Dr Sujoy Dasgupta was invited to deliver a lecture in the CME organized by Pharmed in August 2019 at Kolkata

1. Boosting Endogenous Progesterone
A novel therapeutic strategy to improve clinical outcomes
Dr Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
Advanced ART Course for Clinicians (NUHS, Singapore)
Consultant: Reproductive Medicine, Genome Fertility Centre,
Kolkata
• Managing Committee Member, Bengal Obstetric &
Gynaecological Society (BOGS)- 2019-20
• Secretary, Subfertility and Reproductive Endocrinology
Committee, BOGS- 2019-20
• Winner, Prof Geoffrey Chamberlain Award, RCOG World
Congress, London, 2019

2. Pregnancy and Miscarriage

4. Progesterone- “Pro-Gestation”
• Essential for pregnancy preparation,
implantation, support and continuation
• Preparation of the endometrium for
implantation (secretory changes)
• Imunomodulator- induces the Th2
response, essential for normal pregnancy
• Increases NO production → increases
uterine blood flow and endothelial
adaptation
• Decreases contractility of myometrium

5. Source of progesterone
• Secreted by the
corpus luteum until
7-9 weeks of
pregnancy, when the
placenta takes over
this function

6. Luteal Phase Insufficiency

7. Progesterone Deficiency Causing Miscarriage
• Mifepristone blocks progesterone receptors causing abortion1
• Lutectomy up to 7 weeks gestation results in miscarriage but
pregnancy can be maintained if progesterone treatment is given2,3
• Defective corpus luteum in ART may produce low levels of
progesterone, insufficient for endometrial ripening, implantation
or placentation3
• Abnormal embryo: low hCG from genetic aberrations can lead to
low progesterone levels2
Low progesterone may be a mechanism or a cause
of miscarriage2
1. Spitz IM et al. N Engl J Med. 1998. 30; 338(18):1241-7;
2. Schindler AE. Gynecol Endocrinol 2004; 18(1): 51-57;
3. Engmann L & Benadiva C. Semin Reprod Med. 2010; 28(6):506-12;
4. Verhaegen J et al. BMJ. 2012; 27:345-355.

8. 2017 Study report

9. Progesterone- Mainly 2 forms
Natural Micronized
Progesterone (NMP)
Dydrogesterone
Selectivity to P4
receptor
More selective
Route Oral, vaginal, IM Oral
Bioavailability Better
Metabolism May increase risk of
obstetric cholestasis
Less metabolic load
on liver

10. Oral Vaginal Injectables
•Easiest way •Delivers where needed (“First uterine pass
effect”)
•concentrations in uterus : periphery -
14:1
•Optimum blood level- Oil
base
•Can be taken anywhere •Needs privacy •Extremely painful
•Better acceptability •10% may have vaginal dryness/ irritability •Abscess formation
•Sustained release
formulation –increase in
serum progesterone level
>14 ng/ml during luteal
phase
Gel- 8%
•most comfortable way of administration
•Special applicator – easy to use with no
wastage of drug
•Polycarbophil base: No messy vaginal
discharge as seen with cocoa butter or PEG
base
•Excellent vaginal moisturizing property1
Aqueous injection –
Fastest onset of action,
>50 ng/ml within 1 hour
Route of administration- Does NOT affect the outcome1,2
1. Haas DM, Ramsey PS. Cochrane Database Syst Rev 2013 Oct 31; 10: CD003511
2. Van der Linden et al. Cochrane Database of Systematic Reviews 2015

11. Is Progesterone Effective?

12. • 4 RCTs including 411 women with threatened miscarriage
• Miscarriage was significantly less likely to occur on progestins than placebo or
no treatment (risk ratio 0.53; 95% CI 0.35 to 0.79)
• No evidence of increase in the rate of APH, HDP, or congenital abnormalities.
• Trials are clinically heterogenous and methodologically poor
• The evidence suggesting benefit of progestins for women with recurrent
miscarriage and with threatened miscarriage, remains preliminary and additional
well designed studies are required to confirm these findings.
• Wahabi HA, Fayed AA, Esmaeil SA, Al Zeidan RA.. Cochrane Database Syst Rev. 2011 Dec
7;(12):CD005943

13. • 15 RCTs including 2,118 women
• For an unselected population of women in the1st trimester of pregnancy, there is
no evidence of benefit of progestin for prevention of miscarriage
• no evidence to support the routine use of progestogen to prevent miscarriage in
early to mid-pregnancy.
• Sub-group analysis of 4 of these trials included 223 women with recurrent
miscarriage shows the odds of miscarriage are significantly decreased by
progestin treatment (Peto OR 0.38, 95% CI 0.20 to 0.70)
• Treatment for these women may be warranted
• Haas DM, Ramsey PS. Cochrane Database Syst Rev. 2013 Oct 31;(10):CD003511.

