PCOS and Infertility

- Case based approach

Dr Puneet K Kochhar
MD, DNB, FRCOG (UK), FICOG,
DMAS, DRM (Germany)

Elixir Fertility Centre

ART . GENETICS . STEM CELLS
 Sequential Culture

Force feeding
 Single Step / Monostep Culture

Let the Embryo Choose

As long as concentrations are

within ‘tolerable ranges’, the
embryo itself will adapt and
utilize whatever it requires

Pathophysiologic stress
The switching of embryos may
cause additional osmotic or
other shock to the embryo
and/or deprive it of any autocrine
-paracrine factors it may have
produced during the first culture
period.
 Sequential Culture

HELICOPTER PARENTING
 Single-step Culture

SUBMARINE PARENTING
 Infertility - Definition
Failure to achieve a successful pregnancy
2008 after 12 months or more of regular
American Society
unprotected intercourse.
for Reproductive Earlier evaluation and treatment is warranted
Medicine after 6 months for women over age 35 years.

A disease of the reproductive system defined by

2009 the failure to achieve a clinical pregnancy after
Int. Com. for Monitoring 12 months or more of regular unprotected
Assisted Reproductive intercourse.
Technology and WHO

Prevalence of primary infertility in India - upto 16.8 % Elixir Fertility Centre

Polycystic Ovary Syndrome (PCOS)

¨ Heterogeneous & complex disorder that has both

adverse reproductive & metabolic implications.
¨ Most common endocrine disorder in reproductive-
age women.
¨ Commonest cause of anovulatory infertility

Elixir Fertility Centre

Polycystic Ovarian Syndrome
Most common
female disorder of
ovarian function

DIAGNOSTIC CRITERIA

1. Rotterdam criteria

2. Androgen excess society

criteria

3. NIH criteria

Elixir Fertility Centre

PCOS definition:
The Rotterdam Criteria 2003
PCOS is characterized by any two out of the three
following criteria:
¨ Oligo-anovulation/anovulation (amenorrhea or

oligomenorrhea)
¨ Clinical or biochemical hyperandrogenism

¨ Polycystic ovaries (ultrasound)

Elixir Fertility Centre

 Prevalence

¨ Overall prevalence is 12.5% to 36% in India.

¨ In infertile women of Indian subcontinent
prevalence rates: upto 50-60%.
¨ The prevalence of infertility in women with PCOS
varies between 70 and 80%.

1.Malik et al.Indian Journal of Clinical Practice November 2014 :25 (6):561-564

2.Majumadar et al.J hum repro scie.2009:2(1)
4.Jajoo S et al. Int J Reprod Contracept Obstet Gynecol. 2013 Dec;2(4):528-532
Elixir Fertility Centre
Common signs of PCOS

Elixir Fertility Centre

 Polycystic Ovary Syndrome (PCOS)

Increased ovarian Impaired follicular

androgen production development

Chronic anovulation

Infertility

Adapted from Gervásio CG et al. ISRM Obstet Gynecol 2014:818010.

Elixir Fertility Centre
Case 1
¨ Age: 29 yrs
¨ Trying to conceive for 6 months
¨ Menarche at 11 yrs
¨ Regular 32 days cycles till
marriage 6 months ago
¨ h/o oligomenorheoa since 6
months (5d/45-60d)
¨ Weight: 75kg (h/o 15 kg weight
gain in 6 months); BMI: 28.9
¨ No hirsutism, galactorhoea
¨ Examination: WNL

Elixir Fertility Centre

Case 1

¨ UPT- to rule out pregnancy

¨ A hormonal assay for Day 2 FSH, LH,
AMH, TSH, Prolactin
¨ FSH : 6.5, LH: 7.9 and AMH : 5.8.
¨ TSH, Prolactin: WNL
¨ HSA: WNL
¨ TVS - multiple follicles in both ovary
(AFC: 10-12 on each side)

Elixir Fertility Centre

 Case 1

¨ Lifestyle changes
¨ Weight loss program with diet modification
¨ Energy deficit of 30% or 500 to 750 kcal/d (1200–1500
kcal/d)
¨ Regular physical activity - 150 min/wk of moderate
intensity physical activity or 75 min/wk vigorous
intensity and muscle strengthening activities on 2
nonconsecutive days per week

