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.
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EVIDENCE BASED PRACTICAL TIPS FOR LUTEAL PHASE SUPPORT BY DR SHASHWAT JANI
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
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
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.
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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
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
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
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)
Mob : 9909944160 45Dr. Shashwat Jani
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
Mob : 9909944160 59Dr. Shashwat Jani
60. “ PRO MIS Trial “
PROgesterone in MIScarriage trial
Newer Evidence is coming up as large multicentre study
PROMISE is currently on the Way…
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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