DR SUNITA CHANDRA, LUCKNOW AT WEB CME ON FEBRUARY 19,2020 , ATTENDED BY MORE THAN 60 DRS.

1. Dr. Sunita Chandra
M.D.
❖Chairperson & Director, Rajendra Nagar Hospital & IVF Centre
❖Director, Morpheus Lucknow Fertility Centre
❖Fellowship IVF,Germany

2. Dr . Sunita Chandra , M.D.
Chairperson & Director, Rajendra Nagar Hospital & IVF Centre
Director, Morpheus Lucknow Fertility Centre
➢Member- Quality Council Of India
➢Trained with distinguished experts like Dr. B.N Chakrawarty in Kolkata, Dr. R Rajan in Kottayam
➢Fellowship - IVF,Germany
➢Co-Editor of the manual – Improving surgical skills in Obstetrics (2020)
➢Author of one chapter in the Book— “HOW I MANAGE FIBROIDS”
➢Organizing Committee member of AICOG 2020
➢Presently Secretary , Medico legal committee, LOGS
➢Is founder Joint Secretary UP Chapter of IFS
➢Was organizing secretary of FERTIVISION 2016, held at Lucknow , attended by more than 1000 delegates
➢Has been secretary APGL and joint secretary LOGS
➢Has been Chairperson, panellist, moderator and speaker in many National and International Conference
➢Has attended many committee meetings at Moscow, China and Vietnam as Advisory Board member
➢Was panellist and speaker at the UP HEALTH SUMMIT 2018 and 2019, organised by CII and Department of Medical Health
& Family Welfare, Government of Uttar Pradesh.
➢Has given many lectures in various conferences & CMEs at National and state level
➢Active participant of local bodies like LOGS, took initiative to organize many National level Conferences & CMEs
➢Awarded “ABP NEWS UP BRAND LEADERSHIP AWARD” in Medicine & Hospital sector , handed over by Shri Akhilesh
Yadav, Chief Minister. U.P.
➢Honoured “GOMTI GAURAV” Award by State Ministers
➢Honoured “SAMMAN CHINH” by Lucknow Nursing Home association and LNHA Blood and component Bank
➢Honoured with “ SAMMAN PATRA” by Dr. Neeraj Bora, MLA on Doctors Day ( July 01,2019)

4. RECENT UPDATES
IN OVULATION INDUCTION
IN PCOS

5. • Ovulation induction is process by which the
development of ovarian follicles is stimulated by
medication
• Induction of ovulation is the commonly practiced
therapy interventions to reverse anovulation or
oligo-ovulation in the women who do not ovulate
on their own regularly.
• The most common clinical situation being PCOS

6. • The purpose of using ovulation induction
drugs include:
DEFINITIONS
• Ovulation Induction
• Ovarian stimulation
• Ovulation triggering

7. In 1973, the WHO Scientific Group devised a
classification of anovulatory women primarily
based on the levels of gonadotropins and
oestrogens, as per the classification, there
are 3 groups of anovulatory women:
CLASSIFICATION OF ANOVULATION
• WHO Group I : Hypogonadotropic Hypogonadal anovulation
( Hypothalamic Amenorrhoes)
•WHO Group II : Normogonadotropic Normoestrogenic Anovulation
•WHO Group III: Hypergonadotropic Hypoestrogenic Anovulation

8. Anovulatory PCOS women may
present with different clinical
features and accordingly can be
classified into three broad
subgroups:
CLINICAL PRESENTATIONS

9. CLINICAL PRESENTATIONS
Group A : these patients are:
•Apparently normoestrogenic and normoandrogenic
•Non-hirste, non-obese, no history of genetic background or insulin
resistence.
•Only delayed menstrual cysles ( 35-45 days), no history of typical
oligomenorrhea or secondary amenorrhoes.
•On USG scan, the ovaries may be normal in size or enlarged but no
thecal-stromal hyperplasia.
These cases are typical clomiphene/Letrozole responders

10. CLINICAL PRESENTATIONS
Group B : these patients are:
•Mildly androgenized with hirutism, mild obesity, oligomenorrhea,
and aanovulation
•Ovaries are enlarged, and stromal hyperplasia, and peripheral
cysts may or may not be present.
These patients may still respond to CC/Letrozole,
but a better option is to combine CC with metformin

