1. Challenges of
Progesterone usage
DR G A RAMA RAJU

3. OUTLINE MY TALK
LUTEAL PHASE
DEFECT
PREGNANCY
• MISCARRIAGE
• PRETERM
INFERTILITY
• LUTEAL SUPPORT
• IVF CYCLE
• FROZEN
TRANSFER

4. . Pharmacodynamic profile of micronized progesterone [P4] in gynecology.
P.C.M. Piette / Best Practice & Research Clinical Obstetrics and Gynaecology 69 (2020) 13e29

5. Pharmacodynamic profile of micronized
progesterone [P4] in pregnancy maintenance.
P.C.M. Piette / Best Practice & Research Clinical Obstetrics and Gynaecology 69 (2020) 13e29

6. 32
Luteal Phase Support ???

7. LUTEAL PHASE ABNORMAL IN STIMULATED CYCLES
Day 6
Trigger
Luteal phase length (days)
Day 8
LHactivitydeficient period
Day 14
hCG
GnRHa
28-32h
LHactivitydeficient period
Courtesy of Prof. Humaidan;
Adapted from data of Damewood et al., 1989; Gonen et al., 1990; Itskovitz et al., 1991; Weissman et al., 1986 ; Bonduelle et al., 1988
Esteves,5

8. Premature onset of menses.1949:
Luteal phase deficiency of progesterone production, which was shown to
be correctable by exogenous progesterone administration (Jones, 1979)
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)
8
LPS in Natural Cycle

9. CURRENT CONTRAVERSIES IN LUTEAL
PHASE

10. How to Define a Luteal Phase Defect
The defective luteal phase in natural cycle was defined as serum
mid-luteal progesterone levels less than 10 ng/mL (Jordan et al,
1994)
Mid-luteal P levels do not always reflect endometrial maturation
(Batista et al, 1994)
The most reasonable consensus on a defective luteal phase is a
lag of more than 2 days in endometrial histological development
compared with the expected day of the cycle (Jones, 1991;
Dawood, 1994)
10

11. 2012

12. 2015
REPLACED BY 2021

13. 2021
(Fertil Steril! 2021;115:1416–23. !2021 by American Society for Reproductive

14. Causes of
luteal
phase
deficiency.
HYPOTHALAMIC AMENORRHEA
EATING DISORDERS
EXCESSIVE EXERCISE
SIGNIFICANT WEIGHT LOSS
STRESS
OBESITY
POLYCYSTIC OVARY SYNDROME
ENDOMETRIOSIS
AGING
UNDIAGNOSED OR INADEQUATELY TREATED 21-HYDROXYLASE DEFICIENCY
THYROID DYSFUNCTION
HYPERPROLACTINEMIA
OVARIAN STIMULATION ALONE
ASSISTED REPRODUCTIVE TECHNOLOGY USE
Fertil Steril! 2021;115:1416–23. !2021

15. Venn diagram outlining number and overlap of cycles with clinical LPD
Luteal Phase Deficiency in Regularly Menstruating Women: Prevalence and Overlap in Identification Based on Clinical
and Biochemical Diagnostic Criteria

16. PROPOSED DIAGNOSTIC TESTS FOR LPD
Diagnosis of LPD is made clinically. Multiple diagnostic tests have been
proposed,
including clinical, biochemical,
histologic tests,
but none have been able to differentiate between
fertile and infertile women reliably
Fertil Steril! 2021;115:1416–23. !2021

17. PROPOSED
TREATMENTS
Empiric strategies have included
supplemental
luteal
progesterone,
luteal
progesterone
plus estrogen,
luteal hCG,
ovarian
stimulation with
clomiphene or
gonadotropins.
The first approach to the treatment
of potential LPD is the correction of
any underlying condition,
Fertil Steril! 2021;115:1416–23. !2021

18. Idiopathic LPD has not been
proven to cause infertility
Fertil Steril! 2021;115:1416–23. !2021

19. Progesterone in
luteal phase
no evidence that progesterone is
beneficial for treating LPD.
The data on the use of progesterone
supplementation for recurrent
pregnancy loss are conflicting and
may not necessarily be reflective of
patients with LPD.
Fertil Steril! 2021;115:1416–23. !2021

20. LUTEAL PHASE SUPPORT IN OVULATION INDUCTION

21. only one small study has investigated the effect of clomiphene in subjects with LPD
(diagnosed by out-of-phase endometrial biopsy).

