Increasing maternal age, need for assited reproduction also has increased the need for appropriate luteal phase support During the luteal phase of the menstrual cycle, progesterone plays a crucial role in preparing the uterine lining for potential embryo implantation. In assisted reproductive technologies (ART) and fertility treatments, optimizing luteal phase support is essential for successful outcomesAdministering exogenous (external) progesterone during the luteal phase is associated with significantly higher pregnancy rates compared to placebo or no treatmentWomen undergoing ART are appropriate candidates for luteal phase supportchoosing the right progesterone for luteal phase support is critical for optimizing fertility treatments. Collaboration among specialists ensures better outcomes for patients

1. Choosing the right
progestogens for Luteal
Phase Support
Evidence based discussion on safety and
efficacy of progestogens

2. Table of contents
Efficacy of Progestogens used for Luteal Phase Support
• Introduction
• Role of progesterone
• Mechanism of action on progesterone in ART
• Progesterone formulations
• Clinical evidence
• Summary
Safety of Progestogens used for Luteal Phase Support

3. Introduction
• In vitro fertilization (IVF) is commonly used by reproductive endocrinology and
infertility specialists to help subfertile couples become pregnant
ART cycles with GnRH agonists
Pituitary Gland: Suppression of pulsatile secretion of LH
Luteal phase insufficiency
Inadequate endometrial secretory transformation- affects implantation
Luteal Phase Progesterone Support essential
Luteal Phase Progesterone Support in ART/IVF. MedScape. Janelle Luk, MD; Pasquale Patrizio, MD

4. Progesterone for LPS in Pregnancy
Supports endometrial growth
Improves blood flow & oxygen
supply by increasing nitric oxide
(NO) production
Keeps myometrium quiescent
by utero relaxing effect
Sustain survival of embryo by
shifting immune system towards
production of T-helper (Th2)
response
Progesterone
Shah D et al. Luteal insufficiency in first trimester. Indian Journal of Endocrinology and Metabolism. 2013; 17 (1).
Progesterone secretion by corpus luteum is required for success of early
human pregnancy
LPS, Luteal phase support
4

5. Progesterone, Progestins or Progestogens?
J Steroid Biochem Mol Biol. 2013 Sep; 137: 27–49. BMJ 2009;339:b4380
Compounds with biological activities like those of progesterone are referred to as progestins, progestational
agents, progestagens, progestogens, gestagens, or gestogens.
-Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Ed. 2018
5
Progestogens1
(Compounds with
progestational activity)
Bioidentical
(Natural Progesterone)
E.g. Micronized Progesterone
Different Chemical Structure
(Synthetic Progestins)
E.g. Dydrogesterone, 17-Hydoxy
Progesterone, Medroxyprogesterone
etc.
A word of clarification “Natural”: In the context of Hormone, Term ‘Natural’ is
based on its bioidentical chemical structure and not based on its source2
1. Endocrine Reviews, April 2013, 34(2):171–208 2. Women Health Primary Care 1998:1(8):671-687

6. Progesterone: Actions on Uterus
Progesterone
Stimulates growth of
uterus & stabilizes
endometrium
Maintains uterine
quiescence
Decidualization
↓myometrial
contractions Secretory endometrial
transformation
Immunomodulation
↑Vascularity of
endometrial lining
↑Uterine blood flow
↑NO Production
Malik S, et al. J Clin Diagn Res. 2016 Feb;10(2):QE01-4.
6

7. Progesterone ensures “in-phase” secretory
transformation of endometrium
Induces normal secretory endometrial changes
during the mid-luteal phase like
• Coiled glands with active secretion
• Minimal residual vacuole in glands
• Stromal oedema
• Ensures favorable endocrine hormonal
parameters during mid-luteal phase (High
progesterone level, Low FSH & LH level)
• A prospective study evaluated the endometrial histology
and endocrine profiles on day 21 of an artificial cycle in
women with premature ovarian failure treated with DG
or vaginal micronized progesterone.
0
1
2
3
4
5
6
7
Vaginal NMP Dydrogesterone
No.
of
Patients
Patients with 'In-Phase'
biopsy
Total Patients
this study concluded that there was more synchronous ‘in-phase’
development of endometrium with micronized progesterone.
Fatemi HM et al, Hum Reprod. 2007 May;22(5):1260-3.

8. Progesterone: Ensures optimum endometrial receptivity
Alpha-V-beta-3 integrin expression
•Promotes embryo attachment & is a marker of
endometrial receptivity
•‘alpha-V-beta-3 integrin’ expression during window
of implantation (day 21) helps in integration of
blastocyst
Pinopodes formation
•Pinopodes are required for successful implantation
•Progesterone alone is responsible for highest
frequency of pinopodes formation
•Pinopodes helps in apposition, adhesion &
implantation of blastocyst
•Increases pregnancy rate by 2 fold
A blastocyst approaching receptive endometrium
3. Alpha-V-beta-
3 integrin
expression 1. In-Phase secretory
endometrium
2. Pinopodes
formation