11. CLINICAL PRESENTATIONS
Group C : these patients are:
•Typical obese and stocky subjects with family history of diabetes or
PCOS
•Presents with oligomenorrhea or secondary amenprrhea , and
•May have HAIR-AN syndrome, and ovaries are polycystic with
sromal-thecal hyperplasia.
This group of patients are ideal candidates for
•Insuline –sensitizing agent (ISA : Metformin) with CC or Gonadotropin
•ISA plus ovarian drilling
•Down regulation followed by gonadotropin plus ISA, bu may also require
follicular spiration ( to avoid the risk of ovarian hyperstimulation)

12. WHY AN ENIGMA ?
The presentations of PCOS are heterogeneous & may
change through out the lifespan, starting from adolescence
to postmenopausal age, & may have health impaction later
in life.

13. • Heterogeneous, reproductive-metabolic,pathological disorder
• Primary cause: Ovarian androgen overproduction
• Associated with insulin resistance and obesity
Major symptoms
• Menstrual disorders
• Hyperandrogenaemia
• Metabolic syndrome
• Infertility
1. Allahabadia GN et al. Polycystic Ovary Syndrome in the India Subcontinent. Semin Reprod Med 2008;26:22–34.
2. Badawy A et al. Treatment options for polycystic ovary syndrome. Inter J Women’s Health 2011:3 25–35
3. Malik et al. Management of Polycystic Ovary Syndrome in India. Fertility
4. Science & Research. Jan-Jun 2014; 1(1): 23-4

14. Global prevalence -2.2% to 26%
Roughly 1 in 15 women worldwide, (Lancet, 2007)
36% of women
in India are
suffering from
PCOS
Hereditary:
Affected mother- 35%
Affected sister- 40%

15. Diagnostic criteria for PCOS
(Summary)

16. Failure of stimulation
Hyperstimulation
Premature Lutenization
PROBLEMS IN OVULATION INDUCTION & PCOS.

17. Minimize amount of medication.
Ease of compliance.
No multiples (as high as 15%-20%)
No OHSS (10%-15%)
No cancellations
(poor response/high response or premature luteinization 10%-40%)
No miscarriages (30%-50% higher)
ELEMENTS OF THE IDEAL OVULATION
INDUCTION PROTOCOL FOR PCOS

18. Polycystic ovary syndrome is a common cause of
anovulatory infertility and many treatment
alternatives exist. We review the various
treatment options and suggest a ranking of
these based on simplicity, efficacy, and
adverse effects.

20. WEIGHT REDUCTION AND LIFESTYLE CHANGES

21. ➢ 5 % - 10% wt. loss can improve I.R, ovulation rate, pregnancy rate even if
BMI > normal range
➢ No consensus on commencement of fertility Rx based on optimal BMI.
Ref. Practice Committee of ASRM – Obesity & Reproduction Fertil Steril 2008, 90:S21-9
Contd…
Weight loss in infertile obese PCOS
Ref. Clark AM, et. al. Hum Reprod 1998;13:1502-5
ASRM recommends that though BMI of < 35 should be
achieved before conception, “the benefits of postponing
pregnancy to achieve wt. loss must be balanced against
risk of declining fertility with advancing age.

22. Randomized Controlled Trial of Preconception
Interventions in Infertile Women With PCOS
Richard S. Legro, William C. Dodson, Penny M. Kris-Etherton, Allen R. Kunselman, Christy M. Stetter, Nancy I. Williams, Carol L.
Gnatuk, Stephanie J. Estes, Jennifer Fleming, Kelly C. Allison, David B. Sarwer, Christos Coutifaris, and Anuja Dokras 2015
Conclusions:
A preconception weight loss intervention eliminates the adverse
metabolic oral contraceptive effects and, compared with oral
contraceptive pretreatment, leads to higher ovulation rates.
(J Clin Endocrinol Metab 100: 4048–4058, 2015)

23. INOSITOL
➢ Myo-inositol promotes glucose uptake and FSH activity
➢ D-Chiro-inositol ameliorates insulin-stimulated androgen synthesis in
the ovary,
➢ both of these effects may positively affect the ovarian function in
PCOS.
➢ Doses used are for myo-inositol 2 g and for chiro-inositol 0.6 g , both
taken twice daily for 2 to 6 months

