It describes the Progesterone physiology. It describes the latest evidence as regards progesterone formulations, use of progesterone as Luteal phase support. It scrutinizes the value of serum progesterone in monitoring luteal phase

1. Progesterone in
Reproduction: Concepts
Dr/ Mahmoud Abdel-Aleem
Professor of Obstetrics and Gynecology, Assiut university.

2. I DECLARE NO CONFLICT OF INTEREST

3. OBJECTIVES

4. To review the major concepts and display the updates as regards:
1- Luteal phase physiology.
2- Progesterone as a hormone.
3- Different Progesterone preparations.
4- Serum Progesterone and ART.
5- Luteal phase management with the use of Progesterone as a luteal
phase support.
6- Pharmacological use of Progesterone during early pregnancy

5. • Multiple uses of progesterone and progestogens for women’s health
in clinical practice are recognized.
• Its use is of good- quality evidence for some indications
• Preterm labor prevention.
• Balance estrogens in hormonal replacement therapies
• For oral contraception
• Palliative care for the treatment of gynecological malignancies.
• On the other hand, the role of progesterone for luteal phase support
still represents a controversial topic, due to its wide and empirically
transverse clinical use, from natural ovulatory cycles to (ART).

6. Progesterone as a hormone
The whole group is named “Progestogens”

7. Progestogens are hormones that bind to
the progesterone receptors.
During the midluteal phase, ovarian P4
production increases up to 25–50 mg/day.
23
members

8. Timeline of development
• 1934: isolated from animal CL.
• 1941: synthesized from plant sterol.
ButPoor gut absorption. Micronisation ButPoor bioavailability 5%.
• 1960s: Dydrogesterone (retroprogesterone) by UV exposure of the
progesterone: 28% bioavailability.

9. Synthesis of progesterone
Starts in response to
LH surge.
LH surge luteinizes
both granulosa and
theca cells.
Rapid increase in
serum of P4 and its
metabolite.

10. Role of progesterone in early pregnancy
• The physiologic effects are mediated by interaction
with progesterone receptor (PR).
• There are two classic PR isoforms: PR-A and PR-B.
• PR-A is required for normal ovarian and uterine function.
• PR-B is critical for mammary development.

11. Secretory
changes
Prevents
Embryo
Rejection
Immunotolerance
during pregnancy
Suppresses
uterine
contractions
Enhances uterine
quiescence
Successful
Implantation

12. Luteal phase physiology.

13. I. Normal Luteal Phase
According to Speroff & Fritz:
(1) normal luteal phase lasts from 12 to 14 days.
(2) progesterone secretion occurs in pulses.
(3) peak of progesterone levels in non-pregnancy cycles occurs 6–8
days after ovulation.
(4) progesterone secretion after implantation is regulated by hCG.

14. Assessment of luteal phase
• Basal body temperature (BBT) evaluation: inconvenient and not
precise
• Urinary luteinizing hormone (LH) surge detection kits: unreliable.
• Serum progesterone levels.
• Endometrial biopsy.
• ERA test
Practice Committee of the ASRM [2015]: “there are no practical standards to
diagnose LPD. The above-described methods (BBT, urinary LH kits, serum P4 levels
and endometrial biopsy are not recommended to confirm LPD”.

15. Serum progesterone levels
Not accurate nor precise:
• It is difficult to know the onset of luteal phase (ovulation time) which
is important to diagnose progesterone peak.
• Progesterone is secreted in pulses as the response of LH pulses/ 90
minutes.
• Intra-cycle variation: During pulse, its level can be 6–8 times higher.
• Inter-cycle variation: The hormonal activity (progesterone secretion)
of corpus luteum is different in subsequent cycles.

16. Endometrial biopsy
• Theoretically, LPD is diagnosed when histologic characteristics is
delayed ≥2 days in relation to known day of luteal phase.
• However, 2 big trials have shown the imprecision to diagnose luteal
phase adequacy and the inability to discriminate between infertile
subjects and fertile controls.