Elixir Fertility Centre

Case 1

¨ Advised follow up after 3 months

¨ Reported back with regular menses
¨ Conceived naturally in 4 months

Elixir Fertility Centre

 Obesity & PCOS
¨ Obese women are 3 times more
likely to have Infertility than
normal women
¨ 80% of women with PCO have
high BMI
¨ RR of anovulation is 2.7 times
with BMI>30kg/m2
¨ Follicular fluid insulin and
androgen levels correlate with
BMI in obese infertile women
even in absence of PCO, leading
to follicular atresia, anovulation
& Infertility
Elixir Fertility Centre
PCOS: Management

Elixir Fertility Centre

Non-pharmacological measures

¨ Lifestyle changes (Diet, exercise) - first-line treatment

for infertility in women with PCOS.
¨ Counseling of pregnancy complications
¨ Administering folic acid to reduce the risk of fetal
neural tube defects
¨ 5 to 10% loss in body weight associated with
improvement in ovulation rate

Elixir Fertility Centre

Case 2
¨ Age: 32 yrs
¨ Trying to conceive for 2 yrs
¨ Oligomenorrhoea since
menarche (4d/45d)
¨ BMI: 27.4
¨ h/o hirsutism
¨ No h/o galactorhoea
¨ Family h/o DM in mother
¨ Pelvic Examination: WNL
¨ Taken COC (EE+Cyproterone)
– stopped 2yrs ago

Elixir Fertility Centre

Case 2

¨ UPT – r/o pregnancy

¨ Day 2 FSH, LH, AMH, TSH, Prolactin,
¨ OGTT/ BS(F/PP), HBA1c
¨ FSH : 7.5, LH: 12.9 and AMH : 4.8.
¨ TSH, Prolactin: WNL
¨ HSA: WNL
¨ TVS – PCO appearance

Elixir Fertility Centre

Case 2

¨ Wt loss advised.
¨ OI with Letrozole 2.5-5mg Odx 5 days with follicular
monitoring
¨ 2 ovulatory cycles, No pregnancy - HSG
¨ CC 50-150mg OD x 5 days (multifollicular development,
SERM: thin ET)
¨ IUI (conceived in 2nd IUI cycle with Letrozole)
¨ COH with Gonadotropins (FSH/ HMG)
¨ Metformin

Elixir Fertility Centre

Ovulation induction vs. Controlled
ovarian stimulation

OI: Induction of monofollicular development and

ovulation in anovulatory women

COH: Aim is to induce the ongoing development of

multiple dominant follicles and to mature many oocytes to
improve chances of conception with in vivo (with TI or IUI)
or in vitro (IVF) approaches.

Elixir Fertility Centre

Goals of Ovarian Stimulation

Maximize Minimize
beneficial effects complications
of treatment and risks

Cycle cancellation,
OHSS, multiple
pregnancy
PROTOCOLS

1. CC/ LETROZOLE only with TI or IUI

2. CC/ LZ + gonadotropins with IUI
3. Gonadotropins only
¤ Conventional regime
¤ Low dose step-up

¤ Step down protocol

4. Gonadotropins with antagonist

Elixir Fertility Centre

Standard plan of OI

Elixir Fertility Centre

CC - How many cycles ?

No ovulation No ovulation
50 mg/day 100 mg/day 150 mg/day

No ovulation
2-3 cycles with the same dose

No pregnancy

Suboptimal Injectable gonadotropins

endometrium

Elixir Fertility Centre

Gonadotropin Therapy in PCOS

¨ Clomiphene Resistance: Failure to ovulate after

2-3 successive cycles of CC at the maximal dose
(20-30%)
¨ Clomiphene Failure: Women who respond
normally to CC but fail to conceive after 6 to 12
cycles of treatment (~60%)
¨ Suboptimal endometrium thickness (< 7mm)
after CC-OI

Elixir Fertility Centre

Gonadotropins

The challenges in the case of PCOS are:

ü Increased risk of hyperstimulation

ü Increased risk of multiple pregnancy
ü Premature rise of LH
ü Increased chance of cycle cancellation

Elixir Fertility Centre

Gonadotropin regimes
¨ Conventional regime
75 – 150 IU/day

0 6 12
¨ Chronic low dose step-up

150
112.5 IU/day
75
37.5 IU/day
IU/day
IU/day
0 7 14 21 28

¨ Step down
150
IU/day 112.5
75
IU/day
IU/day
10 mm follicle Elixir Fertility Centre
The Optimum Stimulation Cycle
¨ Recruitment of two follicles measuring >16 mm with an
E2 concentration >500 pg/mL on the day of hCG
administration.
Fertility and Sterility Vol. 93, No. 1, January 2010

¨ Since in cycles with three or four follicles the multiple

pregnancy rate increased without substantial gain in
overall pregnancy rate, IUI with COH should not aim
for more than two follicles.
Human Reproduction Update, Vol.14, No.6 pp. 563–570, 2008

Elixir Fertility Centre

Insulin Sensitizers

¨ IR exacerbates ovulation dysfunction.