24. Myo-inositol + D-chiro-inositol
➢ Research indicates that a combination of myo- and D-
chiro-inositol, in the body’s physiological ratio of 40:1, is
more beneficial than either alone.
➢ This combination improved metabolic parameters
more than myo-inositol alone after 3 months of treatment
in overweight women with PCOS. Nordio and Proietti,
2012
➢This combination improved lipid profile in obese women
with PCOS. Minozzi, 2013
➢This combination (vs. D-chiro-inositol alone) improved
egg and embryo quality, and pregnancy rates, in
women with PCOS undergoing IVF. Colazingari, 2013

25. Inositol treatment of anovulation in women with
polycystic ovary syndrome:
a meta-analysis of randomised trials
J Pundir,a D Psaroudakis,a P Savnur,a P Bhide,b L Sabatini,a H Teede,c A Coomarasamy,d S Thangaratiname 2017
Conclusions:
Inositol appears to significantly improve the ovulation rate, and
metabolic and hormonal profiles in women with PCOS compared
with placebo. There is a need to assess its effect on pregnancy and
live birth rates and on longer term metabolic health outcomes. This
review shows promising but
preliminary favourable results with myo-inositol in women with PCOS.
A well-designed and well-conducted multicentre trial to address this
issue to provide robust evidence of benefit is warranted before the
widespread use of inositol can be recommended. Disclosure of
interest None declared. Completed disclosure of interests form

26. Metformin is an insulin sensitizer that lowers fasting levels of
plasma insulin, C-peptide,and proinsulin-like molecules,
binding of insulin to its receptor,
peripheral utilization of glucose, and decreases hepatic
glucose production.
Doses used are in the range of 1500-2500 mg per day
divided into 2 or 3 doses.
METFORMIN

27. The effectiveness of inositol and metformin on infertile polycystic
ovary syndrome women with resistant to letrozole
Sajadeh Pourghasem Fatemeh Bazarganipour Seyed Abdolvahab Taghavi Maryam Azizi Kutenaee 2019
Conclusions:
The addition of inositol and metformin to the treatment of infertile
PCOS women with letrozole resistance improves the ovarian function;
however, it is not significant. Of note, inositol was more effective than
metformin in patients with normal BMI.

28. The Current and future aspects of several adjunctive
treatment strategies in polycystic ovary syndrome
BeataBanaszewskaLeszekPawelczykRobertSpaczynski 2019
we assessed the evidence for the effectiveness and safety of selected adjunctive
agents (metformin, statins, resveratrol, melatonin, and inositols) for the treatment of
women with PCOS. Metformin is a safe medication used in PCOS for 25 years that is
currently recommended in select PCOS subpopulations, such as adolescents, women
with metabolic disorders, and infertility infertile women undergoing ovarian
hyperstimulation. Statins are also suggested in PCOS therapy, as these compounds
decrease testosterone concentrations, improve lipid profiles, and ameliorate
inflammatory reactions. Despite promising results, the role of statins in PCOS
management needs to be further validated. Dietary supplements have also been
tested in PCOS patients. Resveratrol was shown to decrease total testosterone
production and improve fasting insulin but, until recently, only in one randomized
study. Data on the therapeutic efficacy of melatonin and inositols on endocrine and
metabolic abnormalities are limited and inconclusive. The multifactorial etiology of
PCOS makes tailoring of its treatment more demanding, and there is a constant need
for causative and effective modes of PCOS therapy.

29. . Clomiphene citrate (CC) is a selective estrogen receptor modulator
(SERM) consisting of 2 isomers, zu-and en-clompihene, of which the
former is the most biologically active one.
. Blocking the estrogen receptors at the level of the hypothalamus and
the pituitary results in an increased output of gonadotropins from the
anterior pituitary,
. thereby stimulating the final maturation of follicles.
. Standard treatment for ovulation induction with CC in women with
PCOS has been doses of 50-150 mg per day for 5 days starting on day 3-
5 after the onset of a withdrawal bleeding.
SELECTIVE ESTROGEN RECEPTOR MODULATORS

30. CLOMIPHENE CITRATE FOR OI:
➢First line drug for Ovulation Induction (OI)
RCOG recommendations:
➢Should be used for a maximum of 12 months in a
woman’s lifetime; maximum 6 months continuous
use
➢Most widely used
➢Cost effective
➢Simple to use
Most abused
drug

31. DOSAGE
➢50-100mg per day for five days (up to 200mg per day)
➢There is no difference in pregnancy rate whether
clomiphene is commenced on day 2, 3, 4 or 5 of the cycle,
although there is perhaps a tendency to multiple follicular
development the closer the agent is commenced to menses.