9. Implanting blastocyst: Progesterone regulates endometrial function and
trophoblastic proteolytic activity

10. Immunomodulation for Maintenance of
Pregnancy
Embryoprotective immunomodulation mediated by progesterone-induced blocking factor.
Th, T-helper; ABs, antibodies; NK, natural killer; TNF, tumour necrosis factor; IFN, interferon; IL, interleukin.
Best Pract Res Clin Obstet Gynaecol. 2008 Apr;22(2):375-89.
11

11. Immunomodulation: TH1-TH2 Paradigm
Cytokines
Messengers of the immune system
TH1 TH2
TH1 Cells
Proinflammatory cytokines
IL2, TNFα, TNFβ, IFNγ
Cell Mediated Immunity
TH2 Cells
Anti-inflammatory cytokines
IL3, IL4, IL6, IL10
Humoral Immunity
T Helper Cells = Subset of Lymphocytes
IL, Interleukin, TNF, Tumor necrosis factor, IFN, Interferon
12

12. Immunomodulation: TH1-TH2 Paradigm
TH2
TH1
Miscarriage/
Abortion
↓ Progesterone
↓ PIBF
1. Norwitz ER et al. N Engl J Med 2001; 345(19): 1400-1408; 2. Raghupathy R et al. BJOG 2005; 112(8):1096-1101; 3. Szekeres-Bartho J, Wegmann TG. J Reprod Immunol 1996; 31(1-2): 81-95; 4. Szekeres-
Bartho J. Int Rev Immunol 2002; 21(6): 471-495; 5. Raghupathy R et al. J Reprod Immunol 2009; 80(1-2): 91-99.
NK, natural killer; PIBF, progesterone-induced blocking factor; Th,
T helper
Lymphocyte
Progesterone
TH1
TH1
TH2
TH2
PIBF
Progesterone inhibits the production of TH1 cytokines
& upregulates production of TH2 cytokines2
Progesterone stimulates production of PIBF which induces TH2 response &
down-regulates NK activity, thus exerting an anti-abortive effect2-5
Normal
Progressing
Pregnancy
Progesterone
is
essential
for
maintenance
of
pregnancy.
Produced
by
corpus
luteum
until
7-9
wks,
later
placenta
takes
over
1
13

13. When to Start Luteal Support?
 Progesterone supplementation may be started
 On day after ovulatory hCG dose
 On day of oocyte retrieval
 On day of embryo transfer
Muñoz E et al. Current Drug Targets. 2013; 14: 832-842; Fertil Steril. 2015 Apr; 103(4): 939–946.e3.
There appears to be a window for progesterone start time
between the evening after oocyte retrieval and day 3 after
oocyte retrieval.
15

14. Progestogens formulations
Natural Micronised Progesterone
• Vaginal
• Oral
• Rectal
• Intramuscular (IM)
• Subcutaneous (SC)
Synthetic Progestogen
• Dydrogesterone
Fatemi HM, et al. Human Reproduction Update. 2007;13(6):581–590.

15. Clinical evidence

16. Jan 2022
All programs used a combination of follicle-
stimulating hormone and luteinizing hormone for
IVF stimulation, intramuscular progesterone in
frozen embryo transfer cycles, ultrasound-
guided embryo transfers, and a required semen
analysis before starting the IVF cycle.
All clinics used intramuscular
progesterone for
frozen embryo transfers, and
the majority started
intramuscular progesterone
120 to 131 hours before
transfer
Fertil Steril2022;117:42–50.

17. Fertility and Sterility® Vol. 116, No. 3, September 2021 0015-0282/$36.00
Sep 2021
44%
27%
46%
IM Prog Daily Vag. Prog. 400mg Daily Vag. Prog + IM Prog
Live Birth Rate, n=1060 FETs Addition of Intramuscular
progesterone injection every 3rd
day to daily Vaginal
progesterone group significantly
improves live birth rate, like that
of daily IM progesterone
injection group

18. Objective: To compare the hypertensive disorders of pregnancy (HDP) risk between vaginal and intramuscular (IM) progesterone in
programmed frozen–thawed embryo transfer (FET) cycles.
Prevalence of HDP
n=5891 FET cycle
6.54%
IM
Prog
9.17%
Vaginal
Prog
The prevalence of HDP in the IM
progesterone group was
significantly lower
The prevalence of gestational hypertension (3.57% vs 4.94%, P = 0.009) and pre-
eclampsia (2.97% vs 4.23%, P = 0.009) in the IM progesterone group were all
significantly lower as compared to the vaginal progesterone group
Conclusion
Among women undergoing programmed FET cycles, progesterone
supplementation with IM progesterone was associated with reduced HDP
risk compared to vaginal progesterone.