22. Luteal phase support with progesterone does not improve pregnancy
rates in patients undergoing ovarian stimulation with letrozole

23. Miscarriage
Facts
An estimated 23
million miscarriages
occur every year
worldwide.
44 pregnancy
losses each
minute.
Pooled Risk of
miscarriage is
15% of all
recognized
pregnancies.

24. The data.

25. Schematic representation of the human progesterone receptor gene
and protein domains of progesterone receptor (PRG) B, A and C
isoforms
M. Halasz, J. Szekeres-Bartho / Journal of Reproductive Immunology 97 (2013) 43–50

26. Regulation of
endometrial receptivity
and trophoblast
attachment to the
endometrial surface by
progesterone
M. Halasz, J. Szekeres-Bartho / Journal of Reproductive
Immunology 97 (2013) 43–50

27. The role of
progesterone
in
implantation
and
trophoblast
invasion
Progesterone regulates not only the peri-
implantation period and immune responses during
pregnancy, but also the induction of labour and
cervical ripening.
progesterone exerts its effects via genomic and non-
genomic actions that converge to produce tissue- and
cell-specific responses
The genomic actions of progesterone are mediated
via the classical nuclear progesterone-receptors (PRs),
PR-A and PR-B (Li and O’Malley, 2003)
different intracellular progesterone-receptor variants
have also been detected, including the PR-C (60 kDa),
PR- M (38 kDa), PR-S and PR-T isoforms
Membrane-bound progesterone receptors (Zhu et al.,
2003) have been implicated in rapid non-genomic
actions of progesterone (

28. women with a history of miscarriage who present with bleeding in early pregnancy may benefit
from the use of vaginal micronized progesterone 400 mg twice daily.

29. PROMISE trial data on live birth >24 weeks by the number of previous
miscarriages
PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent
miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and
economic evaluation. Health Technol Assess. 2016 May;20(41):1-92.

30. PROMISE TRIAL
PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent
miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and
economic evaluation. Health Technol Assess. 2016 May;20(41):1-92.

31. PRISM trial data on live birth >34 weeks
by the number of previous miscarriages

32. PRISM TRIAL:PROGESTERONE IN BLEEDING
IN EARLY PREGNANCY
Progesterone is
likely to be cost-
effective for all
women at risk,
but particularly
for women with
one or more
previous
miscarriages
who present
with bleeding in
early pregnancy.
The PRISM trial - bleeding in early pregnancy and
miscarriage

33. PRISM trial:
The cost-effectiveness of
progesterone in preventing
miscarriages in women with
early pregnancy bleeding: an
economic evaluation
The PRISM trial - bleeding in early pregnancy and
miscarriage

34. PRETERM BIRTH

35. PRETERM BIRTH
Activated T cells, preterm labor and birth prevented by treatment with progesterone [
Effector and Activated T Cells Induce Preterm Labor and Birth That Is
Prevented by Treatment with Progesterone. J Immunol 1 May 2019;

36. T he only class of medication to demonstrate significant reductions repeatedly in the rate of
early preterm birth are progestogens, natural progesterone or the synthetic 17-
hydroxyprogesterone caproate (17-OHPC).
Oct. 30, 2015.

