This document provides evidence-based practical tips for luteal phase support. It summarizes various diagnostic criteria and treatments for luteal phase deficiency, including progesterone, hCG, and estrogen. While no single diagnostic test is definitive, vaginal progesterone is widely considered the most effective treatment due to its direct delivery to the endometrium. Progesterone supplementation is recommended over hCG to prevent ovarian hyperstimulation syndrome.

1. Evidence Based Practical Tips
For
Luteal Phase Support
Dr. Shashwat Jani.
M. S. ( Obs – Gyn )
Diploma in Advance Laparoscopy.
Consultant Assistant Professor,
Smt. N.H.L. Municipal Medical College.
Sheth V. S. General Hospital , Ahmedabad.
Mobile : 99099 44160.
E-mail : drshashwatjani@gmail.com

2. What is E.B.M. ...???
 Evidence Based Medicine…? 
 Experience Based Medicine…? 
 Eminence Based Medicine....? 

Mob : 9909944160 Dr. Shashwat Jani 2

3. Mob : 9909944160 Dr. Shashwat Jani 3

4. Sources
 Cochrane library .
 Royal College of Obstetricians &Gynecologists (RCOG)
Guidelines.
 American Society of Reproductive Medicine (ASRM)
( April, 2015 )
 European Society of Human Reproduction & Endocrinology
( ESHRE )
 National Institute of Health & Care Excellence. ( NICE )
 Journal of Evidence Based Obstetrics & Gynecology.
 National Guideline Clearinghouse . ( U.S. Govt. ).
 Royal Austr. & NZ College of Obst. & Gynec .( RANZCOG )
 PubMed.
Mob : 9909944160 4Dr. Shashwat Jani

5. Once Upon a Time….
ƒ In 1949, the premature onset of menses was
recognized as indicative of a luteal phase deficiency
of progesterone production, which was shown to
be correctable by exogenous progesterone
administration (Jones, 1979). ƒ
 The prevalence of a luteal phase defect in
natural cycles in normo-ovulatory patients with
primary or secondary infertility was demonstrated
to be about 8.1%
(Rosenberg et al., 1980)
Mob : 9909944160 5Dr. Shashwat Jani

6. Maintenance of
pregnancy
 Corpus luteum  Progesterone
–After ovulation ~ during the early first trimester ~
until placental function established
–Removal of the corpus luteum  spontaneous
pregnancy loss
 Ovarian progesterone production 
implantation & early pregnancy support.
Mob : 9909944160 6Dr. Shashwat Jani

7. Luteal phase deficiency (LPD)
 Endogenous progesterone is NOT sufficient to
–Maintain a functional secretory endometrium
–Allow normal embryo implantation and
growth
–1st described in 1949.
Mob : 9909944160 7Dr. Shashwat Jani

8. Who requires
Luteal Phase Support ?
 Confirmed cases of luteal phase defect
 Unexplained infertility
 Advanced reproductive age
 ART techniques – IUI / IVF / ICSI
 Hyper- prolactinaemia
 All down regulated cycles
 Recurrent pregnancy loss
 PCOS
 Women with strenous exercises and
underweight Who require Luteal support .
Mob : 9909944160 8Dr. Shashwat Jani

9. Luteal Phase Deficiency (LPD)
Purportedly been associated with:
1. Infertility
2. 1st trimester pregnancy loss
3. Short cycles
4. Premenstrual spotting
5. Anorexia
6. Starvation
7. Eating disorders
8. Excessive exercise
9. Stress
10. Obesity & PCOS
11. Endometriosis
12. Aging
13. Inadequately treated 21-
hydroxylase deficiency
14. Thyroid dysfunction &
hyperprolactinemia
15. Ovulation stimulation alone
16. Ovulation induction with or
without GnRH agonists
17. ART
Mob : 9909944160 9Dr. Shashwat Jani