19. Aim Evaluate the reproductive outcome in patients receiving frozen–thawed embryo
transfer before and after doubling of the vaginal progesterone gel supplementation
N 346
Intervention 90mg progesterone gel once daily from Jan 2006 to Nov 2007 following which dose
changed to twice daily.
Day-3 embryos were thawed and transferred on day 4 of progesterone treatment
Reproductive BioMedicine Online (2013) 26, 133– 137

20. The pregnancy rate increased significantly
after doubling of the progesterone dose
(26.7% (90 mg) vs 38.4% (180 mg); P = 0.021).
Early pregnancy loss rate decreased significantly
(67.4% versus 43.7%, respectively; P = 0.014),
which significantly increased the delivery rate
(8.7% versus 20.5%, respectively; P = 0.002).
Conclusion: Doubling of the vaginal progesterone gel supplementation during frozen–thawed embryo transfer cycles
decreased the early pregnancy loss rate, resulting in a significantly higher delivery rate.
Reproductive BioMedicine Online (2013) 26, 133– 137

21. N= 179
Cohort – Patients with endometriosis
Endometrial priming
Vaginal progesterone 90mg twice
daily
When
Endometrial
thickness >7mm
(On 4th day of
vaginal
progesterone
If Pregnancy positive –
Vaginal progesterone and estradiol
Continued till 10th week of gestation
IM progesterone continued till 7-8th
week of gestation
Birgit Alsbjerg Et Al , RBMO VOLUME 46 ISSUE 1 2023; DOI: Https://Doi.Org/10.1016/J.Rbmo.2022.09.005

22. Overall
positive
HCG
live birth
(LBR)
Total
pregnancy
loss rates
60% 39% 34%
Birgit Alsbjerg Et Al , RBMO VOLUME 46 ISSUE 1 2023; DOI: Https://Doi.Org/10.1016/J.Rbmo.2022.09.005
Live birth Rate was significantly higher in patients
with progesterone measuring 118 nmol/l or above
compared with patients with progesterone measuring
less than 118 nmol/l (51% [44/86] versus 34%
[59/176], P = 0.01),
Odds ratio for a live birth was 2.1
(95% CI 1.2 to 3.7)

23. Multicenter
prospective
trial
N=90
women
undergoing
ICSI cycle
25
Divided into
3 groups
Protocol I - 100 mg
progesterone daily as single
IM dose from day of ovum
pick-up till day of
pregnancy test
Protocol II – Protocol I + 6
mg estrogen daily in 3
divided doses from 7th post
embryo transfer to day of
pregnancy test
Protocol III – Protocol I + s.c
0.1 mg Triptorelin daily
from day 6 post embryo
transfer
*from day of ovum pick-up until day
of pregnancy test
Implantation rate,
Clinical pregnancy
rate, or
Ongoing
pregnancy rate

24. Results
32.90%
45%
42%
28.90%
44.60%
41.80%
29.80%
44.70%
41.60%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
40.00%
45.00%
50.00%
Implantation rate Clinical pregnancy rate Ongoing pregnancy rate
Protocol I Protocol II Protocol III
There is no difference between any of the luteal phase support protocols used however, using single dose of
progesterone injection (100mg) daily is the simplest and most cost-effective protocol
P=0.81
P=0.68
P=0.91

25. Retrospective,
observational,
case-control study
172 A-GnRH down-
regulated IVF-ET
cycles in patients
with age <40 years
IM progesterone
(50 mg daily)
N= 86
V GEL
progesterone
(90 mg daily)
N= 86
Biochemical
pregnancy,
clinical
pregnancy,
miscarriage,
ongoing
pregnancy
rates.
Eur Rev Med Pharmacol Sci. 2010 Feb;14(2):103-6

26. Results
38.40%
6.90%
31.30%
22.20%
24.40%
29.10%
5.80%
19.70%
35.30%
12.70%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
40.00%
45.00%
Pregnancy rate/cycle % Biochemical
pregnancy/cycle %
Clinical pregnancies/cycle % Miscarriage/clinical
pregnancy %
Ongoing pregnancy/cycle %
I.M. Progesterone Intravaginal progesterone
P=NS
P<0.05
P=NS
P=0.08
P=NS
In standard IVF cycles, results showed that IM progesterone appears to be more effective at
providing luteal support when compared to intravaginal progesterone
Eur Rev Med Pharmacol Sci. 2010 Feb;14(2):103-6

27. Randomized
control trial
182 infertile
patients between
20-40 years for
rapid ZIFT cycles
Intravaginal
progesterone
suppository
(800mg daily)
N= 77
Intramuscular
progesterone (100
mg daily).
N= 85
Biochemical
pregnancy,
clinical
pregnancy,
ongoing
pregnancy
rates.
ZIFT - Zygote intra fallopian transfer
Journal of Family & Reproductive Health, 2008 2(2):99-102

28. Results
27.30%
22.10%
15.60%
30.60%
27.10%
18.80%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
Biochemical pregnancy Clinical pregnancy Ongoing pregnancy
Intravaginal progesterone suppository Intramuscular progesterone
Chemical pregnancy, clinical pregnancy and ongoing pregnancy rates were
similar in vaginal and intramuscular progesterone groups
P=0.7
P=0.4 P=0.6
Journal of Family & Reproductive Health, 2008 2(2):99-102

29. Retrospective
analysis
460 cycles in
IVF/ICSI–blastocyst
transfer (BT)
treatment
Intravaginal
progesterone gel
N= 230 patients
Intravaginal
progesterone
capsule
N= 230 patients
Implantation
rate, clinical
pregnancy
rates
Taiwan J Obstet Gynecol 2009;48(4):375–379
Progesterone
Progesterone

