Luteal phase insufficiency is one of the most important aspect of fertility treatment . But due to lack of proper understanding many unwanted medications are prescribed . This ppt will give an idea on the best evidence based luteal phase support for an ivf cycle.

1. Dr Raju Nair
Head – Fertility Unit
Mitera Hospital, Kottayam
Kerala, India
Luteal Phase Insufficiency

2. Dr.Raju Nair
Director & HOD Reproductive medicine
Mitera Hospital, Kottayam, Kerala
Education:
MBBS : Government medcial college, Kottayam, ( 94-99)
MS( OBG) : Armed forces medcial college ( AFMC), Pune 2004
Reproductive Medicine Fellowship: CMC, Vellore 2007
Member- ESHRE, ASRM,ISAR, FOGSI, IAGE,ACE,IMA,IFS, ASPIRE
Reviewer : Cochrane network- sub fertility group
Scientific achievements :
11 articles in Indexed Journal
3 national best papers
>200 scientific lectures in state and national level ,5 international level scientific lectures
Contributed many chapters in Textbook related to ART
Academic activities:
Course director – Fellowship in Reproductive Medicine, Mitera Hospital, FNB examiner
Area of Interest :
IVF lab quality control, PCOD, Minimal stimulation ART

3. • Luteal phase deficiency (LPD) has been described as a condition in
which
• endogenous progesterone is not sufficient to maintain a functional secretory
endometrium and allow normal embryo implantation and growth

5. What happens normally…
hcg
Corpus
luteum
LH on
Granulosa
cell
P4
Endometrial
glands
OVULATION

6. Luteal phase in a natural cycle
• Which hormones seem to be crucial during the luteal phase in a
natural cycle

7. The role of LH in the luteal phase: Crucial
• Totally responsible for steroidogenic activity of the corpus luteum (Casper
and Yen, 1979)
• Upregulation of growth factors, VEGF-A, FGF2 (Sugino et al., 2004; Wang et al., 2002)
• Upregulation of cytokines involved in implantation (Licht et al., 2001)
• Stimulation of LH receptors in endometrium (Rao, 2001; Tesarik et al., 2003)

8. The role of progesterone
• Induces secretory transformation of the endometrium in the luteal
phase (Bourgain et al., 1990)
• Progesterone deficiency delays endometrial maturation (Dallenbach-Hellweg, 1984)
• Removal of CL prior to 7 weeks of gestation leads to pregnancy loss
(Csapo, 1972)
• Normal pregnancy was sustained when progesterone was given after
removal of CL (Csapo, 1973)

9. What happens normally…
• Corpus luteum - Initial support
• Once pregnancy begins, corpus luteum rescue and maintenance
require a series of well-known endocrine, paracrine and autocrine
actions.
• luteoplacental shift (onset of placental steroidogenesis) is around the seventh
gestational week

10. Progesterone Production: Luteal Placental
Shift
Adapted from: Schindler AE. Gynecol Endocrinol 2004; 18(1): 51-57.

11. Luteal phase deficiency (LPD)
• A condition of insufficient progesterone exposure to maintain a normal
secretory endometrium and allow for normal embryo implantation and
growth
Obstet Gynecol Clin North Am. 2015 March ; 42(1): 135–151.

12. Luteal phase deficiency
• 1970s, the Norfolk group performed several studies on premature
onset of menses due to low progesterone concentrations in the luteal
phase, which they called luteal phase deficiency (Jones, 1991).
• Luteal phase deficiency is defined as a
• luteal phase shorter than 11 days
• a lag of more than 2 days in endometrial histological development
• low mid-luteal progesterone values <10 ng/ml

13. LPD
• Infertility
• First trimester Pregnancy loss
• Short cycles
• Premenstrual spotting
• Anorexia
• Starvation, and eating disorders
• Excessive exercise
• Stress
• Obesity and polycystic ovary syndrome
• Endometriosis
• Aging
• Inadequately treated 21-hydroxylase deficiency
• Thyroid dysfunction
• Hyperprolactinemia
• ART cycles
• Random cycles with or without stimulation
Controversy regarding the clinical
significance of LPD is due in part to
the lack of a reliable test to diagnose
this disorder.
Luteal phase deficiency has
purportedly been associated
LPD is only clinically relevant if it is consistently present in most cycles

14. Detecting Luteal Phase Insufficiency
• Serum progesterone level: <3 ng/ml
• Mid-luteal phase: At least 6.5 ng/ml and preferably 10 ng/ml or more
• Blood levels range from 2 to 40 ng/ml within a brief time period
• Random serum progesterone levels are difficult to interpret beyond
documenting ovulation
• Endometrial biopsy is no longer the gold standard for assessment of
endometrial maturation
There is no consensus on minimum serum progesterone
concentration that defines luteal function
Indian J Endocrinol Metab. 2013 Jan;17(1):44-9.