10. Luteal Phase Deficiency (LPD)
Has been shown to occur:
During the postpartum period
With significant weight loss or exercise
In random cycles of normally
menstruating women.
Mob : 9909944160 10Dr. Shashwat Jani

11. Are There Diagnostic
Criteria For
Inadequate Luteal
Function ???
Mob : 9909944160 Dr. Shashwat Jani 11

12. Diagnostic tests are influenced by and
based on the following
Physiologic observations:
1. Normal luteal phase length is relatively
fixed at 12 – 14 days.
2. Progesterone levels peak in nonpregnancy
cycles 6–8 days after ovulation.
3. Progesterone is secreted in pulses.
12

13. 4. The endometrial response is a reflection of
the follicular phase estrogen and the luteal-
phase estrogen and progesterone.
5. Once implantation occurs, progesterone
secretion by the corpus luteum depends on
rising hCG levels.
6. Failure of hCG levels to increase directly
causes corpus luteum failure and a decline in
progesterone levels.
Mob : 9909944160 Dr. Shashwat Jani 13

14. Methods proposed for diagnosing LPD
 Basal body temperature (BBT) charting:
 Inaccuracy, inconvenience, should be discouraged
 Serum progesterone levels
 Endometrial biopsy
 TVS
 Ovulation & adequate luteal length:
 Urinary LH surge detection & Monitoring of luteal
length
Mob : 9909944160 14Dr. Shashwat Jani

15. Sonographic Criteria :
 Rupture of follicle < 17 mm
 Poorly formed or ill defined dominant follicle
 Luteinised unruptured follicle ( LUF )
 Lutein cyst formation
 Absence of corpus luteum
 Lack of endometrial echogenicity on 7th
postovulatory day .
Mob : 9909944160 15Dr. Shashwat Jani

16. Endometrial Biopsy
 Abnormalities of endometrial maturation:
• Inadequate ovarian hormone secretion
• Intrinsic endometrial abnormality
• ‘‘Gold standard’’ to diagnose luteal inadequacy.
 However, prospective, blinded, randomized
clinical trials (RCTs) suggest that the
endometrial biopsy is an imprecise tool for
differentiating fertile women from women
with LPD (infertility).
16

17. April 2015
 In summary, currently there is no reproducible,
pathophysiologically relevant, and clinically
practical standard to diagnose LPD and distinguish
fertile from infertile women.
 The roles of BBT, urinary LH detection kits, luteal
progesterone levels, endometrial biopsy, and other
diagnostic studies have not been established, and
performance of these tests cannot be
recommended.
Mob : 9909944160 17Dr. Shashwat Jani

18. If Diagnosis Is Not
Possible,
Is Treatment For
Luteal Inadequacy
Ever Appropriate ???
Mob : 9909944160 18Dr. Shashwat Jani

19. Treatment Of Potential Luteal
Inadequacy
 1st approach: Correction of any underlying
condition …
(hypothalamic or thyroid dysfunction, hyperprolactinemia)
 2nd approach : Empiric Treatment
(based on limited reliable data)
• Promote endometrial maturation
• Enhance endometrial receptivity
• Support implantation and development of an
early pregnancy
Mob : 9909944160 19Dr. Shashwat Jani

20. What to use for LPS …???
 Progesterone,
 progesterone + estrogen,
 hCG
 Ovulation induction with clomiphene or gonadotropins
 GnRHa
 Prednisolone
 Aspirin
 Heparin
 Ascorbic acid
 Immunoglobulins
Mob : 9909944160 20Dr. Shashwat Jani

21. PROGESTERONE
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22. Action
Improves endometrial receptivity
(Kolibianakis & Devroy, 2002)
Promotes local Vasodilatation and uterine
musculature quiescence by inducing nitric
oxide synthesis in decidua
(Bulletti & de Ziegler, 2005)
Act as immunologic suppressant blocking Th1
and inducing release of Th2 cytokines
Mob : 9909944160 22Dr. Shashwat Jani