30. Results
58.70%
32.04%
5.19%
44.30%
23.89%
8.82%
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
Clinical pregnancy rate/transfer cycle % Implantation rate % Abortion rate %
Intravaginal progesterone gel Intravaginal progesterone capsule
P=0.001
P=0.002
P=0.269
Luteal phase support with Progesterone vaginal gel (90 mg daily) resulted in better clinical pregnancy
and implantation rates than Progesterone vaginal capsules (200 mg, 4 times daily) in IVF/ICSI–BT cycles
[Taiwan J Obstet Gynecol 2009;48(4):375–379
Taiwan J Obstet Gynecol 2009;48(4):375–379

31. Prospective
Randomized
Clinical Trial
1,500
progesterone-
supplemented
FET cycles
Intravaginal
progesterone gel
N= 750 cycles
Intramuscular
progesterone
injection
N= 750 cycles
Live birth,
clinical
pregnancy,
implantation,
abortion or
ectopic
pregnancy
Wang Y, He Y, Zhao X, Ji X, Hong Y, Wang Y, et al. (2015). PLoS ONE 10(7): e0133027.
doi:10.1371/journal.pone.0133027
Progesterone

32. Results
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
40.00%
45.00%
Live birth Clinical pregnancy Implantation Abortion Ectopic pregnancy
Intramuscular progesterone injection Intravaginal progesterone gel
P=0.71
P=0.772
P=0.514
P=0.228
P=0.831
Using progesterone vaginal gel in FET cycles achieved similar pregnancy outcomes to intramuscular progesterone,
indicating that vaginal gel is a viable alternative to intramuscular injection
Wang Y, He Y, Zhao X, Ji X, Hong Y, Wang Y, et al. (2015). PLoS ONE 10(7): e0133027.
doi:10.1371/journal.pone.0133027

33. Prospective
Randomized
Clinical Trial
frozen-thawed
embryos
transfer in
3013 patients
progesterone
intramuscular
injection (60
mg/d) +
dydrogesterone
(N= 1988)
progesterone
vaginal SR
gel (90 mg/d) +
dydrogesterone
(N= 1025)
Implantation,
clinical
pregnancy,
delivery, live
birth and
ectopic
pregnancy
https://doi.org/10.1038/s41598-019-51717-5

34. Results
37%
56.00%
45.10% 45.00%
3.00%
34.40%
52.50%
41.00% 40.80%
2.20%
0%
10%
20%
30%
40%
50%
60%
Implantation rate Clinical pregnancy rate Delivery rate Live birth rate Ectopic pregnancy rate
Vaginal progesterone SR gel Intramuscular progesterone injection
P<0.05
Vaginal gel progesterone supplementation has good effects on frozen-thawed embryo transfer and can significantly
increase the rate of implantation, delivery and live birth but decrease the abortion rate compared with intramuscular
progesterone injection
P<0.05
P<0.05
P>0.05
P>0.05
https://doi.org/10.1038/s41598-019-51717-5

35. N= 370 women aged <45 years undergoing IVF-ET treatment
Gynecological Endocrinology, December 2011; 27(12): 1010–1013
Progesterone supplementation begun on the day of oocyte retrieval and continued until pregnancy was tested and in the case of pregnancy until week 8
39.50%
6.40%
33.50%
15.60%
Ongoing pregnancy rate (per ET) Abortion rate
Oral Progesterone 300mg + Vaginal NMP Gel 90mg Vaginal NMP Gel 90mg
The comparable rates of ongoing pregnancies were
noted with use of combined-progesterone therapy
(39.5%) and progesterone-monotherapy (33.5%).
Abortion rate (6.4% vs. 15.6%) was significantly
lower with the use of combined therapy

36. Progesterone may be supplemented exogenously in obstetric conditions associated with
insufficient levels. Natural micronized progesterone is a commonly used progestogen in obstetrics.
NMP is available as oral, injectable and vaginal dosage forms.
Aim/Objective:
To assess the effectiveness of the oral NMP-SR in obstetrical conditions.
Modi S et al, Effectiveness of the oral sustained release formulation of natural micronized progesterone (NMP SR) in obstetrics: A retrospective, multicentre, real world study. Eposter
presented at: FOGSI South Zonal Conference With Yuva; 2023 Mar 10-12; Calicut, Kerala, India

37. Threatened abortion/
Recurrent Pregnancy Loss
13
12
No. of Patients with
Threatened Abortion
Pregnancy continued
>20 wks
92.3%
Pregnancy
Continuation
Rate
Luteal Phase Support
88%
Clinical
pregnancy
rate
(14/16)
93%
pregnancy
continued
>20 wks
(13/14)
Modi S et al, Effectiveness of the oral sustained release formulation of natural micronized progesterone (NMP SR) in obstetrics: A retrospective, multicentre, real world study. Eposter
presented at: FOGSI South Zonal Conference With Yuva; 2023 Mar 10-12; Calicut, Kerala, India