15. • IF DIAGNOSIS IS NOT POSSIBLE, IS TREATMENT
FOR LUTEAL INADEQUACY EVER APPROPRIATE?

16. TREATMENT FOR
LUTEAL
INADEQUACY
• The first approach to treatment of
potential luteal inadequacy is the
correction of any underlying condition.
• hypothalamic dysfunction, thyroid dysfunction,or
hyperprolactinemia
• Rest are all empiric
• to promote endometrial maturation
• to enhance endometrial receptivity
• to support implantation and development of
an early pregnancy.
• Strategies
• supplemental progesterone
• progesterone plus estrogen
• human chorionic gonadotropin (hCG)

17. LPD: Prevalence
• 5-10% pregnant women have prevalence of LPD
• 25-40% women with ‘Recurrent pregnancy lose’ have prevalence of
LPD
• 15-20% women with ‘Unexplained infertility’ have prevalence of LPD

18. The luteal phase in stimulated cycles

19. Luteal phase defect in all stimulated cycles
• Schematic representation of
changes in luteal phase length
and progesterone profile
induced by ovarian
hyperstimulation for IVF (Macklon et al.,
2006)

20. Why in ART Cycles….
• Suppression of endogenous luteinizing hormone secretion during the luteal phase as a result of persistent pituitary
suppression by GnRH agonists.
• Supraphysiological levels of both estradiol and progesterone in the early luteal phase may lead to advanced development
of the endometrium, hence asynchrony between the embryo and the endometrium and decreased pregnancy rates in IVF
cycles.
• Duration of ovarian steroid production is shorter in stimulated cycles compared with that of natural cycles. Early menses
may prevent successful implantation due to abrupt decreases in serum concentrations of estradiol and progesterone in
ART cycles compared with those of natural cycles.
• The aspiration of the granulosa cells that surround the oocyte can interfere with the production of progesterone.
• LH levels are lowered by high steroid levels, These steroid levels are high because of the multiple corpora lutea,which
produce more steroids than in a natural cycle. This causes a negative feedback on the pituitary gland and lowers the LH
levels. In this way the length of the luteal phase is shortened (known as premature luteolysis) and the chances of
pregnancy are reduced.

21. Etiology of luteal phase deficiency
• Follicular phase events
• Luteal phase events
• Luteal rescue events

22. Follicular Phase Events
Trophic alterations
• Inadequate FSH stimulation
• Increased inhibin
• Alterations in LH secretion
Intrinsic ovarian defects
• Defective granulosa cells
• Decreased inhibin levels
• Decreased follicular phase diameter
• Decreased primordial follicles
Intrinsic endometrial defects
• Inadequate estrogen priming

23. Luteal Phase Events
Trophic alterations
• Alterations in LH secretion
• Decreased LH surge and luteal levels
• Systemic factors
• Factors acting upon corpus luteum
Intrinsic corpus luteum defects
• Specific cellular defects
• Large and small cell abnormalities
Intrinsic secretory endometrial defect
• Deficient number of progesterone receptors

24. Luteal Rescue Events
Trophic alterations
• Defective hCG stimulus
Intrinsic corpus luteum defects in early pregnancy
• Defective progesterone synthesis
Intrinsic endometrial defects

25. Progesterone deficiency and
failure of embryo implantation

26. Progesterone deficiency in ARTs
• Progesterone important for early embryonic development
• Deficient progesterone responsible for
• Implantation failure
• Miscarriages and
• unsuccessful ARTs
• In ART procedures, iatrogenically low progesterone environment is
created
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2012 Nov;98(5):1112-1117.
Shah and Nagarajan. Indian J Endocrinol Metab. 2013 JanFeb;17(1): 44–49.