32. OUTCOME AFTER CLOMIPHENE CITRATE
➢Pregnancy: 30%
➢Failure (no pregnancy despite
ovulation): 40%
➢Resistance: no ovulation: 25%
➢Antiestrogenic effect: 5%

33. CLOMIPHENE CITRATE
➢ In combination with Metformin the results are better for PCOS patients
➢ In combination with Gonadotropins the antioestrogenic side effects are
overcome.
➢ Used also in minimal stimulation for ART
Adverse effects:
➢ Hot flushes, visual disturances, ovarian hyperstimulation, abdominal
discomfort and multiple pregnancy
➢ More than 6-8 cycles are not reommended
➢ Ovarian cyst formation and cancer is documented beyond 12 cycles.

34. ➢ should be considered first line pharmacological
treatment for ovulation induction
➢ Other ovulation induction agents can be used if
➢letrozole is not available
➢use is not permitted
➢cost is prohibitive.
➢ Multiple pregnancy appears to be less with
letrozole, compared to CC.
LETROZOLE

35. LETROZOLE
➢ Aromatase inhibitor, it acts against aromatase in the final rate imiting step of
estrogen production.
➢ Releases the negative feedback at hypothalamic level leading to gonadotropin
production
➢ No adverse effects on endometrial thickness or cervical mucus.
➢ More of a monofollicular growth compared to CC
➢ Better PR than CC
➢ In combination with gonadotropin, better response even for poor responder.
➢ Dosage 2.5 5 mg daily for 5 days
➢ REGIMENS
➢ Regular therapy 2.5 to 5 mg /day from day 3
➢ Single dose therapy 20 mg on day 3
➢ Extended therapy 2.5 mg daily from day 1-10.(better no. of dominant follicles, higher
PR)
➢ Step up therapy 2.5 mg starting on day 2, tab 1,2,3,4,till day 5. ( this extend the FSH
window due to prolonged suppression of estrogen)

36. Letrozole vs.Clomiphene for infertility in PCOS
N Engl J Med. 2014 10:371 (2):119-129
Conclusions
As compared with Clomiphene , Letrozole was associated with higher
live birth and ovulation rates among infertile women with the PCOS.
750 patients trial

37. The American College of Obstetricians and Gynecologists (ACOG)
now recommends Letrozole as the first line treatment for ovulation induction in women with
PCOS due to data demonstrating increased ovulation rates, clinical pregnancy rates and
live-birth rate vs Clomiphene citrate.
The starting dose is 2.5 mg/day for 5 days typically starting on day 3,4,or 5 after a
spontaneous menses of progestin-induced bleed., if ovulation does not occur, the dose can
be increased to 5 mg/day for 5days with a maximum dose of 7.5 mg /day
Doses higher than 7.5 mg/day have ben associated with thinning of the endometrium as
seen with clomiphene citrate

38. Gonadotrophins
used as second line agents
➢in women with PCOS who have failed first line oral
ovulation induction therapy
➢ could be considered as first line treatment
➢ in the presence of ultrasound monitoring
➢following counseling on
➢cost
➢potential risk of multiple pregnancy

39. HOW MUCH?
➢Age
➢BMI
➢Type/ cause of infertility
➢AFC/ Ovarian volume/ AMH/ D2
FSH
➢Presence or absence of PCOS
➢Previous follicular response to Gn