38. Open label,
prospective,
observational
study
60 women
with unexplained
infertility aged
>18 to 33 years
Oral natural
micronized
Progesterone 400
mg HS
X 4 weeks
Oral
dydrogesterone 10
mg BD X 4 weks
On day 22+/-1,
the serum
progesterone
levels were
assessed
IUI
procedure
Gopinath et al. Int J Med Res Health Sci. 2014; 3(4): 933-936

39. Gopinath et al. Int J Med Res Health Sci. 2014; 3(4): 933-936
Oral NMP SR
• No significant difference between mean serum progesterone achieved in the both groups
• overall pregnancy rate was 5% (3/60). Out of these 2 pregnancies were reported in patients who were administered
natural micronized progesterone and 1 pregnancy was reported in patients with Dydrogesterone
P-value
not
available

40. Purandare et al. Int J Med Res Health Sci. 20144;3(4):975-976
Prescription event
monitoring to
study safety profile
of oral NMP-SR
Patients with bad obstetric history (BOH)
or unexplained infertility
prescribed either 300 or 400 mg SR OD
following Natural or Stimulated ART cycle
X 2 months
• 153 patients completed study with a mean of 27yrs& 55kgs
• Infertility patients with BOH: 87% patients had ≥ 2 abortions
• The formulation was prescribed for Luteal Phase Support in Unexplained infertility (43.8%) or BOH (50%) and Secondary
Amenorrhoea (5.9%)
• Oral NMP 300 mg SR was the most commonly prescribed formulation.

41. Journal of Clinical and Diagnostic Research. 2016 Jan, Vol-10(1): QC08-QC10
Open label,
prospective,
observational
study
120 cases of
unexplained
infertility
Oral natural
micronized
Progesterone
200/300 mg HS
X 2 weeks
Oral
dydrogesterone 10
mg BD X 2 weks
On day 21+/-2,
the serum
progesterone
levels were
Assessed
In case of
pregnancy
being
confirmed, the
progesterone
regimen was
continued for
upto 8 to 12
weeks further
IUI
procedure

42. Oral NMP SR attains required mid-luteal serum progesterone
level
• UK MHRA guideline suggests >14 ng/ml mid-luteal serum progesterone level for
maintenance of pregnancy
• Serum progesterone level attained with oral NMP SR formulation (Mean, mid-luteal serum
progesterone level after 7 daily dosing)
Formulation Sr. P4 level (ng/ml)
Oral NMP SR 400 mg daily 46.2 ng/mL Achieves > 14 ng/ml serum P4
level
Oral NMP SR 300mg daily 36.1 ng/mL
Oral NMP SR 200mg daily 20.6 ng/mL
By releasing progesterone gradually and circumventing first-pass metabolism, NMP-SR elicits the
desired therapeutic effect with benefits over conventional oral NMP in terms of bioavailability, once-daily
dosing and improved tolerability. Oral NMP-SR appears to be a valuable option for treating obstetric
conditions associated with insufficient progesterone exposure.
Wagh GN et al, A review of conventional and sustained-release formulations of oral natural micronized progesterone in obstetric indications. Drugs
Context. 2021;10:2021-7-1. https://doi.org/10.7573/dic.2021-7-1

43. Summary
• Progesterone induces secretory transformation of endometrium in luteal phase. By
inducing this change after adequate estrogen priming, progesterone improves
endometrial receptivity
• Endometrial receptivity is a self-limited period in which endometrial epithelium acquires
functional & transient ovarian steroid-dependent status that allows blastocyst adhesion
• Decreased endometrial receptivity is considered largely responsible for low implantation
rates in IVF
• Studies show that progesterone improves pregnancy outcomes such as clinical pregnancy
rate, ongoing pregnancy rate, implantation rate, delivery rate, live birth rate and
decreases early pregnancy loss

44. Evidence of fetal safety of
natural progesterone and synthetic progestogens
“primum non nocere”
("first, do no harm”)
Safety Matters Most!

45. Safety is a very important aspect to consider
while choosing any molecule
• Congenital anomalies present with significant financial, social, and moral issues/questions to the family
and society; difficult to rehabilitate
• Congenital anomalies survey conducted by WHO in 193 countries in 2010
• 270,000 of 3.1 million newborn deaths were caused by congenital anomalies
• In India, >1.7 million children are born with birth defects every year
• In utero exposure to teratogenic agents and infection are two most important causes of nongenetic
acquired anomalies presenting at birth
• Fetal response and susceptibility to such agents are variable, and the effects depend on the type,
timing, and duration of intrauterine exposure
https://www.intechopen.com/chapters/72507
https://www.who.int/india/Campaigns/and/events/world-birth-defects-day-2020

46. Progesterone use in early pregnancy
• Progesterone in pregnancy has been in use for over 60 years, having its start in the 1940s
• Progesterone supplementation during early gestation is common
• During assisted reproduction
• Treatment/prevention of miscarriage in high risk patients
• Reports have been issued by the US FDA linking exposure to progestins (synthetic derivatives of
progesterone) to an insignificantly increased risk of perinatal death in singleton/twin pregnancies
• Furthermore, therapies applied in pregnancy might have differing effects in the neonatal period
and early childhood (benefit in one and harm in another)
Use of steroid hormones in first trimester is a serious issue, as organogenesis takes place at this time and therefore
there is the possibility of harm not only from congenital anomalies, but also long-term, intergenerational effect
J Perinat Med. 2017 Jan 1;45(1):11-20
Lancet 2016; 387: 2106–16