17. “ERA test”
The endometrial window of implantation (WOI), the cycle days during which normal embryo
implantation can occur, has generally been assumed to begin on cycle day 19 or 20 of an idealized 28
days cycle and last for 4 to 5 days.
The endometrial receptivity array [ERA] test is a molecular diagnostic
biomarker tool that identifies the receptive endometrium in natural and artificial
(hormonal replacement therapy) cycles.

18. II. Embryo Implantation
Receptive
endometrium Synchronized
dialog
A functional
embryo at the
blastocyst
stage
Implantation Window

19. Different Progesterone preparations

20. I. Types of progesterone supplementation
Selection of the most optimal
route of administration
should consider:
-Peak plasma concentrations.
-Possible side effects.
-Patient compliance.
Progesterone is administered
in 3 different ways:
-Oral.
-Vaginal.
-Intramuscular.

21. I- IM (Progesterone in oil)
Advantages
• Long lasting since 1980s
• Effectiveness.
• The gold standard.
Disadvantages
• Local side effects: pain/ swelling
and redness
• Painful nodules and aseptic
abscesses
• Severe cases of acute
eosinophilic pneumonia

22. II- SC progesterone
Advantages
• Subcutaneous (comfortable)
• 25 mg
• Safe
• Cmax values: 4-folds higher than
progesterone-in-oil IM
• Effective in supporting the luteal
phase in IVF patient.
• Non-inferior to Vaginal
Progesterone on the on-going
pregnancy rates at 10 weeks.
Disadvantages
• Rare: local reactions.

23. III. Oral route
Advantages
• Optimal compliance
Disadvantages
• Absorption can be affected by food,
rate of gastric emptying, GI motility,
GI secretions and increasing
splanchnic blood flow
• Hectic plasma concentration
(enterohepatic circulation and
variable gastric filling).
• Side effects: nausea & sleepiness
• Metabolites produced during passage
through the liver

24. Oral forms
Micronized progesterone
• In the late 1980s,
• Derived from plants.
• Micronization of progesterone in
particle sizes of < 10 um increases
the available surface area of the
drug and enhances the aqueous
dissolution rate and intestinal
absorption of progesterone.
• Not preferred now as oral route
Dydrogesterone
• Selective and strong receptor
affinity.
• High oral bioavailability.
• May have lower side effects.
• Active metabolites
• immunological beneficial effects
• Lotus I study
• Lotus II study

25. Dydrogesterone
Advantages
• Low dose
• Minimal side-effects
• Reduce the likelihood of altered
liver function.
Disadvantages
• Extensive first-pass metabolism
of oral progesterone limits its
efficacy
• May increase the risk of
intrahepatic cholestasis in
predisposed women

26. Lotus I: 05/ 2017
• RCT, double-blind, double-dummy,
Phase III
• For luteal phase support in fresh
cycle IVF.
• 1031 patients.
• Oral dydrogesterone (30 mg Vs
micronized vaginal progesterone
capsules (600 mg [200 mg three
times daily).
• Non-inferiority of dydrogesterone
to micronized vaginal progesterone
capsules was demonstrated (33.1%
Vs 37.6%)
Lotus II: 12/2018
• RCT, open-label, Phase III
• For luteal phase support in fresh
cycle IVF.
• 1034 patients
• Oral dydrogesterone (30 mg Vs 8%
micronized vaginal progesterone gel
(90 mg once daily).
• Non-inferiority of dydrogesterone
to micronized vaginal gel

27. IV. Vaginal Route
• Higher concentrations of the drug in the uterine tissue.
• First direct preferential vagina-to-uterus transport
• Treatment effects are significantly improved.
• Reducing the likelihood of undesirable side effects.
• Time-to-peak concentration tends to be slightly longer.
• After vaginal administration, plasma concentrations achieves
a plateau-like profile and are more constant in comparison to
oral delivery.
Passive diffusion through tissues.
Transluminal passage
Venous or lymphatic transfer.
Countercurrent vascular exchange.

28. Vaginal soft capsules of micronized
progesterone
Advantages
• Long lasting: 1990s.
• Compliance.
• Limited side-effects.
• Proper secretive transformation
of the endometrium.
• Provides greater bioavailability
of the active component at
endometrial level with lower
plasma progesterone levels.
Disadvantages
• Low doses were less effective than
IM route. However, the 600
mg/day yields comparable results
to IM.
• Vaginal leakage, which implies that
the real dosage adsorbed cannot
be assured.
• Local discomfort as genital itching,
genital irritation, vaginal discharge,
candidiasis, dyspareunia.