40. INDIVUDUALISATION OF PROTOCOL, DOSE SELECTION AND TRIGGER
PREDICTIVE FACTOR OF OVARIAN RESPONSE
Patient characteristics: Age,parity, reproductive history, BMI, previous respone to ART
treatment
Endocrine markers of ovarian response : Day 2 or Day 3 FSH, AMH, Estradiol, inhibin B,
Hyper responder Normal responder Poor responder
AMH ˃3.5 ng/ml 2 to 3.5 ng/ml ˂ 2 ng/ml
AFC ˃15 8 to 15 ˂ 7
Protocol Antagonist Long protocol Antagonist protocol
Antagonist protocol Mild stimulation
Ultra short protocol
Starting dose of GNT(IU) 150 225 300 to 375
Trigger Antagonist trigger and freeze
all Dual trigger and inte sive
and intensive Luteal support
HCG trigger HCG trigger

41. Gonadotrophins, where available and affordable,
➢should be used in preference to CC combined with
metformin in CC-resistance PCOS
Gonadotrophins with the addition of metformin
➢could be used rather than gonadotrophins alone, in
➢CC-resistance PCOS
➢ Either gonadotrophins or laparoscopic ovarian surgery
could be used in, CC-resistance PCOS, following
counseling on benefits and risks of each therapy.

42. Where gonadotrophins are prescribed,
the following should be considered:
➢ cost and availability
➢ expertise required for use in ovulation induction
➢ degree of intensive ultrasound monitoring required
➢ lack of difference in clinical efficacy of available
gonadotrophin preparations
➢ low dose gonadotrophin protocols optimise monofollicular
development
➢ risk and implications of potential multiple pregnancy

43. WHICH Gn????
RECOMBINANT VS URINARY GONADOTROPINS???
➢Better safety, purity & potency
➢Batch to batch variability less
➢Similar PR with 50% less dose
➢SC self injection with pen injectors
➢Patient friendly

44. WHICH PROTOCOL ?
➢CC/ AI with Gn
➢Low dose step up protocol
➢Conventional step up protocol
➢Step down protocol
➢Antagonist protocol

45. GnRH ANTAGONIST PROTOCOL
➢In cases of premature LH surge
➢To time weekend IUI
0.25 mg / day started
when dominant
follicle 14-15 mm size
till hCG
administration

46. ADVANTAGES OF ANTAGONIST PROTOCOLS
➢Allows the manipulation of follicular development so that IUI can
be avoided at weekends without any detrimental effect on PR
➢Compared to agonist , it is relatively simple and inexpensive.
➢There is no suppression of oestrogen and the effects are easily
reversible
➢Antagonists are associated with lower rates of OHSS

47. GnRH a vs hCG
• Aiming to reduce severe OHSS
• Only in Antagonist cycles
• GnRHa works for 48hrs max
• hCG works for 8-10 days
• If safer, why not to apply for all cases?

48. Triggering final oocyte maturation with a GnRH agonist
and freezing all suitable embryos
➢could be considered
➢with a GnRH antagonist protocol
➢at an increased risk of developing OHSS or
➢where fresh embryo transfer is not planned.
An elective freeze of all embryos.
➢should be considered

49. DUAL TRIGGER
➢ Previous history of > 25% immature oocytes retrieved.
➢ Empty follicle syndrome
➢ To prevent OHSS in PCOS patients
➢ To get adequate e support in PCOS patients
➢ Poor responders

50. Adjunct metformin
➢could be used before and/or during follicle
stimulating hormone ovarian with a gonadotrophin
releasing hormone agonist protocol,
➢to improve the clinical pregnancy rate and
reduce the risk of OHSS.
Benefits in a gonadotrophin releasing hormone
antagonist protocol to reduce risk of OHSS

51. In-vitro fertilisation (IVF)
IVF third line
➢In the absence of an absolute indication for IVF ± ICSI
➢where other ovulation induction therapies have failed.
IVF is effective
➢when elective single embryo transfer is used, multiple
pregnancies can be minimised.

52. Counseling prior to starting treatment, including on:
➢availability, cost and convenience
➢increased risk of OHSS
➢options to reduce the risk of OHSS

53. Laparoscopic ovarian surgery
➢could be second line therapy for CC resistant
PCOS,
➢could potentially be offered as first line
treatment if laparoscopy is indicated for
another reason
➢Risks
➢should be explained to all women with PCOS
considering laparoscopic ovarian surgery.