47. Progestogens in Pregnancy
Obstet Gynecol. 2016 Aug;48(2):161-70.
BMJ 2009;339:b4380
Progestogens
Progesterone (P4)
Endogenous Exogenous
Micronized progesterone
(oral, vaginal, IM & SC)
Progestins
Synthetic
Dydrogesterone (Oral)
Hydroxyprogesterone
caproate (IM)

48. Data on Natural Micronized
Progesterone

49. Issues in Law & Medicine 2015;30(2): 159-168
The Pope Paul VI Institute, USA publishes largest study
of its kind on the safety of progesterone use in pregnancy
An analysis of the fetal safety of isomolecular (Natural)
progesterone administration during the course of 1,310
pregnancies over a 35-year period of time (1979-
2014) was undertaken. While there have been other studies on
the fetal safety of progesterone, this study’s sample size was 2.5
times larger than any previous study of its kind.
Route of progesterone administration was oral, injectable,
vaginal or combination of routes in some patients.
https://www.drhilgers.com/2016/02/progesterone-study/

50. The overall incidence of fetal anomalies observed in patients who took
progesterone and those who did not take progesterone was identical: 2.2%.
Progesterone is not a cardiac teratogen, nor does it cause any limb reduction
defect, neural tube defect, hydrocephalus or genital abnormalities.
Between 150–200 pregnancies are managed each month at the Pope Paul VI
Institute with progesterone support.
The study concluded that bio-identical progesterone posed no risk
of teratogenicity or malformations when used to support
pregnancy, either in the early or later days of gestation.
Issues in Law & Medicine 2015;30(2): 159-168

51. Natural Micronised Progesterone:
Approved, Globally Available, Good safety profile
Regulatory Agency US FDA
(Food and Drug
Administration)1
EMA
(European Medicines
Agency)2
TGA
(Australia, Therapeutic
Goods Administration)3
Micronised Progesterone Approved Approved Approved
1. Drugs@FDA: FDA-Approved Drugs, Search: “Progesterone”, Data accessed online as on 03/06/2022 from https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process
2. Data accessed online as on 03/06/2022 from https://www.medicines.org.uk/emc/search?q=Progesterone
3. TGA Drug database accessed online as on 03/06/2022 from https://search.tga.gov.au/s/search.html?collection=tga-websites-web&query=progesterone&op=Search
4. Elizur SE, Tulandi T. Drugs in infertility and fetal safety. Fertil Steril. 2008 Jun;89(6):1595-602.
5. TGA Drug database accessed online as on 03/06/2022 from https://search.tga.gov.au/s/search.html?collection=tga-websites-web&query=progesterone&op=Search
Pregnancy Category Micronised Progesterone
US FDA4 B
Australia TGA5 A

52. Fetal safety Evidences of
Synthetic progestogens

53. Head-to-head comparison to progesterone,
showed an increased reporting of birth defect
with dydrogesterone (ROR 5.4, 95%CI [3.7- 7.9]). These
results were confirmed in both sensitivity analyses.
55
60 cases of Birth Defects with Dydrogesterone
↓
44 (73.3% ) of these cases were compatible with
major birth defect (MBD) cases according to
EUROCAT classification
• Genital defects such as hypospadias (n = 18,
32.7%),
• Congenital heart defects (n = 15, 27.3%)
• Limb defects (n = 10, 18.2%) and
• Digestive system defects (n = 6, 10.9%).
Annual Meeting of the ESHRE, Copenhagen – Denmark, 25-28 June 2023
Human Reproduction, Volume 38, Issue Supplement_1, June 2023, dead093.177
2023
Case-non-case study using PV database

54. Cardiovascular malformations form the largest group of congenital anomalies, typically quoted at 0.8% of all live
births. Several medicinal drugs have been proven to cause cardiovascular malformations. We discuss here the
risks of the major known medications, including lithium, valproic acid, ondansetron, methylphenidate, topiramate,
and the newly recognised dydrogesterone. In contrast, we discuss the controversial and debated effects of
selective serotonin reuptake inhibitors (SSR) and selective serotonin norepinephrine reuptake inhibitors (SNRI).
DYDROGESTERONE
In 2015, a case control study from Gaza, Palestine compared neonates born to women treated with DYD to untreated controls showing a 2.5-
fold increased risk for cardiac malformations. To address this safety question, we utilised Maccabi Health Services in Israel, with more than 2.1
million insured members. We identified all cases of pregnant women receiving DYD between 1 January 1999 and 31 December 2016.
With DYD exposure only, there were increased teratogenic risks for congenital aortic insufficiency and overall cardiac malformations, as well as
for hypospadias, spina bifida, and congenital hydrocephalus. When DYD was combined with IVF/ART, there was also increased risk for
cryptorchidism, hip dislocation, and renal dysplasia
The increased risk of cardiovascular defects was consistent with the case control study reported from Gaza [24]. The increased risks of
hypospadias and cryptorchidism were consistent with the biological effects of a potent progestin on male genitalia. The increased risk for
spina bifida was consistent with the documented effects of oral contraceptives on lowering of plasma folic acid levels [26]. We also detected
increased risk of hydrocephalus without neural tube defects.
The cumulative evidence suggests that DYD increases the risk of specific congenital malformations, including several serious
cardiovascular anomalies.
Prenat Cardio 2020, DOI: https://doi.org/10.5114/pcard.2020.94827