23. I. M. Progesterone
 Effective
 Physiological serum levels
Painful (long, thick needles)
 Occasional sterile abscess
 Occasional allergic reaction (oil vehicle)
 Needs to be administered by trained person
 Acute eosinophilic pneumonia associated with IM
administration of progesterone as luteal phase
support after IVF: 3 case report
Mob : 9909944160 23Dr. Shashwat Jani

24. Vaginal Progesterone
 Effective
Convenient (self-administration)
First uterine pass effect / targeted delivery
 Might require multiple dosing /day
(suppositories)
High uterine concentration of progesterone
 Minimizes the potential for adverse systemic
effects (Bulletti et al., 1997)
Mob : 9909944160 24Dr. Shashwat Jani

25. Dosage
 Micronized Progesterone:
No dose finding studies.
 Most frequently:
300–600 mg daily,
spread over 2-3 dosages
(Tavaniotou et al., 2000; ASRM, 2013 )
 Vaginal progesterone pessaries:
no dose finding studies.
 Most frequently used:
400-800 mg daily,
spread over 3-4 doses
(NG et al, 2002, Tay et al, 2005)
Mob : 9909944160 25Dr. Shashwat Jani

26. Vaginal Gel
 8% gel in a dose of 90 mg once daily
 No differences when administered twice daily
(Tavaniotou et al, 2000)
Low dose or high dose vaginal progesterone gel
Both are equally effective
(van der Linden et al., 2012)
Mob : 9909944160 26Dr. Shashwat Jani

27. Which Vaginal
Preparation…???
Gel or Capsules ?
 Both are equally effective (Daya & Grundy, 2004)
 Capsule: solid evidence of effectiveness and
convenience (Elenany et al, 2011) more cost effective
than gel.
 Gel is at least 4 times more expensive than Capsules.
 No difference exists regarding CPR between vaginal P
gel and all other vaginal preparations for LPS
(MA: Polyzoz et al, 2010)
Mob : 9909944160 27Dr. Shashwat Jani

28. Oral Progesterone
 Ineffective ?
 Low bioavailability
 High rate of metabolites
(scant endometrial effect)
 High rate of side effects (somnolence)
Mob : 9909944160 28Dr. Shashwat Jani

29. Rectal Progesterone
 Resulted in serum concentration during
the first 8h twice as high as other forms.
 No prospective RCT to compare the rectal
administration of progesterone with other
administration routes for IVF
(Chakmakijan & Zachariah, 2008)
Mob : 9909944160 29Dr. Shashwat Jani

30. S/C Progesterone
A new water-soluble progesterone
Implantation rate, PR, LBR and early
miscarriage rate for Prolutex were similar to
those for Crinone.
The adverse event profiles were similar and
Prolutex was safe and well tolerated.
Less painful than IM
Mob : 9909944160 30Dr. Shashwat Jani

31. 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)
Mob : 9909944160 31Dr. Shashwat Jani

32. Vaginal progesterone increases
endometrial tissue levels (Fert.Steril, 2012)
Mob : 9909944160 32Dr. Shashwat Jani

33. IM progesterone is associated with the
highest serum levels (Fert.Steril, 2012)
Mob : 9909944160 33Dr. Shashwat Jani

34. For Ideal LPS…
IM Progesterone for the Highest
Serum levels and Vaginal
Progesterone for increasing the
Endometrial levels, Until Placental
progesterone production adequate,
around week 8-10 w of gestation.
(Fert.Steril, 2012)
Mob : 9909944160 34Dr. Shashwat Jani

35. Mob : 9909944160 35Dr. Shashwat Jani

36. hCG
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37. hCG
 “Progesterone and estradiol are hormone
supplementations, whereas hCG is used to stimulate
these hormones in the corpora lutea. “
 Placental protein 14 (Anthony et al., 1993),
integrin άν (Honda et al., 1997) and relaxin (lutel
peptide hormone) concentrations, which has been
shown to increase at the time of implantation are
higher with hCG support ( Ghosh and Sengupta,
1998).
Mob : 9909944160 37Dr. Shashwat Jani

