INDIA

PCOS
TUTORIALS
A Post Graduate
Certificate Course in
PCOS Management

Module 4
PCOS and Infertility

Brought to you by The PCOS Society (India)

 INDIA

Course Directors

Dr. Duru Shah Dr. Madhuri Patil

Founder President Chair, Scientific Committee
The PCOS Society, India The PCOS Society, India

Course Faculty for Module 4

Dr. Madhuri Patil

Chair, Scientific Committee
The PCOS Society, India
 Module IV
PCOS and Infertility

1
Table of Contents
1. Pre-Test 4
2. Introduction 6
3. Prevalence
• PCOS in Cases of Infertility 7
• Infertility in PCOS Patients 8
4. Pathophysiology of Infertility in PCOS 9
5. Management of Infertility in PCOS
• Role of Hormonal Testing in Infertility 16
• Consensus on Infertility Treatment Related to 18
PCOS: ESHRE/ASRM, 2007
• Lifestyle Modification 19
• Ovulation Induction in PCOS 20
o First Line/Oral Options
– Clomiphene Citrate 22
– Alternative Therapies: Letrozole and Tamoxifen 24
– Adjuvants for Ovulation Induction 27
o Second Line of Treatment 37
– Gonadotropins 38
– Laparoscopic Ovarian Drilling 46
• Complications 49
6. In vitro Fertilisation 59
7. Emotional well-being 62
8. Conclusion 63
9. Key Points 64
10. Suggested Readings 65

2
Module Overview
• Prevalence of polycystic ovarian syndrome (PCOS) has been reported as nearly
40% among women with infertility; while on the other hand prevalence of
infertility has been reported as high as 72% in women with PCOS.1 This signifies
the high impact of PCOS on the reproductive career of a woman.
• This module is designed to provide in-depth understanding of the
pathophysiology of infertility in PCOS.
• It would further discuss stepwise options beginning with easy to implement and
those with lesser adverse effects to more specialised, sophisticated treatments
of infertility in PCOS. The latter may need experts in the field to implement these
treatments.
• Infertility in PCOS is associated with considerable psychological turmoil and it is
important for the clinician providing holistic treatment to include the care for
emotional well being of the patient. The same has been discussed briefly in this
module.
Reference:
1. Joham AE, Teede HJ, Ranasinha S, et al. Prevalence of infertility and use of
fertility treatment in women with polycystic ovary syndrome: data from a large
community-based cohor t study. J Women’s Health (Larchmt).
2015;24(4):299–307.

Learning Objectives
At the completion of this module the participant is expected to be able to:
• Understand the burden of infertility associated with PCOS
• Understand the pathophysiology of infertility in PCOS
• Implement a stepwise management plan for infertility in PCOS
• Support the PCOS patients for their emotional well being

3
 PCOS and Infertility

PRE-TEST
State whether the following statements are True or False

1. PCOS will always be diagnosed way before the patient starts having
infertility concerns.

True

False

2. Infertility issues arise in all patients with PCOS.

True

False

3. There is a link between nutrition and reproduction.

True

False

4. PCOS is linked largely with anovulatory infertility.

True

False

5. More severe sequelae of PCOS are seen among those who are obese when
compared to those with normal BMI.

True

False

6. Insulin resistance and infertility are independent problems that can be

dealt separately.

True

False

7. Weight loss is associated with improved fertility among obese PCOS

patients.

True

False

4
8. Laparoscopic ovarian surgery is the first line of treatment for patients
with PCOS.

True

False

9. Bariatric surgery can be considered for all obese patients with PCOS.

True

False

10. Myoinositol improves ovarian function and the pregnancy rate.

True

False

Answers: 1. False; 2. False; 3. True; 4. True; 5. True; 6. False; 7. True; 8. False; 9. False; 10. True

5
 Introduction

• Polycystic ovarian syndrome(PCOS) is one of the commonest endocrine

disorder among the women.
• It carries an increased risk of metabolic aberrations that raise the likelihood of
suffering from type 2 diabetes (T2DM), dyslipidemia, cardiovascular disease,
and endometrial carcinoma.
• PCOS also hugely impacts the women’s reproductive career and it’s one of the
primary causes of anovulatory infertility.
• In addition to menstrual irregularities and hyperandrogenic manifestations;
infertility is one of the prime cause of concern and may be the presenting
complaint among these women.
• In this module we shall focus on the infertility associated with PCOS and its
management.

Causes of female infertility

infert
Unexp ity 15%

fa Uter
il
lained

cto in
r5 e
%

Ovulatory PCOS
Disorder 40% 85%
Tubal factor Other 15%
40%

• PCOS is one of the commonest gynaecological endocrine disorders.

• In addition to several metabolic dysfunctions and long term consequences
such as diabetes, cardiac diseases and cancers, it is also a prime cause of
anovulatory infertility.
• The basic pathology of arrest of ovulation in PCOS leads to infertility.
• Many patients may present in clinics with infertility as the presenting
complaint.
• Thus, in all patients presenting particularly with infertility due to
anovulation, screening for PCOS must be conducted.
• Rotterdam criteria,1 discussed in module 1 and 2, are the most widely
accepted diagnostic criteria for PCOS.

6
Reference:
1. The Rotterdam ESHRE/ASRM sponsored PCOS con-sensus workshop group. Revised 2003
consensus on diagnostic criteria and long-term health risks related to polycystic ovary
syndrome (PCOS). Human Reproduction. 2004;19:41–47.

Prevalence
PCOS in Cases of Infertility
• The reported prevalence of PCOS ranges between 2.2–26% in various
countries. It varies due to differences in recruitment method, the kind of
study population, the criteria used for PCOS definition and the methods
used to define each criterion.
• The prevalence of PCOS has been reported as:
100%
90
90%
80% 75
70%

60%
50%
40
40%
30
30%
20%
10%

0%
Secondary Infertility Oligomenorrhea Hirsutism
amenorrhea

• Prevalence rate of PCOS is very high affecting nearly 1 in 5 women

• The prevalence of PCOS has been reported as:
o Thirty percent in women with secondary amenorrhea
o Fourty percent in women with infertility
o Seventy five percent in women with oligomenorrhea, and
o Ninety percent in women with hirsutism1
Reference:
1. Hussein B and Alalaf S. Prevalence and characteristics of polycystic ovarian syndrome in a
sample of infertile Kurdish women attending IVF infertility center in maternity teaching
hospital of Erbil city. Open Journal of Obstetrics and Gynecology. 2013; 3:577–585.

7
 Infertility in PCOS Patients
• The cross-sectional analysis of a longitudinal cohort study, the Australian
Longitudinal Study on Women's Health (ALSWH) reports:
• Self-reported PCOS prevalence : 5.8% (95% CI: 5.3%–6.4%)
• Infertility was noted by:
o Seventy-two percent of 309 women reporting PCOS, compared with
o Sixteen percent of 4,547 women not reporting PCOS (p<0.001)
• Infertility was 15-fold higher in women reporting PCOS, independent of body
mass index (BMI)

• ALSWH 1 included women of 28–33 years of age from the general community,
who were randomly selected from the national public insurance database.
• Mailed survey data were collected at multiple time points.
• Of 8,612 women with known PCOS status, 478 women reported having
PCOS.
• Information regarding fertility status was available for 4856 women which
was used in this analysis.
• Significantly higher prevalence of infertility was seen in women with PCOS. 2
References:
1. The Australian Longitudinal Study on Women's Health (ALSWH), 2017. Available at:
[Link] Last accessed on: 19th
July, 2017.
2. Joham AE, Teede HJ, Ranasinha S, et al. Prevalence of infertility and use of fertility treatment in
women with polycystic ovary syndrome: data from a large community-based cohort study.
J Women’s Health (Larchmt). 2015;24(4):299–307.

8
 Pathophysiology of Infertility in PCOS

PCOS
Hypothalamic Adrenal

Ovary

Obesity
Inherent defect in androgen-secreting tissue
Insulin resistance

Hyperinsulinemic state

Dysfunction within the ovary & external influences modify ovarian behavior

• Ovary is a dynamic multicompartmental organ, which is under the chief

regulatory control of hypothalamic and pituitary hormones.
• However multiple internal and external factors influence these hormones.
• Obese women with PCOS are likely to experience more severe sequelae,
such as hyperandrogenism and metabolic syndrome, than those with a
normal BMI.
• Abnormal folliculogenesis is the primary cause of infertility in PCOS
women.1,2
References:
1. Frank S, Stark J, and Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome.
Hum Reprod Update. 2008;14(4):367–378.
2. Chavez-Ross A, Franks S, Mason HD, et al. Modelling the control of ovulation and polycystic
ovary syndrome. J Math Bio. 1997;36:95 –118.

9
 Reasons of Abnormal Folliculogenesis

Primary cause of follicular dysfunction is at the level of ovary and not pituitary
Leading to variable responsiveness of GT

Abnormal pre-antral follicle development

Due to precocious acquisition of LH receptors in granulosa layer arrest of follicular growth occurs

Abnormal response to GT
Characterised by enhanced relative sensitivity to FSH and LH in a subpopulation of follicles

Follicles hyper-responsive to GT
Follicles prematurely reach level of maturity and produce sufficiently high concentration of circulating E2
which suppresses FSH to a level that is too low to encourage further development of healthy follicles in the cohort

LH: Luteinising hormone; FSH: Follicle stimulating hormone; E2: Oestradiol; GT: Gonadotrophin; T: Testosterone

• Primary cause of follicular dysfunction is at ovarian level and not pituitary.

• This is influenced by various endocrine and paracrine factors.
• Hyperandrogenism and hyperinsulinism affects the competence of oocyte
development.1,2

Reproductive Impairment in Women with PCOS

Abnormalities in Compromised maturation

Failure to
circulating of oocyte or
ovulate
hormones:↑ T and LH endometrium or both

With OI

• Unpredictable response
• Response may be slow
• Hyper-response: OHSS
• Risk of cyst formation

LH: Luteinising hormone; T: Testosterone; OI: Ovulation induction; OHSS: Ovarian hyperstimulation syndrome

References:
1. Frank S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum
Reprod Update. 2008;14(4):367–378.
2. Chavez-Ross A, Franks S, Mason HD, et al. Modelling the control of ovulation and polycystic
ovary syndrome. J Math Bio. 1997;36;95–118.

