Use of Melatonin in ART with Focus on Combined effect of melatonin with Clomiphene Citrate in Anovulatory Infertility : Dr Sharda Jain

1. Use of Melatonin in ART with Focus on
Combined effect of melatonin with
Clomiphene Citrate in
Anovulatory Infertility

2. For Gynecologist in
ovulation induction

3. What is
Melatonin?
Its Effect in ART

4. Effect of
Clomiphene +
Melatonin

5.  Infertility is defined as one year of unprotected intercourse without
conception1
 Polycystic ovarian syndrome (PCOS) is the leading cause of anovulatory
infertility, accounting for 70% -80% of cases due to anovulation1
 Infertile anovulatory women are the best candidates for ovulation
induction1
 Clomiphene citrate (CC) has been the standard drug for ovulation induction1
 About 25%–30% of PCOS women of reproductive age need to seek help
because of ovulatory dysfunction infertility 2
2. Front. Endocrinol. 11:532692.
1.Int J Gynaecol Obstet. 2021 Mar;152(3):345-350

6. Major Causes of female infertility
Failure to ovulate
Dysfunctional fallopian
tubes
Endometriosis
•Hormonal problems
•Scarred ovaries
•Premature menopause
•PCOS
•Excessive growth of the
lining of the uterus
•Infection
•Abdominal diseases
•Previous surgeries
•Ectopic surgeries
•Endometriosis
IJPRD/2009/PUB/ARTI/VOL-8/OCT/010
20-40%

7. Ovulation
Induction
remains a
crucial step
in
Pregnancy

8. DO NOT WANT TO GO INTO
CONTROVERSY
LETROZ V/S
CLOMIPHENE

9.  Clomiphene, also called clomiphene citrate, a selective estrogen receptor
modulator (SERM) 1
 FDA-approved medication indicated for the treatment of anovulatory or
oligo-ovulatory infertility to induce ovulation for patients desiring to
conceive
 CC promotes follicular development through blocking the negative
feedback of estrogen to the hypothalamus and making the pituitary
secrete gonadotropin 2
 Still Used as the traditional first-line medication for inducing ovulation in
PCOS women by few gynacologist2
1.Clomiphene. [Updated 2021 Jul 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls
Publishing; 2021 Jan 2. Front. Endocrinol. 11:532692

10. • Despite recent advances in assisted reproductive technology (ART), a poor
ovarian response (POR) remains one of the most challenging tasks for
reproductive clinicians during Controlled Ovarian Stimulation.
• Patients with POR usually have higher basal FSH levels, lower antiMüllerian
hormone (AMH) levels and low numbers of oocytes retrieved using
conventional ovarian stimulation protocols.
• Various stimulation regimens and interventions have been proposed to
improve pregnancy outcomes for patients with POR.
Human Reproduction Update, Vol.26, No.2, pp. 247–263, 2020

11. • Strategies include different regimens for pituitary suppression, increased
gonadotrophin dosages, the addition of adjuvant agents during ovarian
stimulation, and the implementation of a modified natural IVF cycle
• Use of adjuvant therapy may improve the IVF outcome.
• Beneficial for women with a history of repeated IVF failure.
Obstet Gynecol Surv. 2010;65(4):260–272.

12.  Mechanism of Action-
 Selectively binds to estrogen receptors in the hypothalamus, ovary, endometrium,
cervix and produces estrogenic and anti-estrogenic effects.
 Acts as a partial estrogen agonist in the hypothalamus resulting in an estrogenic
negative feedback inhibition, thus increasing gonadotropins.
 Increases the secretion of luteinizing hormone as well as follicle-stimulating
hormone, thus increasing the production of serum levels of testosterone.
 Used as an adjuvant to alleviate pituitary suppression.
Clomiphene. [Updated 2021 Jul 2]. In: StatPearls [Internet]. Treasure Island
(FL): StatPearls Publishing; 2021 Jan

13. • Adjuvant therapies are helpful in various infertile situations, primarily in
polycystic ovarian syndrome (PCOS) and in poor responders.
Need of adjuvant therapy in ovulation induction.
1.Obstet Gynecol Surv. 2010;65(4):260–272.
2. Fertil Steril. 2006;85(2):277–284
3. J Hum Reprod Sci. 2016;9(2):70

14. • Few drugs are approved as adjuvants in ovulation induction, while others
are off-label drugs.
Approved and off-label drugs used as adjuvant therapy in
ovulation induction
Fertil Steril. 2015;103(3):583–594. 2. Fertil Steril. 2015;103(3):605–611.
(Melatonin)

15. 1. Fertil Steril. 2015;103(3):583–594. 2. Fertil Steril. 2015;103(3):605–611.