37. PREVENTION OF PRETERM BIRTH
Boelig RC, Schoen CN, Frey H, et al. Vaginal progesterone vs intramuscular 17-
hydroxyprogesterone caproate for prevention of recur- rent preterm birth (VIP): a randomized
controlled trial. Am J Obstet Gynecol 2022;226:722.e1-12

38. Boelig RC, Schoen CN, Frey H, et al. Vaginal progesterone vs intramuscular 17-
hydroxyprogesterone caproate for prevention of recur- rent preterm birth (VIP): a randomized
controlled trial. Am J Obstet Gynecol 2022;226:722.e1-12

39. Luteal Phase Defect in Stimulated
Cycles

40. Nosarka et al. 2005.
LPS is mandatory in IVF stimulated cycles

41. Luteal Phase Defect in Stimulated Cycles
Schematic representation of changes in luteal phase length and
progesterone profile induced by ovarian hyperstimulation for IVF
(Macklon et al, 2006)
This Photo by Unknown Author is licensed under CC BY

42. Mid-luteal LH levels
6.0 IU/l in natural cycle (Tavaniotou
and Devroey 2003)
1.5 IU/l in GnRHa trigger (Humaidan
et al, 2005)

43. Early Luteal Phase After
GnRHa Trigger
Damewood et al., 1989;
Bonduelle et al., 1988;
Gonen et al., 1990;
Itskovitz et al., 1991

44. Luteal phase reality
after HCG trigger:
Weissman et al.,
1986 ; Bonduelle et
al., 1988

45. Luteal effects of Progesterone
Transforms the
endometrium into
the secretory
phase
Regulates the
window of
implantation
(WOI)
Increases
endometrial
vascularization
Immuno-
modulator
Reduces uterine
contractions at
peri-implantation

46. LUTEAL PHASE SUPPORT
GnRHa trigger review :

47. European Concept” – fresh transfer
American Concept
• European Concept” – fresh transfer
• GnRHa trigger and modified luteal phase
support: Dissociation of the trigger from
the luteal phase support
• GnRHa trigger followed by 1.500 IU hCG
on day of aspiration and a standard luteal
phase support
• (Humaidan et al., 2006;2009;2010;2013;
Iliodrommiti et al., 2013)
• Promoting the endogenous steroid
production
• American Concept” – fresh transfer
• GnRHa trigger and modified luteal phase
support:
• GnRHa trigger followed by intensive luteal
progesterone and estradiol support
• (Engmann et al., 2008; Griffin et al., 2012;
Imbar et al., 2012; Iliodromiti et al., 2013)
• Relying on exogenous steroid support -
only

49. LPS
FRESH
CYCLE
LUTEAL PHASE FRESH CYCLE
49

50. LUTEAL PHASE – When in FET?
LPS
Frozen
Thawed ET
(FET)
True Natural Cycle
Modified
Natural
Artificial
Stimulated
50
Endometrial
Priming??

51. ?
LPS
Frozen
Thawed ET
(FET)
LUTEAL PHASE – When in FET
51

52. Key Take Home Messages: FET
Different methods of endometrial preparation and LPS seem
equally effective for Pregnancy Success (Mackens et. al. 2017):
Decision should be based on clinician experience and patient
preference
Duration of PG exposure and dosage might impact pregnancy
outcomes (Deviene et. al. 2018; Alsbjerg et. al. 2012)
52
Different methods of endometrial preparation and LPS seem equally
effective for Pregnancy Success (Mackens et. al. 2017):

53. Progesterone: What Dosage?

54. ROUTE OF ADMINSTRATIONS

55. • Oral vs IM
• Vaginal/rectal vs. IM
• Vaginal/rectal vs. Oral
• Low-dose vs. High-dose vaginal
• Short (Early cessation) vs. Long protocol
• Micronized vs. Synthetic
• Vaginal ring vs. Gel
• Vaginal vs. Subcutaneous
• OHSS rates (Oral vs. IM; Low-dose vs. High-dose)
45 RCT; N=13,814
women
Odds ratios for
pregnancy not
significantly different
Quality of Evidence
varied from low-quality
to very low-quality
Routes/Formulation of LPS with
Progesterone: The best ?.
Almohammadi, A., Raveendran, A., Black, M. et al. The optimal route of progesterone administration for
luteal phase support in a frozen embryo transfer: a systematic review. Arch Gynecol Obstet (2022)