10
 Effect of Androgens on Follicular Endocrine Micro-environment

Testosterone levels in follicular fluid are elevated

Meiotically incompetent oocytes

Affects oocyte maturation and quality

Lowers fertilisation rates

• In women with PCOS, testosterone (T) levels are higher in follicular fluid.
• T inhibits meiotic maturation and embryonic development, negatively
affecting the fertilisation rate.
• Insulin also affect the competence of oocyte development.1
Reference:
1. Dumesic DA, Padmanabhan V and Abbott D. Polycystic ovary syndrome and oocyte
developmental competence. Obstet Gynecol Surv. 2008;63(1):39–48.

11
 Influence of Insulin

Anovulation Increased LH but not FSH

Gonadotropins Insulin Influences

steroidogenesis

Increases leptin
mRNA in adipocytes
Leptin acts on a receptors in
hypothalamus and decreases
Stimulates leptin insulin secretion along with
secretion fall in glucose mediated
insulin secretion

Increased leptin in
PCOS women

LH: Luteinising hormone; FSH: Follicle stimulating hormone; PCOS: Polycystic ovarian syndrome

• Insulin has been shown to increase leptin mRNA in adipocytes, suggesting

its possible role in stimulating leptin secretion
• Possibly elevated leptin in hyperinsulinemic PCOS women is a secondary
consequence of insulin-stimulated synthesis of leptin.
• Leptin on the other hand, inhibits insulin-mediated promotion of
gonadotropin(GT) stimulated steroidogenesis.
• There are reports that leptin decreases glucose-mediated insulin secretion
through its receptors in the hypothalamus, and also attenuates its action at
the cellular level
• In overweight women and/or those with polycystic ovary syndrome (PCOS),
an increase in the number of fat cells results in above mentioned cascade of
changes, involving increased leptin and insulin levels and a preferential
increase in luteinising hormone (LH), but not follicle stimulating hormone
(FSH) levels.
• The net effect of these changes is to stimulate the partial development of
follicles that secrete supranormal levels of T, but which rarely ovulate (hence
low levels of progesterone).1,2,3
• Disrupted endocrinal milieu in the ovary leads to failure of follicle
development and ovulation.1

12
 Schematic Representation of Metabolic and Reproductive
Pathways in PCOS

Central HPO Hypothalamus

axis dysregulation and pituitary Pancreas

Systemic insulin
resistance

↑
Insulin

↑
LH
Liver Muscle

↑
Androgen ↑
Leptin

Ovary
Androgen synthesis
and theca hyperplasia

Obesity–associated
Disrupted early follicle adipose dysfunction
development, anovulation,
infertility Clinical
hyperandrogenism

LH: Luteinising hormone; HPO: Hypothalamus

References:
1. Dumesic DA, Padmanabhan V and Abbott D. Polycystic ovary syndrome and oocyte
developmental competence. Obstet Gynecol Surv. 2008;63(1):39–48.
2. Sharpe RM and Franks S. Environment, lifestyle and infertility — an inter-generational issue.
Nature Medicine. 2002;8(S1);S33–S40.
3. Chakrabarti J. Serum leptin level in women with polycystic ovary syndrome: correlation with
adiposity, insulin, and circulating testosterone. Ann Med Health Sci Res. 2013;3(2):191–196.

13
 Obesity and PCOS
a) Normal nutrition b) Under nutrition c) Over–weight / PCOS

(GnRH) GnRH
Leptin GnRH
(+other
metabolic Leptin ↑
Leptin
Pituitary signals) Fat
gland Fat cells
cells
↑
LH
LH ↓
LH Insulin Pancreas
Insulin Insulin
FSH Pancreas ↓
FSH Pancreas – +
– + – + Insulin
Insulin Insulin
Ovary
Ovary

T ↓ T
E2 ↓ E2 ↑
T
Puberty Delayed
P4 ↓ P4 ↓ P4 Anovulation
Menarche puberty
Sex steroids Sex steroids Sex steroids Hirsutism
Ovulation Amenorrhoea

‘‘Physiological’’ hyperinsulinaemia at puberty Hyperinsulinaemia reduces

reduces SHBG and thus amplifies normal SHBG levels and thus amplifies
production of sex steroids ovarian androgen production

LH: Luteinising hormone; FSH: Follicle stimulating hormone; GnRH: Gonadotrophin relasing hormone; T: Testosterone; E2: Oestradiol;
P: Progesterone; SHBG: Sex hormone-binding globulin

• Leptin mRNA and protein production is seen in:

o Granulosa cells that promote steroidogenesis
o Oocytes that have direct regulatory action in ovarian folliculogenesis
o Early cleavage stage embryos
• Leptin is found to be keenly interrelated with oestrogens, progesterone,
androgens, and insulin2,3

• Nutrition is linked to the female reproductive system through the effects of a

hormone emanating from fat cells (leptin) and by insulin from the pancreas,
which alters the bioavailability of oestradiol (E2) and T by affecting
production of sex hormone-binding globulin (SHBG) from the liver.
• In addition, there is a genetic predisposition to PCOS.
• Several peripheral signals have been identified that form a link between
adiposity and dysregulation in the gametogenic and steroidogenic potential
of an ovary.
• Leptin and advanced glycation end (AGE) products have been identified as
peripheral signals.
• They are the possible link between nutrition and reproduction.

14
• Reproductive potential in women undergoes adverse alteration following
severe changes in nutritional status and energy availability in either
direction.
• These adaptive changes are reversible when nutritional status is
normalised.1,2
References:
1. Sharpe RM and Franks S. Environment, lifestyle and infertility — an inter-generational issue.
Nature Medicine, 2002;8(S1);S33–S40.
2. Chakrabarti J. Serum leptin level in women with polycystic ovary syndrome: correlation with
adiposity, insulin, and circulating testosterone. Ann Med Health Sci Res. 2013;3(2):191–196.

Advanced Glycation End Products Role in Infertility

AGE-RAGE system

Ovary AGEs negatively correlate with:

Abnormal follicular ECM organization • Follicular growth
• Number of oocytes retrieved
Interfere with LH action in granulosa
• Fertilisation rate
cells (↑ERK1/2 pathway)
• Embryo development
↓
Glucose uptake by granulosa cell • Pregnancy rate
↓
Glut-4 in granulosa cell membrane sRAGE positively correlate with:
• Number of oocytcs retrieved
• Pregnancy rate
Adipose tissue Serum • Follicular fluid AMH
↑
Adipogenesis ↑
Inflammatory markers
↑
Insulin resistance

Role in PCOS Role in infertility

AGE: Advanced glycation end products; RAGE: Receptor for AGE; ECM: Extracellular matrix; LH: Luteinising hormone;
ERKs: Extracellular signal–regulated kinases; GLUT-4: Glucose transporter type 4; AMH: Anti-mullerian hormone; s-RAGE: Soluble RAGE

• Relationship of the advanced glycation end products-receptor for advanced

glycation end products (AGE-RAGE) system with PCOS and infertility in
shown in the above figure.
• Increased activity of this system is seen in PCOS in the serum, adipose tissue
and in the ovary.
• In infertility, AGEs are negatively, while soluble RAGE form (sRAGE) are
positively, correlated with assisted reproductive technology (ART) outcome
and measures of ovarian reserve, as reflected by anti-mullerian hormone
(AMH) level.1

15
• Multiple factors influence infertility in PCOS and several such pathways are
being studied to understand this pathophysiology. However, to date, we do
not understand completely the pathophysiology of infertility in PCOS .
• Deeper understanding will enable clinical researchers and scientists
develop prevention and treatment modalities for infertility in PCOS.
Reference:
• Merhi Z. Advanced glycation end products and their relevance in female reproduction.
Hum Reprod. 2014;29(1):135–145.

Management of Infertility in PCOS

Hormonal Testing in Infertility

Table 1: Hormonal levels in PCOS

Hormone In PCOS
• Follicle stimulating hormone Normal or low
• Luteinising hormone Elevated
• Testosterone Elevated
• Oestrogens Normal or elevated
• Sex hormone-binding globulin Reduced
• Androstenedione Elevated
• Anti-mullerian hormone Elevated
• Human chorionic gonadotropin Used to check for pregnancy;
negative unless pregnant
• Insulin levels Deranged hyperinsulinemia,
Insulin resistance, T2DM
• Vitamin D Reduced

Few other tests done in PCOS To rule out

• Thyroid-stimulating hormone Thyroid dysfunction
• Cortisol Cushing syndrome
• Prolactin Hyperprolactinemia
• 17-hydroxyprogesterone The most common form of
congenital adrenal hyperplasia
• Insulin-like growth factor 1 Acromegaly
• Dehydroepiandrosterone Virilising adrenal tumour

• Hormonal testing is necessary for evaluating every case of PCOS.

• Few tests are done to rule out other possible dysfunctions before treating for
PCOS.