16. • Released by the pineal gland.
• Both fat-soluble & water-soluble, &
easily pass through cell membranes.
• Act as a direct free radical scavenger and as an indirect antioxidant.
• Limits oxidative stress in all cells.
• Protects DNA and other components from damages.
• Powerful antioxidant potential than conventional antioxidants such as
vitamin C and E, mannitol, and glutathione.
Int. J. Mol. Sci. 2020, 21, 1135,2-16

17. • Wide range of functions,
 Circadian pacemakers
 Hypothalamic/pituitary axes to vasomotor effects
 Immunomodulatory
 Antioxidative actions and anti-apoptotic effects (direct and indirect).
• Regulates a variety of important central and peripheral actions related to
circadian rhythms and reproduction.
• Powerful free radical scavenger and has a broad-spectrum antioxidant
property.
• Melatonin deficiency seems to be involved in pathophysiology of PCOS.
Cogent Biology. 2016;2:1136257

18. • Acts directly on the ovaries
• Synthesized and secreted into the blood by the pineal gland, taken up by
ovarian follicles, where it locally reduces ROS in the follicles and limits
oxidative stress, thereby protecting oocytes, as well as granulosa cells,
and contributes to oocyte maturation
1.Int. J. Mol. Sci. 2020, 21, 1135,2-16
J Ovarian Res. 2012; 5: 5.

19. Int. J. Mol. Sci. 2020, 21, 1135,2-16

20. • Reactive oxygen species (ROS) produced within the follicles, especially during
the ovulation process, are scavenged by melatonin.
• Excess amounts of ROS may be involved in oxidative stress of oocyte and
granulosa cells.
• Reduces the oxidative-stress-induced DNA damage, mitochondrial
dysfunction, lipid epoxidation, and apoptosis of granulosa cells.
• Protects cells by reducing free radical damage of cellular components including
nuclei, mitochondria, and plasma membranes.
• Balance between ROS and antioxidants (melatonin) within the follicle may be
critical for oocyte maturation, meiosis, and luteinization of granulosa cells.
Int. J. Mol. Sci. 2020, 21, 1135,2-16

21. Melatonin 3
Melatonin 3 mg film-coated tablets are indicated for
short-term treatment of jet-lag in adults.
The standard dose is 3 mg (1 tablet) daily for a
maximum of 5 days.
The dose may be increased to 6 mg (2 tablets taken
together) if the standard dose does not adequately
alleviate symptoms.

22. Clinical Evidence

23. Patients with a poor
oocyte and embryo
quality in a previous IVF
cycle (<60% fertilization
rate) were included in
the study
This study was designed for
two consecutive IVF cycles
First cycle (n=97)
No supplementation
Second cycle (n=97)
Melatonin 3 mg/day
Primary outcome
•Rates of maturation,
fertilization,
•Good quality embryos,
blastocyst
All patients were stimulated with a standard IVF
protocol
Gynecol Endocrinol, 2014; 30(5): 359–362

24. Primary outcomes
• Fertilization rate dramatically increased after melatonin treatment
Gynecol Endocrinol, 2014; 30(5): 359–362
CONCLUSIONS
Melatonin should be considered for poor fertilization & embryo
quality patients due to its safety and simplicity of use

25. Melatonin improves
the oocyte & the
embryo in IVF-ET
patients
Administration of
melatonin Daily 3 mg
orally
J Assist Reprod Genet 2011;28:815–820
60 patients
30 (Melatonin)
30 (control)