56. Which route of administration do you prefer for progesterone in HRT-FET
cycles ?
http://www.ivf-worldwide.com/survey/frozen-thawed-embryo-transfer/results-frozen-thawed-
embryo-transfer.html
56

57. Route of Administration of Progesterone in FET Cycles
Dydrogesterone:
Lower CPR

58. Route of Administration of Progesterone in FET Cycles
58
VAGINAL vs. IM
No differences in implantation,
miscarriage, and live birth rates

59. Progesterone Vaginal Gel in Details
Ficicioglu et al. Gynecol Endocrinol 2004; 18: 240-3

60. Oral Progesterone micronized
Ineffective?
60
• Progesterone administered orally
• Degradation to its 5α- and 5β-reduced metabolites (Penzias, 2002)
• Bourgain (1990) and Devroey (1988) reported absence of any secretory
transformation of the endometrium in patients treated with oral micronized
progesterone compared to IM or vaginal micronized progesterone
Bourgain (1990) and Devroey (1988

61. DG, a retro progesterone with
good oral bioavailability, has an
antiestrogenic
effect on the endometrium,
causing a secretory
transformation (Whitehead,
1980)
Chakravarty et al (2005) in a
prospective, randomized study
compared the efficacy of
vaginal micronized
progesterone with oral DG as
luteal phase support after IVF
Both DG and micronized
progesterone were associated
with similar rates of
successful pregnancies (24.1%
vs 22.8%, respectively; P=0.81)
61
Oral Progesterone Dydrogesterone
(Whitehead, 1980)
Chakravarty et al (2005

62. Endometrial Diffusion: Vaginal Progesterone
Four hours after application
Progressive diffusion of progesterone from
the cervix to
the fundus of the uterus
Bulletti et al. Hum Reprod. 1997;12:1073.

63. P.C.M. Piette / Best Practice & Research Clinical Obstetrics and Gynaecology 69 (2020) 13e29

64. Effective Physiological serum levels Painful (long, thick needles) Occasional sterile abscess
Occasional allergic reaction
(oil vehicle)
Needs to be administered
by nurse, husband
Acute eosinophilic
pneumonia associated with
IM administration of
progesterone as luteal
phase support after IVF: 6
case reports
98
IM Progesterone

65. SC Progesterone. Gaining acceptance
Baker et al, 2014

66. Dydrogesterone vs. Progesterone

67. Dual trigger”– fresh transfer
Combining
GnRHa trigger
and a bolus of
hCG (Shapiro et
al., 2008; 2011;
Griffin et al.,
2012; Lin et al.,
2013)
Trigger and
early luteal
phase support
combined with
a standard
luteal phase
support
Humaidan et al. Hum Reprod. 2013;28(9):2511-‐21

68. • 1,500 IU hCG at OPU & 1,000
OPU +5& standard LPS
≤14
• 1,500 IU hCG at OPU + standard
LPS
15-25
• 1,000 IU hCG at OPU + standard
LPS orFreeze all
26-30
>30
No.
Follicles
day
OPU
Humaidan et al. Hum Reprod. 2013;28(9):2511-‐21 68
HCG AS MODIFIED LPS SUPPORT IN GNRH TRIGGER FOR
FRESH ET
•Freeze all

69. MEASURING PROGESTERONE IN FROZEN CYCLE AND
FRESH TRANSFERS
FROZEN DAY 4
FRESH
MIDLUTEAL
• DAY 6 ?7 OF OPU

70. MY THANKS TO THE CHAIRPERSONS AND THE ZYDUS TEAM

71. THANK YOU