16
• The above table provides the battery of hormonal testing necessary in a case
of PCOS.
• AMH is an important biomarker for the oocyte quality and for further
management of infertility in PCOS.1

Role of AMH in Oocyte Recruitment

FSH dependence

Endocrine control
Paracrine control
Gonadotrophin Ovulatory 20 mm
Gonadotrophin independent Inhibin B dependent
Dominant 10 mm
AMH
Small antral 2 to 5 mm

Secondary
Primary Oestradiol

Primordial

I Recruitment II Recruitment Selection Dominance

>120 days 85 days 14 days
FSH: Follicle stimulating hormone; AMH: Anti-mullerian hormone

• In one of the studies published in the journal ‘‘Human Reproduction’’1 the

following results were noted:
o The mean serum AMH concentrations between women with PCOS
(77.6 pmol/L) and those with polycystic ovarin morphology (PCOM)
(52.2 pmol/L) were significantly higher than demographically similar
controls (23.6 pmol/L) (P < 0.001)
o The combination of AMH >48 pmol/L and LH > 6 IU/L diagnosed 82.6% of
women with PCOS.
o The mean serum FSH was lower in both PCOS and PCOM compared with
controls, whereas LH was higher in PCOS compared with PCOM and
controls, and correlated positively with AMH (r = 0.321, P < 0.01).2
• High-AMH concentrations present in women with PCOS play an integral role
in causing anovulation due to its inhibitory influence on the actions of FSH
that normally promotes follicular development from the small antral stage to
ovulation.3
• A proper balance between FSH and AMH can be restored by cautious
increase of FSH in PCOS which will have inhibiting physiological effect on
AMH

17
References:
1. Lehmann P, Vélez MP, and Saumet J. Anti-Müllerian hormone (AMH): a reliable biomarker of
oocyte quality in IVF. J Assist Reprod Genet. 2014;31(4):493–8.
2. Homburg R, Ray A, Bhide P, et al. The relationship of serum anti-Müllerian hormone with
polycystic ovarian morphology and polycystic ovary syndrome: a prospective cohort study, Hum
Reprod. 2013;28(4):1077–1083.
3. Homburg R and Crawford G. The role of AMH in anovulation associated with PCOS: a
hypothesis. Hum Reprod. 2014;29(6):1117–1121.

Consensus on Infertility Treatment Related to PCOS: ESHRE/ASRM, 2007

• Preconceptional counselling :
o Lifestyle modification
• Recommended first-line of treatment for ovulation induction (OI):
o Clomiphene citrate (CC)
• Recommended second-line of intervention:
o Exogenous gonadotrophins or
o Laparoscopic ovarian surgery (LOS)
• Recommended third-line treatment
o In vitro fertilisation (IVF)

GnRH Hypothalamus
Positive feedback stimulation
Negative feedback
LH FSH Anterior pituitary

Oestradiol and progesterone Corpus Ovary

luteum Follicles
Dominant
follicle

Ovulation Oesradiol

GnRH: Gonadotrophin relasing hormone; LH: Luteinising hormone; FSH: Follicle stimulating hormone

• Before any intervention is initiated, preconception counselling should be

provided emphasising the importance of life style, especially weight
reduction and exercise in overweight women, abstinence or reduction in
smoking and alcohol consumption.
• The recommended first-line of treatment for OI remains the anti-oestrogen
CC and letrazole.
• Recommended second-line of intervention, if CC fail to result in pregnancy,
are either exogenous GT or LOS.

18
• Recommended third-line of treatment is IVF.1
Reference:
1. The Thessaloniki ESHRE/ASRM-Sponsored PCOS consensus workshop group consensus on
infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462–477.

Lifestyle Modification

Obesity is associated with Weight loss of 5 – 10 % associated with

• Anovulation • Reduction in insulin & LH
• Pregnancy loss concentration

• Late pregnancy complications • Increase in insulin sensitivity

(pre-eclampsia, gestational • Increase in SHBG which leads to
diabetes) decreased free T
• Failure or delayed response to • Improvement in reproductive
administration of /menstrual function and fertility
o CC • Reduced hirsutism and acne
o GT and • Correction of defects in meiosis
o Laparoscopic ovarian diathermy and early embryonic development

• Obesity is common in women with PCOS.

• Weight loss is recommended as first-line therapy in obese women with PCOS
seeking pregnancy. 1
• Both diet and physical activity play a vital role as a first step to improve
fertility in obese PCOS patients with anovulatory infertility.
• Bariatric surgery may be considered in cases with BMI 35kg/m2 and where
lifestyle therapy has failed.
• Insulin sensitivity may be the prime factor associated with restoration of
ovarian function by potentially acting through different mechanisms.2
• A study published in a well known journal also highlights increased energy
intake, increased sitting time with low physical activity among women with
PCOS. 3
• The effects of calorie restriction, increased physical activity
pharmacological and weight loss agents in the pre-conceptional period are
unknown and can be potentially harmful.
• These interventions should be restricted prior to conception and not
concurrently with infertility treatment.

19
• The risk benefit ratio of these therapies on pregnancy should be considered
when applied concurrently with infertility treatments. 1,2,3
References:
1. The Thessaloniki ESHRE/ASRM-Sponsored PCOS consensus workshop group consensus on
infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008; 23(3):462–477.
2. Palomba S, Giallauria F, Falbo A, et al. Structured exercise training programme versus
hypocaloric hyperproteic diet in obese polycystic ovary syndrome patients with anovulatory
infertility: a 24-week pilot study. Hum Reprod. 2008;23(3):642–650.
3. Moran LJ, Ranasinha S, Zoungas S, et al. The contribution of diet, physical activity and
sedentary behaviour to body mass index in women with and without polycystic ovary
syndrome. Hum Reprod. 2013;28(8):2276–2283.

Ovulation Induction in PCOS

When Before OI
• Weight loss fails • Analyse ovarian reserve
• Anovulation and menstrual abnormalities • Define the goal of ovarian
are persistent stimulation
• Age > 35 years • Select correct protocol
• Other factors affecting fertility are present

Has2,
Proliferation & Slc38a3 Ptgs2, Ptx3,
Amh LH surge Tnfaip6
differentiation
Cumulus

Preantral follicle

Antral follicle Cumulus expansion

AFC AMH
Analysing ovarian reserve
• Antral follicle count (AFC) and AMH are the currently
preferred biomarkers for analysing the ovarian reserve. 40 High 40
response
• AFC: for ovarian reserve and predicts ovarian response
• AMH: apart from predicting response also assists in 24 20

forecasting the reproductive lifespan and ovarian

Normal
dysfunction in women with PCOS response
• AFC and AMH are complementary and are used for: 10 7
Reduced
o Pretreatment assessment/intervention response
2 1
o To decide stimulation dose and regimen, and Negligible
o To select maturation trigger

20
Goal of ovarian stimulation
• To convert the anovulation to normal ovulatory cycle
• The number of follicles that ovulate is determined by length of time that the
level of FSH remains above the thresh hold value

Single ovulation Multiple ovulations – Wider gate

Threshold LH Threshold LH
FSH FSH
Ovulation Ovulation

Atresia Atresia Atresia Atresia

Monofollicular
for Non ART Cycle Multifollicular
for ART cycles

LH: Luteinizing hormone; FSH: Follicle stimulating hormone; ART: Assisted reproductive technology

Selecting the protocol

• The ovulation induction protocols are designed in the current clinical
practise based on
o Ovarian reserve
o Age
o BMI
o Presence of other infertility factors
o Available resources
o Risk tolerance

Ovulation Induction Prerequisites

Follicular size is < 10 mm ; Absence of ovarian cyst; Endometrial thickness (ET)
< 6 mm; E2 levels < 50 pg/mL and progesterone < 1.5 ng/mL

Selection of dominant follicle occurs in the follicular phase; hence OI is started

within day 3 of the menstrual cycle. Given above are the prerequisites before
initiating OI.

21
 First Line/Oral Options
Anti-oestrogens: Clomiphene Citrate
• Started on day 2, 3, 4, or 5 of spontaneous or induced menses and given for 5 days
• Starting dose: 50 mg; Maximum dose:150–200 mg
• Dose correlates with body weight, age, indication for use (anovulation, PCOS,
controlled ovarian hyperstimulation [COH]) and past history
• Dose cannot be accurately predicted
• Requires empiric incremental titration to establish lowest effective dose
• Treatment is discontinued if 2 consecutive cycles are anovulatory
• It induces
o Ovulation in 75%
o Pregnancy in 35%,
o Miscarriages in 20%
o Multiple Pregnancies (MP) in 8–10 %

• CC remains the first choice of treatment for induction of ovulation in

anovulatory women with PCOS.
• Cost, ease of administration, few adverse effects, supports its widespread
use.
• The mechanism of action involves the blockade of the negative feedback
mechanism which results in enhanced secretion of FSH.
• The main factors that predict responsiveness to CC are obesity,
hyperandrogenemia, age, ovarian volume and menstrual status are
additional factors that help to predict responsiveness to CC.1,2,3

Ultrasound (USG) Monitoring or Not for CC?

With U/S + hCG No U/S or hCG

48% Cumulative conception rate 34.7%
35.6% Deliveries 26.7%
0 Multiple pregnancies 1
CC
USG-monitored CC treated cycles produce better ER
pregnancy rates compared with non-monitored
ER
cycles
FSH E2

FSH: Follicle stimulating hormone; E2: Oestradiol; ER: Endoplasmic reticulum: CC: Clomiphene citrate

22
• USG monitoring is not mandatory in CC cycles
• However as noted better outcomes are seen with USG monitoring
• The outcome of use of hCG in mid cycle is not clear4

When to Stop CC ????

When 6 ovulatory cycles fail When no ovulation with If ET <7 mm at ovulation

to yield a pregnancy 150 – 200 mg/day

• In all the above situations CC must be discontinued and further

evaluation must be done for other infertility factors.

Diagnostic laparoscopy Hysterosalpingography

• If this is already done next line of treatment should be considered.

References:
1. The Thessaloniki ESHRE/ASRM-Sponsored PCOS consensus workshop group consensus on
infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462–477.
2. Homburg [Link] citrate—end of an era? A mini-review. Hum Reprod. 2005;20:2043–2051.
3. Dickey RP, Taylor SN, Curole DN, et al. Incidence of spontaneous abortion in clomiphene
pregnancies. Hum Reprod. 1996;11:2623–2628.
4. Kosmas IP, Tatsioni A, Fatemi HM, et al. Human chorionic gonadotropin administration
vs. luteinizing monitoring for intrauterine insemination timing, after administration of
clomiphene citrate: a meta-analysis. Fertil Steril. 2007:87:607–612.