26. J Assist Reprod Genet 2011;28:815–820
0
2
4
6
8
10
12
11.5
6.9
Melatonin significantly increased
mean number of oocyte retrieved
Melatonin
Control
Mean
no.
of
oocyte
retrieved
P = 0.0001
Melatonin significantly increased
Transfer ratio of Grade I Embryos
0
10
20
30
40
50
60
70
69.3
44.8
Melatonin
P<0.05
Control
Transfer
ratio
of
Grade
I
Embryos
Conclusion
Melatonin increased the fertilization and
pregnancy rates in patients with previous
low-quality oocytes

27. • Women who failed to become pregnant in the previous IVF-ET (fertilization
rate < 50%): 3 mg tablets of melatonin in the next IVF-ET
• Fertilization rate and pregnancy rate were compared to the previous IVF-ET.
Results & Conclusion
• Fertilization rate and pregnancy rate were improved by melatonin
treatment
• Melatonin administration is likely to improve oocyte quality.
W-052, IFFS 2010 Poster Abstracts; 20th World Congress on Fertility and Sterility
September 12–16, 2010, Munich; Pg: 366

28. The relationship between oxidative stress and poor oocyte quality and
whether the antioxidant melatonin improves oocyte quality, was investigated
• 115 who failed to become pregnant with a low fertilization rate (≤50%) in the
previous IVF-ET cycle were,
Divided into two groups during the next IVF-ET procedure.
• 56 patients: Melatonin treatment (3 mg/day)
• 59 patients without Melatonin treatment.
J. Pineal Res.2008,44:280-287

29. Effects of melatonin treatment on clinical outcome of IVF-ET
The fertilization rate was improved by melatonin treatment
compared to the previous IVF-ET cycle.
J. Pineal Res.2008,44:280-287
Conclusion:
• Oxidative stress causes toxic effects on oocyte maturation.
• Melatonin protects oocytes from oxidative stress.
• Melatonin improved oocyte quality and fertilization rate.

30. • After COH for the patients, an USG guided ovum retrieval was conducted;
High quality immature oocytes (germinal vesical: GV or metaphase I: MI
oocyte) were collected for the subsequent IVM culture.
• Collected 193 immature oocytes from the controlled ovarian
hyperstimulation (COH) cycle underwent in vitro maturation (IVM) in IVM
medium contained 10 μmol/L MT (n = 105, M group) and no MT (n = 88,
NM group), followed by insemination and embryo culture.
J Pineal Res. 2020;68:e12621.
COH : Controlled ovarian hyperstimulation

31. • The results showed that the high-quality blastocyst formation rate in the M
group (28.4%) was significantly higher than that in the NM group (2.0%) (P =
.0001), and the aneuploidy rate was low (15.8%).
Melatonin can promote the development of immature human oocytes
retrieved from the COH cycle into healthy offspring by protecting
mitochondrial function
J Pineal Res. 2020;68:e12621.

32. • Objective: To study effect of melatonin addition to clomiphene citrate for
induction of ovulation with a view to improve conception rates.
• Study Design:
 Retrospective analysis
 N= 52 Women
• Dosage & Duration:
6
Int J Reprod Contracept Obstet Gynecol. 2021 Dec;10(12):4438-4442

33. • Result shows 77.9 % ovulation rates and 82% conception rates with CC and
melatonin regimen for Ovulation Induction.
• Most women had no side effects and the drug dose and schedule was acceptable
to all.
Results
Conclusions:
• Melatonin, as an anti-oxidant may improve, conception and live birth rates
when added to clomiphene citrate induction protocols.
Int J Reprod Contracept Obstet Gynecol. 2021 Dec;10(12):4438-4442

34. • Objective: To study the effect of adjuvant melatonin with clomiphene
citrate on ovulution and fertility rates in infertile PCO patients.
• Study Design:
 Prospective comparative randomised trial
 N= 100 Women
• Dosage & Duration:
7
INDIAN JOURNAL OF RESEARCH | Volume - 9 | Issue - 10 | October - 2020