38. Limitations
 OHSS.
 Luteal support with hCG should be avoided: ƒ
- If E2 >2700pg/ml (Buvat et al., 1990) ƒ
- If Number of follicles is >10 (Araujo et
al., 1994)
Mob : 9909944160 38Dr. Shashwat Jani

39. Which is better…???
 Progesterone is as effective as hCG for
luteal phase support but provides a higher
safety with regard to ovarian hyper-
stimulation syndrome .
(Ludwig and Diedrich, 2001)
( RANZCOG 2014 )
Mob : 9909944160 39Dr. Shashwat Jani

40. E2
 No effect of oral estrogens
(van der Linden et al., 2012)
 Transdermal estrogen is beneficial
(van der Linden et al., 2012)
 No effect in antagonist protocol
Mob : 9909944160 40Dr. Shashwat Jani

41. Low dose Aspirin
M.O.A :
 Vasodilatation and decreased platelet
aggregation, increased ovarian and endometrial blood
flow, ovarian responsiveness, endometrial thickness,
decrease uterine contraction at the time of ET
 Low-dose aspirin (100 mg/d) doesn’t improve
ovarian responsiveness, blood flow, and PR
(Dirckx et al., 2009; Lambers et al., 2009).
Mob : 9909944160 41Dr. Shashwat Jani

42. Piroxicam
 An oral dose 10 mg 1-2 h before ET
 significantly improves PR (Moon., 2004)
 Doesn’t improve PR (Dal and Borini, 2009)

Mob : 9909944160 42Dr. Shashwat Jani

43. Indomethacin
 100 mg q12h rectally for 3 doses from the
night before ET does not improve PR in oocyte
recipients
(Bernabue, 2006)
43Dr. Shashwat Jani

44. Low dose Heparin
5000 IU BD and Aspirin 100 mg/day from the
day of ET did not improve PR or IR.
(Stern et al., 2003)
Mob : 9909944160 44Dr. Shashwat Jani

45. Prednisolone
• 10 mg/d before or after ET does not increase
PR
(Ubaldi et al., 2002)
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46. Sildenafil
25 mg qid
vaginally from stimulation D1 to hCG day.
(Sher, 2002;
Paulus,2002)
Not Recommended…. ( ESHRE , 2013 )
Mob : 9909944160 46Dr. Shashwat Jani

47. Ascorbic Acid
 Luteal regression is associated with
ascorbate depletion and the generation of
reactive oxygen species, which inhibit the
action of LH and block steroidogenesis
 No value
(Griesinger et al.,2002)
Mob : 9909944160 47Dr. Shashwat Jani

48. GnRHa in Midluteal phase
• GnRH receptor is expressed in the human
preimplantation embryos, endometrium,
corpus luteum .
• GnRHa has been shown to stimulate
trophoblast production of hCG .
• Increased LBR
(MA: Kyrou et al., 2008)
Mob : 9909944160 48Dr. Shashwat Jani

49. GnRHa Vs no treatment :
 GnRHa is beneficial (Glujovsky et al., 2010)
 Effective (van der Linden et al., 2012)
Which GnRHa is more beneficial?
 No differences (Glujovsky et al., 2010)
Mob : 9909944160 49Dr. Shashwat Jani

50. Cochrane 2012
 Single dose of 0.5 mg S/C on 6 th day after
ICSI Increases implantation rate, CPR per transfer,
increases live birth rate Single dose GnRH
agonist.
 Addition of GnRH agonist to progesterone
improved outcome of live birth, clinical
pregnancy and ongoing pregnancy .
Mob : 9909944160 50Dr. Shashwat Jani