29. Endometrin vaginal tablets
Advantages
• FDA approval.
• Less vaginal irritation and
“messiness”
• Better adhesion and lesser
leakage.
Disadvantages
• Increased expense.

30. Vaginal progesterone bioadhesive gel
Advantages
• The same pharmacokinetic profile
as the capsule formulation.
• Comparable results to IM
progesterone in oil in preventing
spotting.
• Equivalent efficacy to all other
vaginal progesterone forms in
terms of clinical pregnancy rates in
ART
Disadvantages
• Expense

31. Progesterone releasing vaginal ring
• The progesterone vaginal ring is a device used for continuous release
of micronized progesterone; phase III trials are ongoing.
• This type of ring contains 1 g of natural progesterone and provides a
continuous and constant release of approximately 10 mg/day of
progesterone for at least 90 days.
• It can induce secretory transformation of endometrium after an
appropriate pretreatment with estrogens

32. Luteal phase support in ART with the
use of Progesterone
“Luteal Phase Medicine”

33. I. Value
•One of the agreed upon few points
is that progesterone during the
luteal phase increases the success
rate in ART (Higher rate of ongoing
pregnancy or live birth (OR 1.77).

34. II a. When to start ?_Fresh cycle
(i) after hCG
administration
for final oocyte
maturation
(ii) on the day
of oocyte
retrieval
(iii) on the
day of
embryo
transfer
Beginning of the luteal support 6 days after oocyte retrieval is associated with significantly lower
rates of clinical pregnancies because the exogenous progesterone deficit negatively impacts on
anatomical and functional changes of endometrium that characterize the “window of implantation.”

35. IIb. When to start ?_FET cycle
Pregnancy rate is similar when progesterone replacement
started at a time corresponding to the day of pick-up or the
day after pick-up, but worsened when the progesterone was
initiated at a time corresponding to the day before the pick-up
FET should be performed after a progesterone
replacement period equivalent to the embryo age
or to the embryo age plus 1 day. For example, if
the embryo was cryopreserved as a 3-day-old
embryo, the transfer should be scheduled after 3
or 4 days of progesterone administration.

36. III. When to stop?
• hCG secreted by the trophoblast
in progressively increasing
amounts from the beginning of
pregnancy, makes continuation of
exogenous progesterone
supplementation of limited value.
• An RCT found no differences in
terms of ongoing pregnancy,
deliveries or miscarriage rates
between the women (+hCG and 3
weeks)

37. IV. What dose?
Member
• IM progesterone
• SC progesterone
• Endometrin
• Crinone
• Micronized progesterone in capsules
• Dydrogesterone
Dose
50 mg/day
25 mg /day
200-300 mg/day
90-180 mg/day
300-600 mg/day
30 mg/day
The threshold of 10 ng/ml, which is close to the value reported as an
adequate progesterone production by the CL in natural cycles (Hull et al., 1982)

38. Serum Progesterone and ART.
I. Fresh Cycle: Late Follicular Elevated Progesterone
II. Frozen Cycle:

39. Luteal phase monitoring
Early luteal monitoring (OPU + 2)
• P4 levels exhibit a non-pulsatile
pattern in both the natural and
stimulated cycle (low values are
truely low)
• High accuracy of P4 assay.
• Detects a low prevalence of
patients in need of treatment
adjustments.
• A theoretical good chance to
correct for low P4 patients by use
of additional exogenous P4.
Mid-luteal monitoring (OPU + 7)
• Higher risk of P4 fluctuations in the
high P4 group of patients.
• Low accuracy of P4 assay
• Detects a higher proportion of
patients who require a change in
treatment.
• An intensified luteal phase support
to low P4 patients may be less
efficient late in the cycle.
To shift from the ‘one model fits all’ and towards a more individualized luteal phase support policy

40. Serum
P4
Fresh cycle
Basal P4
< 0.7
Late
Follicular
< 1.5
Early
Luteal
20-30
Mid-Luteal
45-80
As compared to Cleavage stage transfer, Blastocyst can
withstand transfer up to serum P4= 1.75 ng/dl

41. Serum
P4
Frozen cycle
Late
follicular
No cut-off
Day (-1)
10.6
Day 0
Art: 10
Mid-Luteal
22-31
ANTARCTICA’ trial Elevated progesterone concentrations, seem not to affect live birth and
pregnancy rates.