27. Implantation failure
• Luteal phase progesterone deficiency – one of the reasons of
implantation failure
• Progesterone insufficiency interferes with secretory transformation of
endometrium
• Up-regulation of pro-inflammatory cytokines is a risk factor
• Pro-inflammatory cytokines- IFN-γ and TNF-α
• Down-regulation of anti-inflammatory IL-4, IL-6 and IL-10

28. Progesterone link with immune system
Progesterone stimulates
the production of
progesterone-induced
blocking factor (PIBF)
and induces via the
cytokines a T-helper 2
response
Progesterone is essential for
the maintenance of pregnancy.
It is produced by the corpus luteum
until week 7–9, when the placenta takes
over this function
Progesterone
CD-8 + T cell
PIBF
Norwitz ER, et al. N Engl J Med 2001; 345(19): 1400-1408.
Szekeres-Bartho J, Wegmann TG. J Reprod Immunol 1996; 31(1-2): 81-95.
Szekeres-Bartho J. Int Rev Immunol 2002; 21(6): 471-495.

29. Th1-Th2 Paradigm
T helper cells = sub-group of lymphocytes
• Th1 cells
Pro-inflammatory cytokines
IL-2, TNFα, TNFβ, IFNγ
Cell-mediated immunity
• Th2 cell
Anti-inflammatory cytokines
IL-4, IL-5, IL-6, IL-10, IL-13
Humoral immunity
Th1 Th2
Cytokines
T Cell Immunology. Available from: http://www.bdbiosciences.com/research/tcell/about/helper.jsp. (last accessed February 2014).
Raghupathy R, et al. BJOG 2005; 112(8): 1096-1101.

30. Decreased survival of embryo due to
hyper immunity
Progesterone
PIBF
Normally
Progressing
Pregnancy
Progesterone
PIBF
Miscarriage
Mifepristone
Progesterone
PIBF
+anti-PIBF
Miscarriage
Adapted from: Szekeres-Bartho J, et al. Int Immunopharmacol 2001; 1(6): 1037-1048.

31. Role of Human chorionic gonadotropin
• Human chorionic gonadotropin (HCG) acts as indirect support of
luteal support
• HCG stimulates corpus luteum
• Increases the concentration of estrogen and progesterone – rescues
failing corpora lutea
• Administration of HCG icreases placental protein 14, integrin and
relaxin
• HCG insufficiency may lead to miscarriage
Hutchinson-Williams et al. Fertil Steril. 1990;53:495–501.
Anthoy et al. Fertil Steril. 1993;59:187–91.
Ghosh et al. Hum Reprod. 1997;12:914–20.

32. Role of HCG in human pregnancy
Adapted from: Polese et al. Front. Endocrinol. 2014; 5:106.

33. Luteal Phase support by
Exogenous Progesterone

34. What is Evidence-Based
Medicine?
• “The integration of individual clinical expertise with the
best available clinical evidence from systematic
research.”
• David L Sackett, W Scott Richardson, William
Rosenberg, R Brian Haynes Evidence Based Medicine--
How to Practice and Teach EBM, 1996
14 March 2023 34

35. • There is a worldwide controversy concerning the
• Requirement of luteal phase support
• Type of hormones used for LPS
• Dose and duration
• When to start
• When to stop

36. • Strategies
• supplemental progesterone
• progesterone plus estrogen
• human chorionic gonadotropin (hCG)

37. Normal cycle
• Role of luteal phase support
• Normo ovulatory patient
• PCOD
• Prevent miscarriage
• No treatment for luteal phase insufficiency has been shown to
improve pregnancy outcomes in natural, unstimulated cycles.

38. non-ART cycle
• Use of supplemental progesterone, in a non-ART cycle beyond the
time of expected menses (i.e., 2 weeks after ovulation), is not proven
beneficial.

42. Etiology of luteal phase defect
• Oocyte retrieval?
• Removal of granulosa cells
• hCG?
• Suppressing LH
• GnRH agonist? GnRH antagonist?
• Combination of these factors?

43. Progesterone
• Why?
• What?
• When?
• How?
• Dose?

44. Dr BN Chakraborthy
2005

45. 2011

46. Cocherane 2011- Intervention review of different progesterone
regimens
• Comparison has 32 studies included with 9,839
women participants
• Investigated difference between different
progesterone regimens:
• Intramuscular (IM) versus oral
• IM versus vaginal or rectal administration
• Vaginal or rectal versus oral administration
• Low dose vaginal versus high dose vaginal progesterone
• Short protocol versus long protocol regimen
• Micronized progesterone versus oral progesterone
Van der Linden et al. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD009154.

