation of P in the early pregnancy (up to 7
weeks of gestation) has no effect on the
miscarriage and delivery rates.
• P can be safely withdrawn after a positive hCG test
Study Group Control group
Ongoing preg. 133 (88.7) 139 (90.8)
Delivery 118 (78.7) 126 (82.4)
Biochemical 10 (6.7) 7 (4.0)
Abortion 22 (14.6) 18 (11.8)

43. F&S, 2010
No difference in ongoing pregnancy and miscarriage
rates on early P cessation
F&S, 2012
F&S, 2010

44. Duration of LPS in IVF
Authors Protocol Study Gp Control Gp
Andersen 2002 Vaginal P
Livebirth
LPS till 7 wks
78.7%
LPS till PT+ve (4 wks)
82.4%
Aboulghar 2008 Vaginal or IM P
Miscarriage
LPS till 10 wks
4.6%
LPS till USS (7 wks)
4.8%
Goudge 2010 IM P
Livebirth
LPS till 8 wks
52.0%
LPS till PT+ve (4 wks)
49.0%
Kyrou 2011 Vaginal P
Ongoing
LPS till 7 wks
82.0%
LPS till PT+ve (4 wks)
73.0%
Kohls 2012 Vaginal P
Ongoing
LPS till 8 wks
73.0%
LPS till USS (5 wks)
75.0%

45. Conclusion
• Prevalence of a luteal phase defect in natural
cycles is about 8.1% (Rosenberg et al., 1980).
• In these cases LPS is controversial
• CC stimulated cycles do not disturb the
luteal phase, however there is an urgent need
for prospective randomised trials.
• HMG/rec-FSH with GnRH agonist and
antagonist cycles must be supplemented.

46. Conclusion
• IVF
✓vaginal P alone for about 2 weeks from day of
hCG, TUGOR or ET
• FET in natural cycles
✓Controversial
• IUI
✓Vaginal progesterone for 2 weeks

47. Dr. Laxmi Shrikhande
Shrikhande IVF & Surrogacy Center
Ph-96234 59766 / shrikhandedrlaxmi@gmail.com

48. 'Spiritual blossoming' simply means
blossoming in life in all dimensions.
Being happy, at ease with yourself
and with everybody around you.
Sri Sri Ravi Shankar
The Art of Living