23
 Alternative Therapies: Letrozole and Tamoxifen

Alternative therapies to clomiphene citrate

Tamoxifen Letrozole

Equally effective Can also be used as

Not licensed first line treatment similar
Consider for women with hot flushes to clomiphene citrate

• Anti-oestrogens other than CC: Tamoxifen appears to be as effective as CC

for OI but is not licensed for that purpose.
• It may be considered as an alternative to CC in women who suffer intolerable
side effects such as hot flushes.1
• Aromatase inhibitors: studies suggest that letrozole appears to be as
effective as CC for induction of ovulation.2

Aromatase Inhibitors
• Mechanism of action
o Suppresses oestrogen biosynthesis
o Increase the follicular sensitivity to FSH secondary to high intra-follicular
androgen levels
o Induction of high intra follicular insulin-like growth factor (IGF-I)
concentrations
• Merits
o No anti-oestrogenic effect on the endometrium or cervical mucus
o Limited number of mature follicles
o Decrease ovarian hyperstimulation syndrome (OHSS) & multiple pregnancy
• Demerits
o There are concerns regarding increased rate of birth defects associated with
use of letrozole
ER ER

ER ER

E2 E2
FSH FSH
AI

Day 5 Day 10

FSH: Follicle stimulating hormone; E2: Oestradiol; ER: Endoplasmic reticulum

24
• Aromatose inhibitor leads to:
o E2 suppression that peaks between day 5–7 of the cycle.
o After day 7, E2 levels rise steadily to trigger LH-surge; around day 12–14
of the cycle.
o Non supraphysiologic rise occurs as against that of CC3
• Letrozole is comparable to CC
o It is as effective as CC for OI in PCOS.4
o There is no statistical difference beteen letrozole and CC5 for:
– Pregnancy rate per patient
– Live birth rate per pregnancy
– Miscarriage rate per pregnancy
– MP rate per patient
o Letrozole was better than CC for ovulation rate per patient5
• No difference was observed in effectiveness between letrozole and
laparoscopic ovarian drilling (LOD).
• Occurrence of OHSS was rare.6
• A double blind randomised controlled trial (RCT) provides evidence of
letrozole superiority over CC as a primary OI agent in PCOS women with a
40% increase in pregnancy rates and with a shorter time to pregnancy.
• This recent study recommends letrozole should replace CC as the first line OI
agent in PCOS.7,8

Table 2: Outcome for letrozole versus CC as primary treatment-intention to treat analysis

Outcome Letrozole CC (N = 79) Rate ratio Absolute P
(N = 80) (95% CI) difference (95% CI)

Pregnancy rate 49/80 (61.2%) 34/79 (43.0%) 1.4 (1.1, 2.0) 18% (3 to 33%) 0.022

Live birth rate 39/80 (48.8%) 28/79 (35.4%) 1.4 (0.95, 2.0) 13% (–2 to 28%) 0.089

Ovulation rate 67/80 (83.8%) 63/79 (79.7%) 1.1 (0.9. 1.2) 4% (–8 to 16%) 0.513

Pregnancies per ovulating patient 47/67 (70.1%) 32/63 (50.8%) 1.4 (1.04, 1.9) 20% (3 to 30%) 0.024

Pregnancies-strata 1 (BMI <30) 37/54 (68.5%) 25/53 (47.2%) 1.5 (1.04, 2.1) 21% (3 to 38%) 0.025

Pregnancies-strata 2 (BMI 30–35) 12/26 (46.2%) 9/26 (34.6%) 1.3 (0.7, 2.7) 12% (–14 to 35%) 0.397

Live births-strata 1 (BMI <30) 29/54 (53.7%) 20/53 (37.7%) 1.4 (0.9, 2.2) 15% (–3 to 30%) 0.122

Live births-strata 2 (BMI 30–35) 10/26 (38.5%) 8/26 (30.8%) 1.3 (0.6, 2.7) 8% (–20 to 30%) 0.771

Pregnancies per cycle 49/261 (19.0%) 34/278 (12%) 1.5 (1.03, 2.3) 7% (0.4 to 1.3%) 0.036

25
 Table 2: Outcome for letrozole versus CC as primary treatment-intention to treat analysis (table contd...)
Outcome Letrozole CC (N = 79) Rate ratio Absolute P
(N = 80) (95% CI) difference (95% CI)

Live births per cycle 39/261 (15%) 28/278 (10%) 1.48 (0.95, 2.33) 5% (–0.7 to 11%) 0.087

Ovulation per cycle 196/261 (75%) 18/278 (67%) 1.1 (1.01, 1.2) 8% (1 to 15%) 0.045

Mono-ovulation 80/94 (85.1%) 64/77 (83.1%) 0.88 (0.4, 1.7) –2% (–13 to 9%) 0.723

ET (mm)[median (IOR)] 8.4 (7.0, 10.2) 9.0 (8.0, 11.0) 0.002

References:
1. Steiner AZ, Terplan M, and Paulson RJ. Comparison of tamoxifen and clomiphene citrate for
ovulation induction: a meta-analysis. Hum Reprod. 2005:20:1511–1515.
2. Balen AH, Morley LC, Misso M et al. the management of anovulatory infertility in women with
PCOS: an analysis of the evidence to support the devlopement of global WHO guidance. Human
Reproduction Update. 2016; 22(6);687–708.
3. Mitwally MFM and Casper RF. Single dose administration of the aromatase inhibitor, letrozole: a
simple and convenient effective method of ovulation induction. Fertil Steril.
2001;76(S-1):S94–S95.
4. He D and Jiang F. Meta analysis of letrozole vs clomiphene citrate in PCOS. Reproductive
BioMedicine Online. 2011;23,91–96.
5. Misso ML, Wong JLA, Teede HJ, et al. Aromatose inhibitors for PCOS: a systematic review and
analysis. Human Reproduction Update. 2012;18(3):301–12.
6. Franik S, Kremer JAM, Nelen WLDM and Farquhar C. Aromatose inhibitors for subfertile women
with PCOS. Fertil Steril. 2015;103(2):353–5.
7. Amer SA, Smith J, Mahran A, et al. Double blind RCT of letrozole vs clomiphene citrate in
subfertile women with PCOS. Human Reproduction. 2017;32(8):1631–38.
8. The Thessaloniki ESHRE/ASRM-Sponsored PCOS consensus workshop group consensus on
infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462–477.

26
4
 Adjuvants for Ovulation Induction
• For treatment of PCOS • Others
o Androgen excess o Antioxidants
– Glucocorticoids: prednisone, methyl o Micronutrients
prednisolone and dexamethasone o Dopamine agonist
o Hyperinsulinemia/ Insulin resistance o Aspirin
– Metformin o Sildinafil
– Myoinositol
o Others
– N Acetyl cysteine
– Melatonin
– Vitamin D
– Chromium polynicotinate

Need for adjuvant therapies

PCOS Others

CC resistance To increase IR and CPR

Insulin resistance and hyperinsulinema

Androgen excess

Obesity

To decrease incidence of
metabolic syndrome

IR: Implantation rate, CPR: Clinical pregnancy rate

• Not all adjuvant therapy is approved by FDA

• Many of them are used as OFF label drugs
• Off-label drugs have been evaluated in the phase I or phase II trials of clinical
research but have not been fully assessed in phase III or phase IV trials

27
26
 Use of Glucocorticoids
• For women with CC resistance and dehydroepiandrosterone (DHEAS)
>200 micrograms/ dL
• For CC-resistant anovulatory patients add prednisone
• Addition of dexamethasone to CC significantly improved ovulation and
pregnancy rates

CC alone CC+ dexa P value

Ovulation rate 15% 75% P <0.001
Pregnancy rate 4.2% 40.5% P< 0.01

Recommended dose: Dexamethasone 2 mg/day days 5 to 14

• Glucocorticoids is now recommended for women with CC resistance irrespective of

DHEAS values,1 although early studies recommended benefits in women with
DHEAS >200 micrograms/ dL.2
• CC-resistant anovulatory patients have high rates of ovulation and pregnancy after
treatment with extended CC and prednisone.3
• Addition of dexamethasone to CC significantly improved ovulation and pregnancy
rates when compared with CC alone.2
• This therapy offers a potential reduction in cost and risk and should be considered in
this group of patients before GT stimulation or surgery.2
• Cochrane data review recommends the use of dexamethasone with CC in resistant
cases.4
• Optimal dosing is not known, but the largest and best designed trial demonstrated
benefit using dexamethasone 2 mg/day days 5 to 14.5

Insulin Resistance and PCOS

• Insulin resistance is intrinsic to PCOS
• It is independent of obesity (Thirty percent of PCOS women are not obese)
• It plays a central role in the pathogenesis of PCOS as insulin-induced
hyperandrogenaemia is the underlying biochemical abnormality in PCOS
• Obesity when present (de novo or as a result of intrinsic insulin resistance is an
extrinsic cause of insulin resistance in PCOS
• Insulin resistance in PCOS Intrinsic
Extrinsic

28
 Tissue specific effects of insulin resistance in PCOS

Insulin resistant Insulin sensitive

Muscle Adipose Ovary Adrenal Liver Pilo-sebaceous unit

↓
Glucose uptake ↑
Lipolysis ↑
Androgen Production ↓ SHGB Proliferation
production

IGT-DM Dyslipidaemia
IGT: Impaired glucose tolerance; DM: Diabetes mellitus; SHBG: Sex hormone-binding globulin

Insulin-sensitizing Agents: Metformins Role in Treatment of

Hyperinsulinemic Hyperandrogenism

Potential advantages Potential disadvantages

Glucose tolerance
• ↑ • Gastrointestinal disturbance in
1/3 of patients
• ↑
Insulin sensitivity
• Generalised feeling of unwellness
• ↓
Blood lipid levels
• Decreased absorption of vitamin B12
• ↑
Weight loss or stabilisation
• Lactic acid buildup
• Improved fat distribution
• ↓
Blood pressure
• ↓
Androgen levels
• Restoration of regular menses
• Stimulates folliculogenesis
• Postponement of diabetes

• There is no evidence that metformin treatment before or during ART cycle

improved live birth rates (LBR) in women with PCOS.
• However, metformim increased clinical pregnancy rates and decresed the risk
of OHSS.
• Obstetrician to decide about continuing insulin sensitizers during pregnancy
in women with glucose intolerance.
• Metformin alone is less effective than CC in inducing ovulation in women with
PCOS.