35. • The Ovulation rates were comparable in both study Vs control group (68% Vs
66%) while there was increase in pregnancy rate in melatonin group (36% Vs
24%).
• Viable Pregnancy Rate After Three Cycles Of Ovulation Induction
Results
Conclusions:
• Melatonin with en-clomiphene citrate in Infertile PCO patients improves
pregnancy rates.
• Strong anti-oxidant effect of melatonin reduces oxidative stress & results
in good quality oocyte production.
INDIAN JOURNAL OF RESEARCH | Volume - 9 | Issue - 10 | October - 2020

36. • Objective- To study the fertility rates of combination of enclomiphene citrate
& melatonin and compare it with fertility rates of plain enclomiphene citrate
in dysovulatory infertility
• Study Design:
 Prospective comparative randomised trial
 N= 100 Women
• Dosage and Duration:
8
Int J Reprod Contracept Obstet Gynecol. 2020 Apr;9(4):1700-1704

37. • The Ovulation rates were comparable in both study Vs control group (68% Vs
66%) while there was increase in pregnancy rate in melatonin group (36% Vs
24%).
Results
Pregnancy rate after three cycles of
ovulation induction.
Ovulation rate after three cycles of
ovulation induction.
Conclusions:
• Melatonin with enclomiphene citrate in dysovulatory infertility improves
pregnancy rates.
• Strong anti-oxidant effect of melatonin reduces oxidative stress & results
in good quality oocyte production.
Int J Reprod Contracept Obstet Gynecol. 2020 Apr;9(4):1700-1704

38. • Contains ovulation inducing agent (Clomiphene) & intrafollicular antioxidant
(Melatonin)
• Rational combination to address reduced folliculogenesis and poor oocyte
quality.
• Increases fertilization and pregnancy rates.
Dosage:
1 capsule OD for 5 days
(From Day 3 to Day 7)
Each capsule contains:
Clomiphene citrate……….50 mg
Melatonin………………………3 mg
Each capsule contains:
Clomiphene citrate…… 100 mg
Melatonin……………………..3 mg
Accumentis

39.  Improves Folliculogenesis
 Improves Oocyte Quality
 Lesser risk of Endometrial Thinning
 Lesser changes in Quality of Cervical Mucus
 Improves fertilization & Pregnancy Rates.
 Decrease Oocyte DNA damage
 Increase Oocyte & Embryo quality.

41. 1. Fondly known as Teacher of Teachers
2. Director Lifecare Centre & Lifecare IVF
3. Founder & Secretary general of Delhi Gynaecologist forum , a body of over 2500
members .
4. Founder & Chairperson of North India Gynaecologist forum (NIGF) , body cover
10 sates .
5. NMC / MCI : Ethical committee member ,an apex body of 14 lacs modern
Medicine doctors since 2018
6. Business World : Included her in Top 20 Most Influential women in Healthcare in
INDIA (8/03/22)
7. DMC Expert since 2009 to till date
8. Passionate medical activist..has given leadership role in removing Female
Feticide , Movement of Anemia, Save Uterus Campaign, Save ovary Campaign
and Every Mother Counts etc.
9. Given concept of JANANI SURAKSHA YOJNA & ASHA WORKER to GOI.
10. Spearheading movement of Doctors safety /Medico legal Awareness Unity of
North India Gynaecologists
11. Decorated with many Lifetime achievement & Living Legend Award from many
bodies including LHMC AA, FOGSI ,DMA ,DGF , WOW India
Dr. Sharda Jain
M.D. (PGIMER),
MNAMS,FICOG,FIMSA,DHM, QM
&AHO
PGDMLS (SYMBIOSIS)

42. Dr Jyoti Agarwal
Ex Hardonian Throughout
MBBS (Gold Medalist)
M.D (Gynae & OBST )
 Senior consultant & Director Lifecare Centre & Lifecare IVF
 President of D.G.F.(East)
 Treasurer of Delhi Gynaecologist Forum
 Certified Trainer for infertility ,IVF & ultrasound
 Awards
“THE TEACHERS EXCELLENCE AWARDS” DGF 2017
APJ Abdul kalam’s Appreciation Award DGF “East” 2015
APJ Abdul kalam’s Excellence Award DGF “East” 2020
 Participated in various national CME & workshop as a faculty