54. Where laparoscopic ovarian surgery is to be recommended,
the following should be considered:
➢ comparative cost
➢ expertise required for use in ovulation induction
➢ intra-operative and post-operative risks are higher in women who are
overweight and obese
➢ there may be a small associated risk of lower ovarian reserve or loss of
ovarian function
➢ periadnexal adhesion formation may be an associated risk

55. A Cochrane review concluded that LOD was as effective as other treatment
options in CC-resistant PCOS, and long-term follow-up studies have shown
that the method is cost-effective compared with other ovulation induction
procedures and has a low risk of multiple pregnancies. Although the effect of
ovarian surgery for PCOS is not fully understood, a decrease in the levels of
testosterone, androstenedione, estradiol, and LH has been shown, while FSH
in some cases increases, possibly due to a reduced negative feedback from
estradiol. Follow ups on the effect of LOD on AMH levels have shown a
significant decline after 6 months, but whether this is caused by damage to
the ovaries or rather from a normalization of the endocrine dysfunction is
currently unknown as there are no long-term follow-up studies.
SURGERY

56. TAKE HOME MESSAGE….
➢ Prefer individualised ovarian stimulation protocol
➢CC/ Letrozole can be the first line management but move to
Gonadotropins after 3 cycles
➢Oral OI drugs may be added to Gonadotropins for better results
➢Letrozole superior to CC when Gonadotropins have to be added
➢Low dose step up protocol ideal for OI in IUI cycles
➢Higher safety, efficacy, purity & potency with recombinants
➢LH may be added in selected patients
➢Limited role of GnRH agonist & GnRH antagonist
➢Aim for OHSS free clinic
➢ Prefer single blastocyst transfer
➢ Random start or Dual stimulation for poor responders & fertility
preservation patients

57. CONCLUSIONS
. Basic defect of anovulation in PCOS women is
hyperandrogenicity ( according to the definition by the
Androgen Excess Society ). Which is not entirely accepted by
Rotterdam Criteria.
. PCOS patients can be categorised into three groups:

58. Summary of Recommendations and Conclusions
➢An increase in exercise combined with dietary change has consistently been
shown to reduce diabetes risk comparable to or better than medication.
➢ Improving insulin sensitivity with insulin-sensitizing agents is associated with a
decrease in circulating androgen levels, improved ovulation rate, and improved
glucose tolerance.
➢ For women with PCOS, letrozole should be considered as first-line therapy for
ovulation induction because of the increased live birth rate compared with
clomiphene citrate.
➢ The addition of eflornithine to laser treatment is superior in the
treatment of hirsutism than laser alone.
Polycystic ovary syndrome. ACOG Practice Bulletin No. 194. American College of Obstetricians and Gynecologists. Obstet Gynecol 2018;131:e157–71
LEVEL A

59. Summary of Recommendations and Conclusions
➢ Women with a diagnosis of PCOS should be screened for type 2 diabetes and impaired
glucose tolerance with a fasting glucose level followed by a 2-hour glucose level after a
75-g glucose load.
➢ Women with PCOS should be screened for cardiovascular risk by determination of BMI,
fasting lipid and lipoprotein levels, and metabolic syndrome risk factors.
➢ Reduction in body weight has been associated with improved pregnancy rates and
decreased hirsutism, as well as improvements in glucose tolerance and lipid levels.
➢ There may be an increase in pregnancy rates by adding clomiphene citrate to
metformin, particularly in obese women with PCOS
➢ If clomiphene citrate or letrozole use fails to result in pregnancy, the recommended
second-line intervention is either exogenous gonadotropins
or laparoscopic ovarian surgery.
Polycystic ovary syndrome. ACOG Practice Bulletin No. 194. American College of Obstetricians and Gynecologists. Obstet Gynecol 2018;131:e157–71
LEVEL B

60. Summary of Recommendations an Conclusions
➢ Combination low-dose hormonal contraceptives are most frequently used for
long-term management and are recommended as the primary treatment of
menstrual disorders.
➢ Women in groups at higher risk of nonclassical congenital adrenal
hyperplasia and a suspected diagnosis of PCOS should be screened to assess
the 17-hydroxyprogesterone value.
➢ A low-dose regimen is recommended when using gonadotropins in women
with PCOS.
➢ There is no clear primary treatment for hirsutism in PCOS.
Polycystic ovary syndrome. ACOG Practice Bulletin No. 194. American College of Obstetricians and Gynecologists. Obstet Gynecol 2018;131:e157–71
LEVEL C