29
 Table 3: Rate of LBR on PCOS treatment with metformin and/or CC
PCOS medication Live birth rate
Metformin only 7.2%
Clomiphene citrate only 22.5%
Clomiphene citrate/Metformin combination 26.8%

• Metformin increased clinical pregnancy rates only in GT cycles and

decreased the risk of OHSS.6
• Two RCTs reported a live birth rate of 46% in the metformin group and 27% in
the placebo group after three and six treatment cycles, respectively.
• Metformin use was associated with a higher LBR. For a control LBR of 27%
after FSH, the addition of metformin resulted in a LBR ranging between
32%–60%.
• Metformin use was associated with a higher ongoing pregnancy rate vs
placebo.
• No evidence of a difference in miscarriage rates between metformin and
placebo.7
• Obstetricians must decide about continuing insulin sensitizers during
pregnancy in women with glucose intolerance after careful evaluation of
risks and benefits.
• Metformin alone is less effective than CC in inducing ovulation in women
with PCOS as seen in the table above.8,9
• There is insufficient data to advise short-course metformin pretreatment as
against long term treatment before initiation of CC for OI in infertile women
with PCOS.

Inositol
• Inositol, is a member of the B-complex family of vitamins
• It’s not an essential vitamin, as it can be manufactured by the body, but it
tends to be deficient in women with PCOS
• It is present in cereals with high bran content, nuts, beans, and fruit,
especially cantaloupe melons and oranges
• Human adults consume approximately 1 g of inositol per day in different
biochemical forms
• Free inositol is actively transported across the intestinal wall by a
mechanism dependent on sodium and energy, a process that can be
inhibited by glucose
• Circulating free inositol is taken up by most tissues by a membrane-
associated sodium-dependent inositol co-transporter

30
4
 Function of Myo-inositol on insulin signaling transduction pathway

Glucose
Improves insulin's action

Myoinosital

Translocation of GLUT4
Production and activation of PI 3 Kinase

Myoinositol is a
IRS precursor of PI3
GLUT4
IRS: Insulin receptor substrate; P13: Phosphatydil inositol 3 kinase; GLUT4: Glucose transporter type 4

Myoinositol in PCOS
Myoinositol

↑
Insulin sensitivity Improves pregnancy rates

Restores menstruation
↓
Insulin resistance & normal ovulation

Improve glucose utilisation ↓

Free & serum testosterone

• Women with PCOS demonstrate low levels of inositol

• Myoinositol is an insulin sensitizer with beneficial effects on ovarian function
and response to ART in women with PCOS
• Its use decreases insulin resistance, free and serum T
• It improves insulin sensitivity, glucose utilisation
• Its use leads to restoring normal menstruation and ovulation
• And all the above factors assist in improved pregnancy rates with
myoinositol use10

31
 Myoinositol in PCOS
Myoinositol

Normalises Hormones: Improves general performance

LH, FSH, Insulin, PRL of reproductive axis

OHSS by decreasing
↓
Cardio risk androgens and E2

Increases HDL and

↓
Weight, BMI, leptin levels
decreases LDL cholestrol

LH: Luteinising hormone; FSH: Follicle stimulating hormone; E2: Oestradiol; OHSS: Ovarian hyperstimulation Syndrome; PRL: Prolactin;
BMI: Body mass index; HDL: High density lipoprotein; LDL: Low density lipoprotein

• It induces nuclear and cytoplasmic oocyte maturation and promotes embryo

development.11
• Myoinositol administration increases clinical pregnancy rates, lowers total
recombinant FSH (rFSH) dose and the duration of the ovulation induction.12
• 2017 Cochrane review suggests that inositol appears to regulate menstrual
cycles, improve ovulation and induce metabolic changes in PCOS; however,
evidence is lacking for pregnancy, miscarriage or live birth.12

Use of Vitamin D as Adjuvant in OI

Role in PCOS
Hyperandrogensim
Hirsutism ↑
Testosterone
Acne Infertility and
Development of
Anovulatory infertility menstrual
follicular arrest
dysfunction

↓
SHBG
Calcium dysregulation
Menstrual
abnormalities

Vitamin D
↓
1,25 OHD deficiency ↑
PTH

↓
Insulin secretion ↓
Insulin receptor Obesity

↑
Inflammation

Insulin resistance

PTH: Parathyroid hormone; SHBG: Sex hormone-binding globulin

32
 How Vitamin D Enhances Ovulation in PCOS?
Vitamin D binds to vitamin D receptor

Activates peroxisome proliferator activator receptor-d (PPAR d)

Stimulates the expression of insulin receptor

Enhances insulin-mediated glucose transport

Vitamin D plays a physiologic role in reproduction including ovarian follicular

development and luteinisation via AMH signalling, FSH sensitivity and
progesterone production in human granulosa cells.13
• It also affects glucose homeostasis through manifold roles.
• Vitamin D supplementation can lower abnormally elevated serum AMH levels.13
• Vitamin D and calcium supplementation in women with PCOS could result in
the beneficial effects on the menstrual regularity and ovulation.13,14

Role of N-acetyl Cysteine

Control of follicle selection and dominance
Nutritional influences
FSH/LH transition

Selection
Recruitment
FSH wave Dominance (ovulation rate will
depend on species and breed)

Atresia
Atresia
Gonadotropin influenced FSH dependent LH dependent
LH: Luteinizing hormone; FSH: Follicle stimulating hormone

Mechanism of action
• Improves insulin sensitivity, quality of cervical mucus & decreases androgen level
• Prevents follicular cohort atresia
N-acetylcysteine: adjuvant to CC
• Improves ovulation and pregnancy rates
• Beneficial impacts on embryo transfer
N-acetyl-cysteine: adjuncts to GT Therapy
• Improves the insulin sensitivity and hormonal profile and IVF outcomes
• Beneficial in improving ovarian response to ovarian stimulation

33
• N-acetyl cysteine improves insulin sensitivity and reduces
hyperandrogenemia
• It is used as an adjunct for CC and GT therapy
• Its use has been associated with improvement in ovulation and pregnancy
rates
• It may have beneficial effect on the ET as well15,16
• However at this time, there isn’t enough evidence for use of supplemental
oral antioxidants for subfertile women16

Melatonin as an Adjuvant

Melatonin Exogenous
supplementation of
DNA Oestradiol- 17ß
Bax fragmentation
Clomiphene citrate Granulosa cell apoptosis
H2O2
Theca cells Signal molecules
Oestradiol- 17ß

Growth and
Deterioration survival factors
of oocyte
Gap junction quality
Mural
granulosa cell
Germinal vesicle
Cumulus granulosa cells

Antral follicle of mammalian ovary

• Melatonin is taken up into the follicular fluid from the blood

• Reactive oxygen species (ROS) produced within the follicles, especially
during the ovulation process, were scavenged by melatonin, and reduced
oxidative stress involved in oocyte maturation and embryo development
• High intra-follicular melatonin concentrations, reduces intra-follicular
oxidative damage
• Despite the antioxidant action of melatonin as per recent meta-analysis,
there is no clarity regarding benefit of adding melatonin in all PCOS women17

34
 Other Adjuvants

CoQ1018
• Promising adjuvant to oral ovulatory agents such as CC
• Effective, inexpensive and safe for stimulating follicular development in CC
resistant PCOS
Phytoestrogens19
• Can be used as an alternative to CC for OI in women with PCOS
• No large trials yet
Alpha lipoic acid20
• Modulates insulin sensitivity
Vitamin B12, folic acid pyridoxine
• Reduces homocysteine levels, which if raised can lead to defective ovulation
Iron
• Reduces risk of anovulatory infertility
Green Tea22
• Has positive effect on glucose metabolism
Zinc23
• Plays important role in ovulation
L arginine21
• Helps to optimise oocyte quality & maturation
Chasteberry24
• Used to treat hormonal imbalances in women because it has an immediate
effect on pituitory gland

References:
1. Elnashar A, Abdelmageed E, Fayed M, et al. Clomiphene citrate and dexamethazone in
treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective placebo-
controlled study. Hum Reprod. 2006;21:1805.
2. Daly DC, Walters CA, Soto-Albors CE, et al. A randomized study of dexamethasone in ovulation
induction with clomiphene citrate. Fertil Steril .1984;41:844.
3. Isaacs JD Jr, Lincoln SR, and Cowan BD. Extended clomiphene citrate (CC) and prednisone for
the treatment of chronic anovulation resistant to CC alone. Fertil Steril. 1997;67:641.
4. Brown J, Farquhar C, Beck J, et al. Clomiphene and anti-oestrogens for ovulation induction in
PCOS. Cochrane Database Syst Rev. 2009;4:CD002249.
5. Parsanezhad ME, Alborzi S, Motazedian S, et al. Use of dexamethasone and clomiphene citrate
in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome and
normal dehydroepiandrosterone sulfate levels: a prospective, double-blind, placebo-controlled
trial. Fertil Steril. 2002;78:1001.