¨ A Pathophysiological contributor in up to 80% of
PCOS women
¨ Insulin sensitizers - Commonest drug used is
Metformin.
¨ Metformin improves parameters of IR,
hyperandrogenemia, anovulation, and acne in PCOS
¨ Dose of 1500 –2000 mg/day in divided doses.
Causes G.I. side effects

Elixir Fertility Centre

Insulin-sensitising drugs for women with PCOS

¨ 48 studies (4451 women).

¨ Metformin alone may be beneficial over placebo for live
birth
¨ An improved clinical pregnancy and ovulation rate
with metformin and clomiphene citrate versus
clomiphene citrate alone suggests that combined
therapy may be useful
¨ Women taking metformin alone or with combined
therapy should be advised that there is no evidence of
increased miscarriages, but gastrointestinal side effects
are more likely.
Cochrane Database Syst Rev. 2017 Nov 29;11:CD003053

Elixir Fertility Centre

Case 3

¨ Age: 36 yrs
¨ Trying to conceive for 6 yrs
¨ Oligomenorrhoea since menarche (4d/40-45d)
¨ BMI: 27.4
¨ No h/o hirsutism or galactorhoea
¨ Pelvic Examination: WNL
¨ Had 5-6 OI cycles with normal ovulation and 2
failed IUI cycles

Elixir Fertility Centre

Case 3

¨ FSH : 9.5, LH: 8.9 and AMH : 3.2.

¨ TSH, Prolactin: WNL
¨ HSA: WNL
¨ TVS – PCO appearance
¨ HSG: WNL

Elixir Fertility Centre

ART(Artificial Reproductive Techniques)

¨ ART (IVF, ICSI, IVM) has a role in PCOS

only when pharmacological options have
failed (3rd line treatment)
¨ Other indications - tubal damage or male

factor infertility.
¨ Significantly increased risk of developing OHSS

due to excessive response to FSH stimulation.

Elixir Fertility Centre

ART – Precautions in PCO

¨ Low dose stimulation

¨ GnRH antagonist protocol
¨ GnRH agonist trigger
¨ Freeze all program
¨ Frozen embryo transfer is performed in a later
cycle.

Elixir Fertility Centre

 Alternate Inositol (myoinositol and
D-chiro-inositol) are
therapies Bariatric surgery with
highly obese patients
presenting with PCOS,
chemicals which acts as
insulin sensitizing agent.
It helps in glucose uptake

to control can improve overall

prognosis.
and FSH signaling, and
also ameliorate insulin
resistant related
androgen synthesis.
PCOS
Vitamin D
supplementation is All these adjunct
multipurpose adjunct in therapies has limited
pts with PCOS. Vit D evidence, but can be a
deficiency is associated great adjunct in a
with insulin resistance. suitable candidate with
Women with Vit D faster improvement and
deficiency has lower better chances of
ovulation and live birth conception.
rate.

Ref:
Cunha, Anita MDa,∗; Póvoa, Ana Margarida MD, PhDb,c,d. Infertility management in women with
polycystic ovary syndrome: a review. Porto Biomedical Journal 6(1):p e116, January/February 2021. |
DOI: 10.1097/j.pbj.0000000000000116 :
Fertility related

Elixir Fertility Centre

Principles of OI

Elixir Fertility Centre

Letrozole

Elixir Fertility Centre

CC and Metformin
Gonadotropins
Gonadotropins

Elixir Fertility Centre

Laparoscopic surgery
Bariatric Surgery
IVF
IVF
IVF
 Summary
¨ PCOS accounts for ~80% of cases of anovulatory
infertility
§ Lifestyle changes should be recommended prior
to any therapy.
§ Gonadotrophins are the most effective drugs
with IUI.
§ Gonadotrophins chronic low dose protocols are
advised
§ Metformin improves pregnancy rates and
reduces OHSS when added to OI protocol
Elixir Fertility Centre
THANK YOU

Elixir Fertility Centre

ART . GENETICS . STEM CELLS