14. PROMISE Trial
First Trimester PROgesterone Therapy in Women
with a History of Unexplained Recurrent
MIScarriage
Coomarasamy A., et al. N Eng J Med 2015;373:2141-8

15. PROMISE Trial- Study Details
Sponsor • UK National Institute for Health Research
• Treatment (active and placebo) provided by Besins Healthcare
Location of
study
• 36 centers in the UK
• 9 centers in the Netherlands
Type of study Multi-center, double-blind, randomized, placebo-controlled
Inclusion criteria • Unexplained recurrent miscarriage (≥ 3 miscarriages)
• Women 18–39 years of age
• Spontaneous conception
Objectives • Live births after 24 completed weeks of gestation (primary)
• Clinical pregnancy at 6–8 weeks
• Ongoing pregnancy at 12 weeks
• Miscarriage (before 24 weeks)
• Gestational age at delivery
• Neonatal outcomes at 28 days
• Congenital abnormalities
Treatment Utrogestan® (MVP) 400 mg BID Vaginal suppositories
After a positive UPT and no later than 6 weeks of gestation
Treatment ended at 12 weeks of gestation

16. PROMISE Trial- Conclusion
• Progesterone therapy
in the 1st trimester of
pregnancy did not
result in a
significantly higher
rate of live births
among women with a
history of unexplained
recurrent miscarriages

17. Stephenson MD, et al. Fertil Steril. 2017 Mar;107(3):684-690.e2.
Type of study Observational cohort study using prospectively collected data
Inclusion
criteria
Women with a history of ≥ 2 unexplained pregnancy losses
<10 weeks
Objectives To assess the effectiveness of luteal start vaginal micronized
progesterone in RPL
Main Outcome
Measure
Pregnancy success (an on-going pregnancy >10 weeks)
Intervention nCyclinE elevated (>20%) Normal nCyclinE (≤20%)
Vaginal micronized P 100-
200 mg, q12 h starting 3 days
after LH surge (luteal start)
Empiric Vaginal
micronized P
No treatment (Control)

18. Conclusion
Use of luteal start vaginal micronized P was associated
with improved pregnancy success in women with RPL
Stephenson MD, et al. Fertil Steril. 2017 Mar;107(3):684-690.e2.

19. Peri-conceptional progesterone treatment in
women with unexplained recurrent
miscarriage
Ismail AM, et al. J Matern Fetal Neonatal Med. 2017 Feb 15:1-7.
Progesterone or placebo started in luteal phase & continued
after a positive pregnancy test till 28 weeks of gestation

20. Peri-conceptional progesterone treatment in
women with unexplained recurrent miscarriage: Results
23.3%
12.4%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
Palcebo group (n=335) Progesterone group (n=340)
Rate of miscarriage
P=0.001
Ismail AM, et al. J Matern Fetal Neonatal Med. 2017 Feb 15:1-7.

21. Peri-conceptional progesterone treatment in
women with unexplained recurrent miscarriage: Results
Characteristics Progesterone
group
Placebo group P value
Rate of first trimester
vaginal bleeding
54/340 (15.7%) 100/335 (33.5%) 0.0001
Gestational age at delivery
(weeks) (mean ± SD)
37.4 ± 0.4 34.1 ± 1.2 0.004
Rate of premature delivery 21/298 (7.0%) 39/257 (15.2%) 0.0001
Spontaneous 8 (38.1%) 14 (35.9%)
Iatrogenic 13 (61.9%) 25 (64.1%)
Ismail AM, et al. J Matern Fetal Neonatal Med. 2017 Feb 15:1-7.