47. Intervention result Comments
HCG vs Placebo No effect
P4 vs Placebo Beneficial 1.02 – 8.56 ( OR)
P4 Vs Hcg Same OHSS high
P4 Vs P4 +E2 Same
P4 Vs P4 + GnRh a Benefit 1.03 -1.67

48. Cochrae-2011: Micronized vaginal versus Dydroprogesterone
• Four studies with 698 events in 2388 participants reported
• A significantly better outcome of pregnancy is seen with
dydrogesterone
• Outcome: Pregnancy outcome rates
Van der Linden et al. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD009154.
Treatment A- Micronized Treatment B – synthetic

49. Dydrogesterone in LPS
• 2011, Cochrane Review showed a significant effect in favour of
progesterone for luteal phase support, favouring synthetic progesterone
over micronized progesterone.
• Dydrogesterone, is an oral progestin with improved bioavailability
compared with oral micronized progesterone.1
• In one randomized, controlled trial, pregnancy rates were higher in
women undergoing IVF using oral dydrogesterone for luteal support
versus vaginal micronized progesterone (41.0 vs 29.4%,P≤.01).2
Steroids. 2003; 68(10–13):927–9. ;Gynecol Endocrinol. 2007; 23(Suppl 1):68–72.

51. Dydrogesterone in LPS
Conclusions: Oral dydrogesterone seems to be as effective as vaginal progesterone
for LPS in ART cycles, and appears to be better tolerated

52. Lotus I and Lotus II study
• Lotus I and Lotus II
demonstrate that oral
dydrogesterone is as
efficacious as MVP
(capsules or gel) for
luteal phase support in
fresh-cycle IVF, with a
similar safety profile
Dydrogesterone has the potential to induce a paradigm
shift for luteal phase support in the estimated 1.5
million women undergoing IVF each year
Gynecological Endocrinology. 2016 Feb 1;32(2):97-106.

54. Dydrogesterone in LPS
CONCLUSION:
Since the outcomes of dydrogesterone are comparable to those of intramuscular
and vaginal progesterone, it is a reasonable option to provide luteal phase support
for women who are uncomfortable with injections or vaginal insertions.

55. Despite oral administration and first pass through the liver,
dydrogesterone was well tolerated and may become the new
standard for LPS in fresh embryo transfer IVF cycles

56. Advantages of Dydrogesterone over oral progesterone for LPS
1.Pandya M, Gopeenathan P, Gopinath et al. Evaluating the clinical efficacy and safety of progestogens in the management of threatened and recurrent miscarriage in early pregnancy- A review of the literature. Indian Journal of Obstetrics
and Gynecology Research. 2016;3(2):157–66.
2.Data on file for dydroboon.
Dydrogesterone
• Bioavailability is 5.6 times better
than oral micronized
progesterone1
• Receptor affinity is 1.5 times better
than oral micronized
progesterone1
• Low doses are required due to its
high potency2
Oral micronized progesterone
• Low bioavailability is attributed to its
significant first-pass effect1
• Less receptor affinity1
• High doses are required resulting in
side effects, such as drowsiness,
nausea, and headaches1

57. Advantages of Dydrogesterone from patients’ perspective
1. Griesinger G, Blockeel C, Tournaye H. Oral Dydrogesterone for luteal phase support in fresh in vitro fertilization cycles: a new standard? Fertil Steril. 2018 May;109(5):756-762. 2. Salehpour S, Tamimi M, Saharkhiz N. Comparison of oral
Dydrogesterone with suppository vaginal progesterone for luteal-phase support in in vitro fertilization (IVF): A randomized clinical trial. Iran J Reprod Med. 2013 Nov;11(11):913-8.
01
Preferred route
by majority
patients
02
Higher patient
satisfaction
03
Easiest and
most acceptable
route of
administration
04
Stable form
05
Effective
06
Better
tolerability
07
Low side
effects/ good
safety profile
08
Excellent
patient
compliance
09
No androgenic
effects on fetus/
no side effects
for mother

58. Summary
LPS, Luteal phase support; IVF, In vitro fertilization; IUI, Intrauterine insemination
Progesterone is
essential for
establishing and
maintaining early
pregnancy
Absence of
exogenous
hormonal support
for LPS after IVF
is associated with
significant
reduction in
success rate
Progesterone is
critical to support
the luteal phase
following IVF and
widely used in IUI
cycles
Dydrogesterone,
an active
metabolite of
progesterone has
a good
bioavailability
Several trials have
demonstrated the
efficacy of
Dydrogesterone in
IVF and IUI

59. Thank You