55. CHD: gross structural abnormalities of the heart or intrathoracic great vessels that are actually or potentially of functional
significance.
• Retrospective case–control study of birth defects and associated risk factors.
• Cases- 202 children born with congenital heart disease (CHD)
• Control- 200 children born without congenital heart disease.
• All children were born in the period of 2010-2013.
Results
• Mothers of children born with CHD received more dydrogesterone during first trimester of pregnancy
than mothers of children in the control group [adjusted odds ratio 2.71; (95 % CI 1.54–4.24); P = 0.001].
Conclusion
• We identified a positive association between dydrogesterone usage during early pregnancy and CHD in
the offspring.
• Nevertheless, further studies are needed to confirm these results.
2015

56. 2017
Because of its potential importance this study
was selected by Lancet to be republished to
ensure it gets the visibility and attention.

57. Authors' conclusions
The overall available evidence suggests that progestogens probably make little
or no difference to live birth rate for women with threatened or recurrent
miscarriage. However, vaginal micronized progesterone may increase the live
birth rate for women with a history of one or more previous miscarriages and
early pregnancy bleeding, with likely no difference in adverse events.
There is still uncertainty over the effectiveness and safety of alternative
progestogen treatments for threatened and recurrent miscarriage.
Synthetic Progestin Safety???

58. Hydroxyprogesterone Injection: US FDA Withdrawal
60
17-Hydroxyprogesterone caproate approval
withdrawn by USFDA - 6th April 2023
https://www.fda.gov/news-events/press-announcements/fda-commissioner-and-chief-scientist-announce-decision-
withdraw-approval-makena
Today, the U.S. Food and Drug Administration announced the final decision to
withdraw approval of Hydroxyprogesterone caproate—a drug that had been
approved under the accelerated approval pathway. This drug was approved to
reduce the risk of preterm birth in women pregnant with one baby who have a
history of spontaneous preterm birth. The decision was issued jointly by the FDA
Commissioner and Chief Scientist. Effective today, Makena and its generics are
no longer approved and cannot lawfully be distributed in interstate commerce.

59. 61
HYDROXYPROGESTERONE CAPROATE USAGE IN PREGNANCY:
INCREASED RISK OF CANCER IN FETUS
Conclusion:
Caution using 17α-hydroxyprogesterone caproate in early pregnancy is
warranted, given the possible link with cancer in the offspring.
A total of 1008 offspring were diagnosed with cancer over 730,817 person-years of
follow-up. Exposure in the first trimester was associated with an increased risk of any
cancer (adjusted HR, 2.57), and the risk increased with the number of injections (1-2
injections: aHR, 1.80; ≥3 injections: aHR, 3.07). Exposure in the second or third
trimester conferred an additional risk for the male (aHR, 2.59) but not for the female
offspring. The risk of colorectal (aHR 5.51), prostate (aHR 5.10), and pediatric brain
(aHR 34.72) cancer was higher in the offspring first exposed to 17α-
hydroxyprogesterone caproate in the first trimester than the offspring not exposed.

60. Type Study Profile Sample size Interventions
Meta-
analysis
RCTs & observational studies evaluating 17OHP-C or vaginal progesterone for the
prevention of PTB and that reported outcomes concerning the prevalence of
gestational diabetes mellitus
11 studies; 8085
women
17 OHPC (2068)
VP (891)
No progestogen (5126)
Forest plot diagram of primary analysis
Gestational diabetes mellitus:
Odds ratio was significantly increased among
patients receiving 17-alpha
hydroxyprogesterone caproate.
Am J Obstet Gynecol 2019. https://doi.org/10.1016/j.ajog.2019.05.033

61. NMP VS. DYDROGESTERONE
Parameter Natural Micronized Progesterone Dydrogesterone
Beneficial Actions in Pregnancy6
Tranquilizing
Antiandrogenic
Diuretic
Tocolytic
Neuroprotective
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
Correlation with Serum P levels6 Yes No
Creating ‘in-phase’ secretory endometrium7! More effective Less effective
Effectiveness
Cochrane’s Review on efficacy in TA (2021)8
ESHRE Guidelines on RPL (Update 2022)9
Increase in live birth rate#
Recommended; May improve live birth rate@
Uncertainty over effectiveness
No recommendation; more trials
are needed
Safety
Cochrane’s Review on safety in TA and RM (2021)8 Congenital abnormalities & adverse drug events
similar to placebo$
Uncertainty over safety
TA, Threatened abortion; RM, Recurrent miscarriage; RPL, Recurrent pregnancy loss;
!, secretory transformation of endometrium and luteal endocrine profile was studied in patients with premature ovarian failure after estrogen endometrial priming
#, Vaginal micronized progesterone may increase the live birth rate for women with a history of ≥1 previous miscarriages and early pregnancy bleeding;
@, Vaginal progesterone may improve live birth rate in women with 3 or more pregnancy losses and vaginal blood loss in a subsequent pregnancy;
$, Moderate- and low-certainty evidence with a wide range of effects suggests that there is probably no difference in congenital abnormalities and adverse drug events with vaginal micronized progesterone for threatened or
recurrent miscarriage compared with placebo