22. Clinical Guidelines

24. Recommendation 1 Grade
For an unselected population of women in
the first trimester of pregnancy, there is no
evidence of benefit of progestin for prevention
of miscarriage.
Consensus-based
recommendation
Recommendation 2 Grade
For women presenting with a clinical
diagnosis of threatened miscarriage, there is
now preliminary evidence of a reduction in the
rate of spontaneous miscarriage with the use
of progestins.
Consensus-based
recommendation

25. TREATME
NT
RCOG ASRM ESHRE
Progesterone
supplementa
tion
Insufficient
evidence
Insufficien
t
evidence
Insufficient
evidence

26. FOGSI Position Statement 2015
• No evidence of harm and some evidence of benefit, although not
coming from huge multicentric trial
Threatened Miscarriage
Relative risk reduction in miscarriage rate of 47%
1. Micronized Progesterone: 400 mg/day vaginally till 20 weeks of
pregnancy
2. Dydrogesterone: 10 mg BD orally till 20 weeks of pregnancy
Decision should be based on clinician's discretion until strong
evidence is available to recommend routine use
• http://www.fogsi.org/fogsi-gcpr

27. Drawbacks of Current Progesterone Therapy
Variable & unpredictable absorption
Variable plasma level of progesterone
Unwanted hormonal adverse effects
Variable efficacy
Unpredictable result
Unwanted pregnancy loss

28. Luteal Phase Defect (LPD)
Improper Corpus Luteum Function
Low Progesterone
No/Less uterine lining
Uterus not prepared for pregnancy
Loss of Pregnancy, Subfertility

29. Boosting Endogenous Progesterone Status
• Corpus Luteum Progesterone (Body’s
own)
• Added Progesterone (Empiric)
• (Added to body’s own progesterone )
Endogenous
• Endogenous: Synthesis or formation
inside body
Progesteronefrom
CL
Empiric
Progesterone
Endogenous
Progesterone
Synthesis

30. Improves body’s baseline progesterone level
Natural synthesis
Reduces luteal phase progesterone insufficiency
Well tolerated and safe
Advantages of boosting endogenous Progesterone

31. Improved Pregnancy outcomes & Predictability
• Corrects Corpus luteum insufficiency and increases progesterone secretion
• Reduces chances of Threatened Miscarriage
• Reduces Recurrent Pregnancy Loss
• Improves Pregnancy success rates
E
N
D
E
m
p T

32. Boosting endogenous Progesterone
To increase the synthesis of body’s own progesterone
which occurs from either Corpus Luteum or Placenta

33. PROLIFE
Campesterol 120 mg
Magnesium bisglycinate equivalent to
elemental Magnesium
14 mg
Vitamin E (D-alpha Tocopherol acetate) 10 mg
Vitamin B6 2 mg
Zinc sulphate equivalent to elemental Zinc 12 mg
Selenomethionine equivalent to elemental
Selenium
40 mcg
Beta glucan 40 mg

34. Campesterol: The industrial precursor of Progesterone
Progesterone is produced using Campesterol by
genetically modified recombinant strains of bacteria
through fermentation process.
PLoS One, 11(1), 1-14.
Mediterranean Journal of Chemistry, 3(2), 796-830.
Frontiers in Microbiology, 9(958), 1-15.

35. The most common representatives of plant
derived sterols (Phytosterols) are Sitosterol, Campesterol, and Stigmasterol.
Chemical structures of these sterols are similar to
cholesterol, differing in the side chains.
Campesterol naturally occurs in small
amounts in vegetable oils, especially soybean oil, rice bran oil etc.
Campesterol has a methyl group in C24 position.
Pharmacognosy-Fundamentals, Applications and Strategies, 315-336.
Campesterol

36. Structural comparison between
Cholesterol and Campesterol
Pharmacognosy-Fundamentals, Applications and Strategies, 315-336.

37. Progesterone production in human
Placenta produces progesterone

40. Campesterol: Pharmacokinetics
• Campesterol is mostly absorbed from upper jejunum
• After absorption, it is incorporated into mixed micelles before they are taken up by enterocytes
• Within the enterocytes, Phytosterols are not as readily esterified so they are incorporated into
chylomicrons and then enter into blood circulation
• Achieves higher concentration in intestinal lymphatics
• Campesterol is cleared by hepatic clearance
• Clearance rate of Campesterol is 6 times higher than cholesterol
• Demonstrates preferential uptake & higher absorption over other sterols
• Tissue distribution of absorbed plant sterols, inclusive of Campesterol closely parallels that of
cholesterol and are subjected to similar metabolic reactions
Asian Journal of Plant Science and Research, 5(4), 10-21.

41. Campesterol: Tissue Distribution
• Campesterol appears to be the only sterol, where tissue Campesterol concentration can be
modifiable through external intervention.
• Concentration of Campesterol is 10-times higher in ovary than in other tissues and adrenal
tissue.
• Following administration, Campesterol is preferentially concentrated in the ovary.
Metabolism Clinical and Experimental, 57, 1241-1247.
Justifies additional endogenous progesterone synthesis
from Campesterol in ovary following administration.