35
6. Tso LO, Costello MF, Albuquerque LT, et al. Cochrane review - metformin in women with
polycystic ovary syndrome for improving fertility, 2014. Available at: [Link]
CD006105/MENSTR_metformin-in-women-with-polycystic-ovary-syndrome-for-improving-
fertility. Last accessed on 28th August, 2017.
7. Bordewijk EM, Nahuis M, Costello MF et [Link] review - metformin during ovulation
induction with gonadotrophins followed by timed intercourse or intrauterine insemination for
subfer tility associated with polycystic ovar y syndrome, 2017. Available at:
[Link] Last accessed
on 28th August, 2017.
8. The Thessaloniki ESHRE/ASRM-Sponsored PCOS consensus workshop group consensus on
infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462–477.
9. Legro RS, Barnhart XS, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the
polycystic ovary syndrome. N Engl J Med. 2007;356:551–566.
10. Unfer V, Carlomagno G, Dante G, et al. Effects of myo-inositol in women with PCOS: a systematic
review of randomized controlled trials. Gynecol Endocrinol. 2012;28(7):509–15.
11. Garg D and Tel R. Inositol treatment and ART outcomes in women with PCOS. Int J Endocrinol.
Available at: [Link] Last asscessed on:
28th August, 2017.
12. Emekçi-Özay Ö, Özay AC, Çaglýyan E, et al. Myo-Inositol administration positively effects
ovulation induction and intrauterine insemination in patients with polycystic ovary syndrome: a
prospective, controlled, randomized trial. Gynecol Endocrinol. 2017;33(7):524–528.
13. Lin MW and Wu MH. The role of vitamin D in polycystic ovary syndrome. Indian J Med Res.
2015;142(3):238–240.
14. Dunlop TW, Vaisanen S, Frank C, et al. The human peroxisome proliferator-activated receptor ä
gene is a primary target of 1á, 25-dihydroxyvitamin D3 and its nuclear receptor. J Molecular
Biology. 2005;349(2):248–260.
15. Badawy A, State O, and Abdelgawad S. N-Acetyl cysteine and clomiphene citrate for induction
of ovulation in polycystic ovary syndrome: a cross-over trial. Acta Obstet Gynecol Scand.
2007;86(2):218–22.
16.. Showell MG, Mackenzie-Proctor R, Jordan V, et al. Antioxidants for female subfertility, Cochrane
Database of Systematic Reviews. 2017;28;7:CD007807.
17. Fernando S and Rombauts L. Melatonin: shedding light on infertility? - A review of the recent
literature. Fertil Steril. 2014;101:154–161.
18. Refaeey AE, Selem A, and Badawy A. Combined coenzyme Q10 and clomiphene citrate for
ovulation induction in clomiphene-citrate-resistant polycystic ovary syndrome. Reproductive
Biomedicine Online. 2014;29 (1):119–124 .
19. Shahin AY, and Mohammed SA. Adding the phytoestrogen cimicifugae racemosae to
clomiphene induction cycles with timed intercourse in polycystic ovary syndrome improves
cycle outcomes and pregnancy rates – a randomized trial. Gynecological Endocrinology.
2014;30(7):505–510.
20. Jacob S, Ruus P, Hermann R, et al. Oral administration of RAC-alpha-lipoic acid modulates
insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free
Radic Biol Med. 1999;27(3-4):309–14.
21. Uppala S, and Badikillaya VU. Homocysteine- an amino acid culprit in ill health and disease.
J NTR Univ Health Sci. 2012;1:139–47.

36
22. Kim HY and Kim J. The effects of green tea on obesity and type 2 diabetes. Diabetes Metab J.
2013;37(3):173–175.
23. Ebisch IMW, Thomas CMG, Peters WHM, et al. The importance of folate, zinc and antioxidants in
the pathogenesis and prevention of subfertility. Hum Reprod Update.2007;13:163–174.
24. Firdose KF and Shameem I. An approach to the management of poly cystic ovarian disease in
unani system of medicine: A review. International Journal of Applied Research.
2016;2(6):585–590.

Second Line of Treatment

Gonadotropins Laparoscopic ovarian drilling

• Infertile women who fail to conceive following clomiphene citrate, tamoxifen

or with aromatase inhibitors require an alternative, second-line approach
which includes
o GT
o LOD

Gonadotrophin action on ovary

Hypothalamus

GnRH

Anterior pituitary

FSH LH

Ovary
G cells T cells
Inhibin Androgen

Oestrogen Oestrogen effects on body

LH: Luteinizing hormone; FSH: Follicle stimulating hormone; GnRH: Gonadotrophin relasing hormone

FSH and hMG (Human menopausal gonadotropins) are used for ovulation induction

• The aim of OI for women with anovulatory PCOS is to restore fertility and
achieve a singleton live birth.
• The physiological concept that initiation and maintenance of follicle growth
may be achieved by a transient increase in FSH above a threshold dose for
sufficient duration to generate a limited number of developing follicles is the
rationale behind GT use in OI.1

37
• Gonadotrophin relasing hormone (GnRH) analogues: prolonged activation of
GnRH receptors by GnRH leads to desensitisation and consequently to
suppressed GT secretion. FSH & hMG are GnRH analogues.
• GnRH antagonists: they compete with GnRH for receptors on gonadotroph
cell membranes, inhibit GnRH-induced signal transduction and
consequently GT secretion. They are free of agonistic actions.2 Cetrorelix,
ganirelix, abarelix, degarelix are GnRH antagonists.

Gonadotrophin
Indications
• CC/Tamoxifen resistance
• CC/Tamoxifen failure
• Persistent hypersecretion of LH
• Negative postcoital test
• Intrauterine insemination (IUI) or Assisted conception cycles

• FSH & hMG are GnRH analogues used alone or in combination with
CC/Tamoxifen
• CC/Tamoxifen stimulates recruitment of number of small follicles & GTs
sustain the growth of recruited follicles

Gonadotropin Protocols
• Monitoring
o Transvaginal (TVS) ultrasound for follicular growth and endometrial
thickness (ET)
o Serial serum E2 if hypo or hyper response

• Stringent monitoring is essential when patient is on GT protocols.

• TVS is used for monitoring follicular growth and endometrial thickness ET

38
• Serial measurement of oestrogen hormone is done to assess hyper response
• It is necessary that specific protocols and stringent monitoring is performed
for patient on GT.

Gonadotropin to be used
GT Combinations
• Urinary (u-hMG) or • GnRH agonists with hMG and/or FSH
• Highly purified u-hMG (long, short or ultra short protocol)
• Purified u-FSH or • GnRH antagonists with hMG and/or
FSH (fixed or variable protocol)
• Highly purified u-FSH or r-FSH

LH on Day 2
< 1 mIU/L: Add hMG/ r-LH
> 1 mIU/L: One can use pure FSH/ r-FSH

Fertility Treatments with Gonadotropin

• Conventional regimen
o Starting dose of 150 IU a day
o Increased risk of OHSS
o No longer recommended
• Low dose step up regimen
o Stepwise increase in FSH
o Weekly dose of escalation based on USG monitoring
o Chronic low dose regimen
o Safer for monofollicular development
• Low dose step down regimen
o Loading dose of FSH with stepwise reduction
o USG monitoring
o Requires more experience and skill
• Combined approach
o Sequential use of step up and step down protocols

39
• Different regimens for use of GT are mentioned above1
• Conventional fixed dose regimen:
o Fixed dose regimens comprise of constant daily dose of 75–150 U of GT
from day 2 or day 3 with USG and E2 levels guiding further management.
o Conventional regimen started with very high doses and increased the
risk of OHSS and is hence no longer recommended.3

• CC/ Tamoxifen + GT Protocol

Progesterone
CC/Tamoxifen Oral
100mg/20 mg Vaginal

2 3 4 5 6 7 8 9 10 11 12

FSH/hMG 37.5 to 75 IU 35–37 hr

hCG IUI
USG
5000
10,000
CC: Clomiphene citrate; FSH: Follicle stimulating hormone; hMG: Human menopausal gonadotropins; IUI: Intrauterine insemination;
hCG: Human chorionic gonadotropin; USG: Ultrasound

The commonest protocol used is:

• Five days of CC 100 mg or tamoxifen 20 mg, given once daily, from day 2 to
day 6 followed by a injection of FSH 37.5 U/ hMG 75U from day 7, 8, 9 along
with follicular monitoring by USG.
• When the leading follicle is 18–20 mm and serum E2 not more than 1500–
2000 pg/mL, Injection hCG (5000/ 10,000 units) is given to trigger ovulation.4

40
 • Low Dose Protocol
hCG: 5000 IU
Scan D7 Dominant follicle =>16 mm
Starting dose
Low (37.5–75 IU/d)
Increase dose by 100% FSH dose increased by 100% every 7days
37.5–75 IU
hCG: 5000 IU
Scan D7 Dominant follicle=>16 mm
Starting dose

Low (37.5–75 IU/d) Increase dose by 50%

FSH dose increased by 50% every 7days 37.5–75 IU

FSH: Follicle stimulating hormone; hCG: Human chorionic gonadotropin

Low dose step up regimen

• The principle of this regimen is to find the threshold level of FSH which will
lead to development of single preovulatory follicle
• Low dose regimens utilise (37.5–75 IU/day)
• Step up regimen starts with low dose and weekly dose is escalated
• The dose on the day the follicular growth is noted on USG and is continued as
an optimal dose until the follicular selection is achieved
• For reducing the risk of ovarian hyper-responsiveness, the duration of the
initial dose of FSH was extended (from 7 to 14 days) and the weekly dose
increment was reduced (from 100 to 50% of the dose), leading to the so-called
‘‘chronic low-dose regimen’’5

• Step-down Protocol
Scan D4–5

Starting dose Follicle >9 mm or 10 mm

Scan D8 hCG: 5000 IU
Dominant follicle =>16 mm

112.5 to 187.5 IU/day

Decrease by 37.5 IU Decrease by 37.5 IU

• Monofollicular development achieved, more physiological

• Loading FSH dose (112.5 to 187.5 0 IU/d) decreased by 37.5IU every 3–5 days
FSH: Follicle stimulating hormone; hCG: Human chorionic gonadotropin

41
• Step down regimen is designed to achieve the FSH threshold through a
loading dose of FSH followed by stepwise reduction as soon as follicular
development is observed on USG.