62. Drug Regulator Progesterone Dydrogesterone 17-OHPC
US FDA approval
MHRA, UK approval
TGA Australia approval7,8,9,10,11
• Approved Indication
• Pregnancy Category
Yes1
Yes4
Yes7
Obstetric (LPS, Support
during pregnancy)
A%7
No (Withdrawn)2
No (Withdrawn)5
No (Dyd)/ Yes (E+Dyd)8,9
Gynecologic (HRT) [For E+Dyd]
Standalone Drug not available
No (Withdrawn)3
No6
No10
Not applicable
D11
US FDA, The United States Food & Drug Administration; EMA, European Medical Agency; TGA, Therapeutic Goods Agency; Dyd, Dydrogesterone; LPS, Luteal phase support; HRT, Hormone
replacement therapy
%, Pregnancy Category A- Drugs which have been taken by a large number of pregnant women and women of childbearing age without an increase in the frequency of malformations or
other direct or indirect harmful effects on the foetus having been observed.
&, Pregnancy Category B3- Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of
malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage,
the significance of which is considered uncertain in humans.
Pregnancy Category D- Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage.
1. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
2. Federal Register 2017;82(171):42101
3. https://www.ema.europa.eu/en/medicines
4. https://www.fda.gov/news-events/press-announcements/fda-commissioner-and-chief-scientist-
announce-decision-withdraw-approval-makena
5. MHRA UK Public Assessment Report. 2008.
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/8
52391/Efficacy_of_progestogens_in_the_maintenance_of_early_pregnancy_in_women_with_threaten
ed_miscarriage_or_recurrent_miscarriage.pdf
6. https://www.ema.europa.eu/en/medicines/human/referrals/hydroxyprogesterone-containing-medicinal-
products
7. Utrogeston Prescribing information. 2020. TGA-Australia. https://www.tga.gov.au/product-information
8. Femoston Prescribing information. 2021. TGA-Australia. https://www.tga.gov.au/product-information
9. Zumenon Prescribing information. 2020. TGA-Australia. https://www.tga.gov.au/product-information
10. https://www.tga.gov.au/resources/artg?keywords=hydroxyprogesterone
11. https://www.tga.gov.au/products/medicines/find-information-about-medicine/prescribing-medicines-
pregnancy-database
Regulatory Status of Progestogens

63. Fetal safety: NMP
Parameter Natural Micronized
Progesterone
Dydrogesterone
Similarity to
endogenous P1,2
Identical structure Isomer of P with changes in
orientation of methyl groups
and additional double bond
US FDA approval Yes No (Withdrawn)3
EMA approval Yes No (Withdrawn)4
Conclusion of
Cochrane’s Review
2021 on safety in TA
and RM5
Moderate- & low-certainty
evidence suggests there is
probably no difference in
congenital abnormalities#
Uncertainty over the safety
Pregnancy category-
TGA Australia6,7,8
A Standalone drug not
available
1. Reproductive Biomedicine Online 2019;38(2):249-259. 2. Steroids. 2011 May;76(6):607-15. 3. Federal Register 2017;82(171):42101 4. MHRA UK Public Assessment Report. 2008.
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/852391/Efficacy_of_progestogens_in_the_maintenance_of_early_pregnancy_in_women_with_threat
ened_miscarriage_or_recurrent_miscarriage.pdf 5. Cochrane Database Syst Rev. 2021 Apr 19;4(4):CD013792. 6. Utrogeston Prescribing information. 2020. TGA-Australia.
https://www.tga.gov.au/product-information. 7. Femoston Prescribing information. 2021. TGA-Australia. https://www.tga.gov.au/product-information. 8. Zumenon Prescribing information. 2020. TGA-
Australia. https://www.tga.gov.au/product-information.
TA, Threatened abortion; RM, Recurrent miscarriage; #Compared to placebo

64. Summary – NMP vs. 17- OHPC
Parameter Natural Micronized
Progesterone
17-α-hydroxyprogesterone
caproate
Similarity to
endogenous P
Bio-Identical structure
(Natural)
Synthetic steroid hormone
USFDA approval Approved Withdrawn2
Pregnancy Category
– TGA Australia
A3 D3
Cervical ripening Prevents Unknown effect
Safety Good safety profile Risk of cancer to fetus
Increased risk of
gestational diabetes
mellitus
No Yes
1. Am J Perinatol 2019;36:1–12
2. https://www.fda.gov/news-events/press-announcements/fda-commissioner-and-chief-scientist-announce-decision-withdraw-
approval-makena
3. https://www.tga.gov.au/products/medicines/find-information-about-medicine/prescribing-medicines-pregnancy-database
(Search term: Hydroxyprogesterone & Progesterone)

65. THANK
YOU