51. Natural Cycle
No treatment for luteal phase
insufficiency has been shown
to improve pregnancy
outcomes in natural,
unstimulated cycles.
( ASRM April 2015 )
Mob : 9909944160 51Dr. Shashwat Jani

52. Ovulation Induction
 Improved pre-ovulatory follicular dynamics
 Should improve corpus luteum function
 Use of agents that induce ovulation 
Improved corpus luteum function & fertility
outcomes.
( ASRM APRIL 2015 )
Mob : 9909944160 52Dr. Shashwat Jani

53. ART
 For luteal support in assisted
reproductive technologies (ART),
exogenous progesterone
supplementation is associated with a
significantly higher pregnancy rate.
Strongly Recommended ( ASRM , 2015 )
Mob : 9909944160 53Dr. Shashwat Jani

54. Why in ART Cycles ?
 Abnormal luteal function after COS for IVF
 Suppression of LH
 Continued down-regulation by GnRHa
 Removal of granulosa cells at OR
 Supra physiological E2/P4 in early luteal phase
 hCG injection before OR
Mob : 9909944160 54Dr. Shashwat Jani

55. When to start..?
 From day of OR or ET
 Not be later than day 3 after
OR
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56. How long …???
 Not established firmly
 Often continued Unnecessarily
till 12 week
 Most evidence based studies
suggest to continue till 9 weeks
gestation
Mob : 9909944160 56Dr. Shashwat Jani

57. Pregnancy
 First trimester progesterone
supplementation in IVF may support early
pregnancy through 7 weeks by delaying
miscarriage but does not improve live birth rates .
 First trimester progesterone supplementation
in natural cycle pregnancies also does not
prevent a miscarriage. (Wahabi et al., 2007)
Mob : 9909944160 57Dr. Shashwat Jani

58. Recurrent Miscarriage
There is insufficient evidence to
evaluate the effect of progesterone
supplementation in pregnancy to
prevent a miscarriage .
(RCOG- Green Top Guidelines2011)
Mob : 9909944160 58Dr. Shashwat Jani

59.  It was only in 2011 that Cochrane
meta analysis suggested that
progesterone supplementation has
beneficial effects in patients with
Recurrent Pregnancy Loss.
 It dose, route, frequency & duration
does not affect the outcome.
Cochrane 2011 for Recurrent Miscarriages
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60. “ PRO MIS Trial “
PROgesterone in MIScarriage trial
Newer Evidence is coming up as large multicentre study
PROMISE is currently on the Way…

Mob : 9909944160 60Dr. Shashwat Jani

61. Take Home Message
Abnormal luteal function may occur
as the result of a medical condition (e.g.,
elevated prolactin, abnormal thyroid
function), and infertile women suspected
of having one of these disorders (e.g.,
irregular menses, galactorrhea) should
be evaluated and appropriately treated
for identified conditions.
Mob : 9909944160 61Dr. Shashwat Jani

62.  No diagnostic test for luteal phase
insufficiency has been proven to be
reliable in a clinical setting.
 The roles of BBT, urinary LH
detection kits, luteal progesterone levels,
endometrial biopsy, and other diagnostic
studies have not been established, and
performance of these tests cannot be
recommended.
Mob : 9909944160 62Dr. Shashwat Jani

63.  There is no proven role in adding
progesterone or hCG for luteal support once a
pregnancy has been established.
 Use of supplemental progesterone in a
non-ART cycle beyond the time of expected
menses (i.e., 2 weeks after ovulation) is Not
proven to be beneficial.
Mob : 9909944160 63Dr. Shashwat Jani

64.  No treatment for luteal phase
insufficiency has been shown to improve
pregnancy outcomes in natural,
unstimulated cycles.
 Luteal support after ART procedures
with progesterone or hCG improves
pregnancy outcomes, but hCG increases
the risk of OHSS.
Mob : 9909944160 64Dr. Shashwat Jani