42. Fresh Cycle
Late Follicular Elevated Progesterone
• Defined as a serum P4 of ≥ 4.77 nmol/l (≥1.5 ng/l) on completion of COS,
before administration of HCG (Bosch et al., 2010; Venetis et al., 2015).
• The supraphysiologic milieu of hormones produced during ovarian
stimulation may affect endometrial receptivity (embryo–endometrial
asynchrony) and hinder both pregnancy rates and neonatal outcomes.
A meta-analysis of over 60 000 IVF cycles shows the presence of LFEP is associated with a significant
decrease in the probability of pregnancy, (Venetis et al., 2013).
• This may be due to:
• An abnormal endometrial gene expression (Labarta, et al., 2011, Van Vaerenbergh, et al., 2011).
• An atypical epigenetic profile in the luteal phase.

43. I. Risk factors of LFEP
Non-Modifiable Risk Factors
• Female age.
• Basal FSH.
• Basal Progesterone.
Modifiable Risk factors
• Duration of stimulation.
• Serum E2 on day of hCG.
• Number of oocyte retrieved.
• Number of 2 pronuclear oocytes.

45. II. Diagnosis of LFEP
• Absolute Figure: > 1.5 ng/dL. In average or low responders. 1.75ng/dL
in high responders.
• Single P4 measurement: Not precise.
• P4-to-follicle (Shufaro, et al., 2015)
• P4-to-oocyte (Hill, et al., 2017)
• P4-to-estradiol (Younis, et al., 1998, Lai, et al., 2009, Wu, et al., 2012).

46. III. Basal serum P4 in LFEP
• Basal progesterone (ovarian or
adrenal origin) is exhibits an
independent association with the
occurrence of PE regardless of the
intensity of ovarian stimulation.
• The presence of a corpus luteum
that did not undergo functional
luteolysis

47. IV. How long is the LFEP?
• “For how long can we allow the
endometrium to be exposed to P
above a certain universal
threshold?”.
Cycles with an increasing duration of LFEP >1.50 ng/mL are associated
with a significant decrease in LBR. However, the relative frequency of
having such LFEP levels for >1 day was so rare (1.9%).

48. V. Predict and prevent the “LFEP”
• Identification of variables that could identify patients at risk for PE on
the day of hCG.
• Pretreatment with oral contraceptive pill or corticosteroids might
reduce the reoccurrence of high basal progesterone.
• Careful addition of LH activity during stimulation.
• Prevent the occurrence of PE: milder ovarian stimulation that results
in a lower number of oocytes.

49. VI. Manage the “LFEP”
• Counsel the patient.
• Freezing all embryos and deferring embryo transfer for a
subsequent frozen-thawed cycle Transfer.

50. Pharmacological use of Progesterone
during early pregnancy
Controversial issue

51. Progesterone in miscarriage
threatened/ recurrent
Theoretical
• Improved endometrial blood flow.
• Immunological properties.
• Increase Nitric oxide synthesis in
human vascular endothelial cells in
vitro, mainly mediated through mPRα.
• Dydrogesterone (main metabolite
DHD) elicits a consistent increase in
nitric oxide synthesis from these cells.
PROMISE trial
• 836 patients with RM.
• Vaginal Progesterone 400 mg
vaginally from positive pregnancy
test to 12th week of gestation).
• No significant reduction in live
birth after 24 weeks of gestation,
neither miscarriage rate.
• The main limitation is the lack of
luteal supplementation

52. Conclusions
• Progesterone is essential for pregnancy initiation and maintenance.
• Different progesterone preparations exist allowing alternative choices
for each case.
• LFEP should be first prevented by soft ovarian stimulation protocols.
• Serum progesterone may have a role in standardizing ET protocols.
• Progesterone has little –if any- role in the management of threatened
and recurrent miscarriage.