• Sequential Protocol
Follicle=14 mm
Scan D21
Scan D14 hCG: 5000 IU
Starting dose Scan D7 Dominant follicle =>16 mm

Increase dose by 50% Increase dose by 50%

37.5–75 IU / dL Decrease dose by 50%
hCG: Human chorionic gonadotropin

• Risk of multifolliculogenesis & OHSS reduced

• FSH threshold dose decreased by 50% when leading follicle is 14 mm
Principle
• FSH dependence of leading follicle decreases as follicle grows
• Decrease in FSH threshold contributes to the escape of the leading
follicle from atresia when FSH concentrations start to decrease due to
negative feedback of rising E2

• Combined approach is sequential use of both the regimens- step up and step
down.
• Strict cycle cancellation criteria should be agreed upon with the patient
before therapy is started.
• MP and OHSS may still occur.
• Routine use of GnRH agonists is not recommended due to significantly
higher hyperstimulation rate, the associated risk of multiple pregnancies
and the additional inconvenience and cost in women with PCOS.1,3,5
• It is often prudent to refer patients who need GT for OI to the infertility
specialists.

42
 Why do we Require GnRH Analogues in OI?

Premature LH surge impact upon oocyte/

embryo quality due to increased P4
result in post mature oocytes

Does exposure to FSH and LH affect ART outcome?

No relationship between Insufficient LH impact P4 level which

FSH exposure and oocyte quality advances the implantation window

LH: Luteinising hormone; FSH: Follicle stimulating hormone; GnRH: Gonadotrophin relasing hormone; P4: Progesterone;
ART: Assisted reproductive technology

Methods to Prevent Premature LH surge

FSH
Long agonist protocol
GnRH agonist

FSH
Antagonist protocol
GnRH antagonist
Flare-up

Pituitary down
LH regulation Immediate suppression
Extended Direct gonadotrophin
suppression suppression Immediate recovery

Time

• In PCOS with CC resistance or CC failure, no evidence of a difference in LBR

and OHSS rates was seen between urinary-derived GTs and rFSH or
hMG/highly purified hMG (hp-hMG). One needs to weigh costs and
convenience in the decision to use one or the other6
• In order to minimise this side effect, ovarian stimulation should be initiated
with low doses of GT (100 to 150 IU of follicle stimulating hormone receptor
[FSHr])
• Addition of hMG to recombinant FSH cycles on Day 8 – 9 enhances follicular
growth & increases E2 levels
• Pituitary should be suppressed with a gonadotropin-releasing hormone
(GnRH) antagonist because this method is associated with a reduced risk of
OHSS compared with an agonist7

43
• Is there Role of GnRH Analouges in IUI cycles

LH surge is an absolute requirement

for luteinisation final maturation of
the oocyte and follicle rupture

This may require the use of

GnRH agonist or antagonist
Premature LH surge
Occur in 25–30% of stimulated IUI cycles
May interfere with timing of IUI
Or
Result in cancellation and more treatment failures

GnRH: Gonadotrophin relasing hormone;LH: Luteinizing hormone; IUI: Intrauterine insemination

• Use of GnRH Analogues in Intrauterine Insemination (IUI)

• In comparison of GT alone vs GT with
Hypothalamus GnRH agonists it was seen that
pregnancy rate was higher with use of
GnRH GnRH agonists, however it was also
associated with higher rate of MP and
OHSS.
Pituitary
• In seven RCTs average ongoing
FSH LH pregnancy rate was 5.3% greater with
Oestradiol,
inhibins use of GnRH antagonist
progesterone.... • Number-needed-to-treat (NNT): 20 cycles
of GnRH antagonist for one additional
pregnancy

LH: Luteinising hormone; FSH: Follicle stimulating hormone; GnRH: Gonadotrophin relasing hormone;

44
 • How to Choose Between GnRH Analogues in ART cycle ?

GnRH agonist GnRH antagonist

Fixed and flexible start
Standard treatment protocol
GnRH
GnRH agonist
GT
r-FSH 150 IU MD 1 2 3 4 5 6 7 8 9 10
GnRHant
CD21 M P
Multiple or single dose /M//nnL
Short protocol
GnRH
GnRH agonist
GT
GT 37.5–150 SD 1 2 3 4 5 6 7 8 9 10
GnRHant
M P • • • 96-120 h...

GnRH: Gonadotrophin relasing hormone; FSH: Follicle stimulating hormone; GnRHant: GnRH antagonist ; GT: Gonadotrophin

• Choice between GnRH analogues will depend on :

o Ovarian reserve: based on AMH and AFC
o Hormonal profile
o E2 levels
o Number of growing follicles
• The use ovarian biomarkers to select the appropriate treatment is
recommended.
• AMH stratified treatment for choosing the GnRH analogue and dose of FSH is
helpful for generating customised individualised stimulation protocols.
• Use of oral contraceptive pill (OCP) with GnRH agonists assists in prevention
of asynchronous development of follicles which is found when GnRH
antagonists are used.

45
 Use of OCP in OI Cycle with GT
GnRH antagonist

OCP: 14–28 days Pill-free interval: 2–5 days FSH stimulation

Stop of OCP Stimulation day 1 hCG earlier or later

OCP: Oral contraceptive pill; hCG: Human chorionic gonadotropin; FSH: Follicle stimulating hormone; GnRH: Gonadotrophin relasing hormone;

References:
1. The Thessaloniki ESHRE/ASRM-Sponsored PCOS consensus workshop group consensus on
infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462–477.
2. Ortmann O, Weiss JM, and Diedrich K. Gonadotrophin-releasing hormone (GnRH) and GnRH
agonists: mechanisms of action. Reprod Biomed Online. 2002;5(S1):1–7.
3. Buvat, JB, Buvat-Herbaut, et al. Purified follicle-stimulating hormone in polycystic ovary
syndrome:slow administration is safer and more effective. Fertil Steril. 1989;52:553–559.
4. Palshetkar N and Roongta N. Protocols of ovulation induction. Available at:
[Link]
Last assessed on: 14th August, 2017.
5. Dale O, Tanbo T, Lunde O, et al. Ovulation induction with low-dose follicle-stimulating hormone
in women with the polycystic ovary syndrome. Acta Obstet Gynecol Scand.1993;72:43–46.
6. Weiss NS, Nahuis M, Bayram N, et al. Gonadotropins for OI in women with PCOS. Cochrane
Database of Systematic Reviews. at: [Link]
MENSTR_gonadotrophins-ovulation-induction-women-polycystic-ovarian-syndrome-pcos.
Last acessed on: 28th August, 2017.
7. Al-Inany HG, Youssef MA, Aboulghar M, et al. Gonadotrophin-releasing hormone antagonists
for assisted reproductive technology. Cochrane Database Syst Rev. 2011;5:CD001750.

Laparoscopic Ovarian Drilling

Basic technique
• Grasp ovarian ligament
• Stabilise ovary
• Ovarian drilling
• Electrocautery: monopolar coagulation
o 3–50W, 4–5 punctures,
o 5–7mm in depth
o 4–5 sec for each penetration
• Laser coagulation: CO2 laser, continuous mode
o 10–25W, 10–30 holes,
o 5 sec for each hole

46
Laparoscopic Ovarian Drilling (contd...)
• Avoid the hilum
• Prevention of adhesions by
o Abdominal lavage
o Early II look scopy
Indications
• CC resistance in women with anovulatory PCOS
• For patients who persistently hypersecrete LH
• For women with PCOS who need laparoscopic assessment of their pelvis or
• For those who live too far away from the hospital for the intensive monitoring
required during GT therapy.
Mechanism of action:
• Promotes ovulation through changes in intra-ovarian
hormonal environment
• Decreased LH leads to increased sensitivity of ovaries
to GT resulting in ovulation
Merits:
• Avoids or reduces the need for GT
• It is beneficial in lean women with high LH and androstenedione (ASD)
concentrations
Demerits:
• Possibility of ovarian tissue destruction and reduction can lead to premature
ovarian failure
• Non permanent ovulatory effect
• Possible post-operative adhesions
Results:
• Ovulation rate: 70 – 80 %
• Pregnancy rate: 40 – 47 %
• Miscarriage rate: 14 %

47
 Gonadotropins vs. Laparoscopic Ovarian Drilling

Parameter Inference
1. LBR per couple No difference
2. MPR Lesser with LOD
3. OHSS No difference

• Use of LOD for OI in women with PCOS:

o Beneficial for CC resistant PCOS
o As effective as OI with FSH in terms of live births, and
o Reduces the need for OI or ART in a significantly higher proportion
of women

• It is not the first line of treatment and should be reserved for CC failure cases.
• Surgical approaches to OI have progressed from historical wedge resection
to modern day minimal access techniques, usually employing laparoscopic
ovarian diathermy or laser
• Multiple ovarian puncture performed either by diathermy or by laser is
known as ‘‘ovarian drilling’’
• LOD can achieve unifollicular ovulation with no risk of OHSS or high-order
multiples
• Does not require intensive monitoring of follicular development
• Indications for its use are mentioned above
• LOD is a single treatment using existing equipment
• The risks of surgery are minimal and include the risk of laparoscopy,
adhesion formation and destruction of normal ovarian tissue
• Surgery should be performed by appropriately trained personnel
• LOD should not be offered for non-fertility indications
• There was no evidence of a significant difference in rates of clinical
pregnancy, live birth or miscarriage in women with CC resistant PCOS
undergoing LOD compared to other medical treatments
• The reduction in MPR in women undergoing LOD makes this option
attractive1
• However, there are ongoing concerns about the long-term effects of LOD on
ovarian function2,3

48
References:
1. The Thessaloniki ESHRE/ASRM-Sponsored PCOS consensus workshop group consensus on
infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462–477.
2. Nahuis MJ, Kose N, Bayram n, et al. Long term outcomes in women with PCOS initially
randomised to receive laparoscopic electrocautery of the ovaries or ovulation induction with
gonadotropins. Human Reproduction. 2011:26(7):1899–1904.
3. Farquhar C, Brown J, Marjoribanks J, et al. Laparoscopic 'drilling' by diathermy or laser for
ovulation induction in anovulatory polycystic ovary syndrome, Cochrane primary fertility group
review, 2012. Available at: [Link]
drilling-by-diathermy-or-laser-for-ovulation-induction-in-anovulatory-polycystic-ovary-
syndrome. Last accessed on: 28th August, 2017.