42. Sterol esters are stored in corpus luteum of ovary for steroidogenesis
Campesterol is converted into esterified form and this esterified form of Campesterol is stored in organs, such as the adrenal
gland and the corpus luteum of the ovary, where they serve as precursors for synthesis of steroid hormones such as
progesterone.
Suggested Mechanism of Action of Campesterol in Prolife Physiological and Molecular Aspects of Human
Nutrition, 3rd Edition, Elsevier Publication, Pg no. 104.

43. Efficacy of Campesterol in Boosting Endogenous Progesterone Synthesis
European Journal of Clinical Nutrition
At a dose of 1.6 g per day Double Blind Safety Study: 203 Subjects
with rise in Progesterone levels (0.3 to 1.2 ng/mL in healthy individuals 400%) on 13 weeks of treatment.
Documented Rise in Progesterone Levels in Women with no other significant rise in other hormones
European Journal of Clinical Nutrition, 2003, 57, 681-692.

44. Safety of Campesterol
Consumption for 1 year appeared to have no adverse side effects,
defined as reported adverse events or undesirable changes in clinical chemical parameters,
hematological parameters and urinalysis. The absence of side effects is in agreement with
the observations in earlier, shorter-term, clinical and safety studies
In the United States, Generally Recognized as safe (GRAS) by the FDA.
The scientific committee on foods of the EU also concluded that it is safe for human use. In
animal studies, no oestrogenic or teratogenic effects were observed. In humans, the products
do not cause any side-effects, and the compliance has been good.
No any genotoxicity, mutagenicity and carcinogenicity from Campesterol
European Journal of Clinical Nutrition, 57, 681-692.
Journal of Plant Science and Research, 5(4), 10-21.
Annals of Clinical Biochemistry, 42, 254-263.
EFSA Journal, 10(5), 2659-2698.

45. Safety in Pregnancy: Teratogenicity Study
There is no evidence of a teratogenic effects.
No adverse effect of risk associated with decreased level of fat soluble vitamins like carotene
and tocopherol was seen on consumption of phytosterols. No teratogenic effect and no
toxicity were reported with Phytosterols
Two-generation reproductive toxicity and fetotoxicity study revealed no any maternal and fetal
adverse events related to phytosterols. Further, more importantly, there were no any side
effects or organ damage observed in off-spring of first and second-generation births.
Journal of Applied and Natural Science, 7(2), 1081-1087.
EFSA Journal, 10(5), 2659-2698.
Food and Chemical Toxicology, 37, 683-696.

46. Safety in Pregnancy
Campesterol can be used safely in
pregnancy for boosting endogenous
progesterone synthesis.
Journal of Applied and Natural Science, 7(2), 1081-1087.
EFSA Journal, 10(5), 2659-2698.
Food and Chemical Toxicology, 37, 683-696.

47. FSSAI Approved

48. FOGSI recognizes Campesterol

49. Campesterol
• Preferred over Cholesterol in Luteal Steroidogenesis
• Promotes consistent progesterone synthesis
• Established short & long-term tolerability & safety

51. Beta-Glucan
Beta-Glucan
Binds with Estrogen Receptors
Reduces Estrogen Receptor
Actions/Dominance
Increases Progesterone Actions (Both Endogenous + Empiric)
Better Results

52. Magnesium
Reduces LPI ,Miscarriage, RPL, Subfertility
Increases LUTEAL Progesterone synthesis
Improves new blood vessel formation
Reduces Estrogen Dominance
Improves Progesterone Action

53. ER
ER
ER
ER
ER
ER
Enhances luteal
Progesterone synthesis
Magnesium
Binds to ER and
reduces Estrogen Dominance
Beta-glucan
P P
P
R
P
P
P
P
R
P
R
P
R
P
R
P
R
P

54. Vitamin E
Vitamin E
Improves Corpus
Luteum Function
Increase Progesterone
Reduce Risk of Miscarriage

55. Vitamin E
Campesterol
Progesterone
synthesis
transported to
Corpus luteum
and synthesize
progesterone
Vitamin E
Reduce blood flow
impedance
Blood flow impedance: Reduced blood flow to corpus luteum

56. Selenium, Vitamin B6 and Zinc
Selenium, Vitamin B6 and Zinc
Necessary for Corpus
luteum formation and
viability
Progesterone
synthesis
Maintenance of
pregnancy

58. Indications
• Pregnancy (Miscarriage, recurrent
pregnancy loss, threatened
miscarriage)
• Infertility and during ART
• Luteal phase defect

59. Dosage:
One tablet once daily

60. The source of
Endogenous
Progesterone booster