Complications
Problems associated with GT use
• OHSS
o Leads to cycle cancellation
o Severe morbidity
o Risk of mortality
• MP
o Higher maternal morbidity and mortality
o Increased complications and fetal mortality

• GT use is associated with higher risk of:

o OHSS
o Multifetal gestation
• Both raise the risk of maternal morbidity and can turn fatal
• The new definition of success of ART cycles defines successful singleton
pregnancy and not live births
• With the rise in order of multifetal gestation the complications associated
with triplet pregnancy are greater than complications with twin pregnancy

49
 Ovarian Hyperstimulation Syndrome sVE-cadherin

Pathophysiology

Increased vascular permeability Arteriolar vasodilation Ovarian enlargement

↑
Vascular permiability
VEGF

MAIN CLINICAL FEATURES

Ascites Intravascular dehydration

SEQUELAE
Thromboembolism Renal dysfunction ARDS Liver dysfunction
1–10% 30% 10–12% 25%
VEGF: Vascular endothelial growth factor; ARDS: Acute respiratory distress syndrome; OHSS: Ovarian hyperstimulation syndrome

• OHSS is an iatrogenic complication of ART and is dependent on hCG

administration.
• The relationship between hCG and OHSS is thought to be mediated via the
production of the angiogenic molecule Vascular endothelial growth factor
(VEGF).
• It is characterised by cystic enlargement of the ovaries and a fluid shift from
the intravascular to the third space due to increased capillary permeability
and ovarian neoangiogenesis.
• It has profound impact on the patient’s general health and can turn fatal.1

50
 Classification of Severity
Mild
• Abdominal bloating/discomfort
• Mild pain
• Mild nausea/vomiting/diarrhea
• Enlarged ovaries but <8 cm
Moderate
• Moderate abdominal pain
• Nausea/ vomiting/ diarrhea
• USG evidence of ascites
• Ovaries usually 8–12 cm
• Haemoconcentration (Hct) >41%
• Elevated WBC >15,000 mL
Severe
• Clinical ascites
• Hydrothorax, severe dyspnea
• Intractable nausea/vomiting
• Hct >45%, WBC >25,000/mL
• Oliguria, liver dysfunction (elevated liver enzymes)
• Ovaries usually >12 cm
• CrCl <50 mL/min; Cr >1.6 mg/dL
• Na+<135 mEq/L ; K+ >5 mEq/L

• The incidence of moderate OHSS is estimated to be between 3 and 6%, while

the severe form may occur in 0.1–3% of all cycles.
• OHSS has been recognised in two forms:
o The early form of OHSS, (within days after the ovulation triggering
injection of hCG) although elicited by hCG, is related to an exaggerated
ovarian response to GT stimulation
o The late form (10 days after hCG) is mainly related to the secretion of
placental hCG1

51
 Types of OHSS

hCG
Early OHSS Late OHSS

Ovarian response Pregnancy

hCG 3–9 days 10–17 days

hCG: Human chorionic gonadotropin; OHSS: Ovarian hyperstimulation Syndrome

Prevention
Before
• Identification of risk factors to individualise controlled ovarian stimulation (COS)
• Correct adaptation of stimulation protocols
• Limit the dose or concentration of hCG
• Monitoring COS using USG and E2 assays constitutes the `gold standard‘
• Use of GnRh antagonist
• Cycle cancellation or coasting

During
• Limit the dose or concentration of hCG
• Use r-LH/ GnRH agonist to trigger ovulation
• In vitro maturation (IVM)
• Prophylactic albumin in high risk
• Transfer of single embryo ↓
MPR thus OHSS

After
• Cryopreservation of all embryos for transfer in subsequent cycle
• Using progesterone instead of hCG for luteal phase support
• Dopamine agonist
• Use of antagonist post cryofreezing all embryos or with fresh embryo transfer?

Ovarian stimulation hCG Luteal Phase

hCG: Human chorionic gonadotropin

52
• In the past, apart from cycle cancellation, none of the approaches were
totally efficient, although they decrease the incidence in patients at high
risk of OHSS.
• But today we have a option of GnRH agonist trigger in a GnRH antagonist
cycle with cryopreservation of all embryos to be transferred in the
subsequent cycles.
• HCG is a primary stimulus for the syndrome, with holding hCG is the main
preventive measure against OHSS.

Management
Examination
• General: assess for dehydration, edema- pedal vulval, sacral, heart rate (HR),
respiratory rate (RR), blood pressure (BP), body weight
• Abdominal: assess for ascites, palpable mass, peritonism and measure girth
• Limit the dose or concentration of hCG
• Respiratory: assess for pleural effusion, pneumonia, pulmonary oedema
Investigation
• Full blood count (FBC), packed cell volume (PCV), C-reactive protein (CRP)
• Urea and electrolytes, serum osmolarity,
• Liver function test (LFT), coagulation profile
• USG
Additional tests
• Arterial blood glucose (ABG), D- dimers
• Electocardiography (ECG)
• Chest radiograph (CXR)
• USG: ovarian size, pelvic and abominal free fluid

• In most cases OHSS is self-limiting and requires supportive management

and monitoring while awaiting resolution.
• Women with more severe OHSS may require inpatient treatment to manage
the symptoms and reduce the risk of further complications.
• The key principles of OHSS management therefore are early recognition and
the prompt assessment and treatment of women with moderate or severe
OHSS.1

53
 Treatment
• Nonsteroidal anti-inflammatory drugs (NSAIDS) should be avoided, as they
may compromise renal function.
• Women with severe OHSS should receive thromboprophylaxis with Low-
molecular-weight heparin (LMWH).
• Paracentesis of ascitic fluid by the abdominal or TVS route under USG
guidance.
• There is insufficient evidence to support the use of GnRH antagonists or
dopamine agonists in treating established OHSS.
Out patient department management for mild to moderate cases
• Review in 2–3 days
• Early follow up in case of increased severity of symptoms
• Paracentesis can be done on OPD basis
• LMWH
In patient department management for severe cases
• Analgesia- paracetamol and opiates, avoid NSAIDS
• Maintain fluid balance – replace with intravenous colloids, avoid diuretics
• Paracentesis
• LMWH prophylaxis
• Surgery only for coincident problems such as adnexal torsion, ectopic
pregnancy rupture or ovarian rupture

• NSAIDS should be avoided, as they may compromise renal function.

• Fluid replacement by the oral route, guided by thirst for correcting
intravascular dehydration.
• Women with persistent Hct despite volume replacement with intravenous
colloids may need invasive monitoring with anaesthetist’s input.
• Paracentesis of ascitic fluid may be carried out on an outpatient basis by the
abdominal or TVS route under USG guidance.
• There is insufficient evidence to support the use of GnRH antagonists or
dopamine agonists in treating established OHSS.
• Mild and moderate cases can be managed on OPD basis.
• Women with more severe OHSS may require inpatient treatment to manage
the symptoms and reduce the risk of further complications.
• Women with severe OHSS should receive thromboprophylaxis with LMWH.

54
• The duration of treatment should be individualised, taking into account risk
factors and whether or not conception occurs.
• Surgery is only indicated in patients with OHSS if there is a coincident
problem such as adnexal torsion, ovarian rupture or ectopic pregnancy and
should be performed by an experienced surgeon.
• The treating doctor should be aware, and patient should be informed, that
pregnancies complicated by OHSS may be at increased risk of pre-eclampsia
and preterm delivery.1
References:
1. Kumar P, Sait SF, Sharma A, et al. Ovarian hyperstimulation syndrome. J Hum Reprod Sci.
2011;4(2):70–75.
2. Practice committee of ASRM. Prevention and treatment of moderate and severe ovarian
hyperstimulation syndrome: a guideline. Fertility and Sterility. 2016;106(7):1634–1647.
3. Banker M and Velasco JAG. Revisiting ovarian hyper stimulation syndrome: towards OHSS free
clinic. J Hum Reprod Sci. 2015;8(1):13–17.
4. Royal College of Obstetricians and Gynaecologists, The Management of Ovarian
Hyperstimulation Syndrome. Available at: [Link]
guidelines/green-top-guidelines/gtg_5_ohss.pdf . Last accessed on: 28th August, 2017.

Multifetal Gestation
• Maternal morbidity and mortality is higher in twins and higher order
pregnancies
• Fetal morbidity mortality is also higher in twins and higher order pregnancies
• All complications are higher in triplets compared to twins
• Multiple birth parents face higher financial and psychosocial stress which
tends to persist long after the newborn stage

Maternal mortality X 2 or 3 Infant mortality X 5

• The presence of multifetal gestation blemishes the outcomes of ART.

• Prevention of MP is essential to prevent maternal and neonatal
complications.
• Multifetal gestation leads to higher maternal mortality and morbidity as
stated in the table below and higher infant mortality and morbidity as well.
• They also face higher financial and psychosocial stress which extends
beyond the newborn stage.

55
 Table 4: Effects of multifetal gestation on mother, infant and the family
Maternal health Infant health Psychosocial effects on
the family
• Pre-eclampsia • Placental problems • Postpartum depression
• Gestational diabetes o Premature aging (mother and father)

• Placental previa o Twin-to-twin transfusion • Relationship stress

• Placental abruption syndrome • Financial stress

• Preterm premature • Spontaneous abortion o Obstetric costs and

rupture of the • Intrauterine growth restriction neonatal intensive
membranes care admission
• Preterm (< 37 weeks), very
• Cesarean delivery preterm (< 32 weeks), and o Costs for caring for
extreme preterm (< 28 weeks) multiple children
• Postpartum
birth throughout
haemorrhage
childhood
• Death • Perinatal and infant mortality
• Low (< 2500 g) and very low
birth weight (< 1500 g)
• Intraventricular haemorrhage
• Periventricular leukomalacia
• Respiratory distress syndrome
• Bronchopulmonary dysplasia
• Hypoxic-ischemic
encephalopathy
• Necrotising enterocolitis
• Sepsis
• Jaundice
• Retinopathy of prematurity
• Cerebral palsy
• Neural tube defects, heart
malformations, and other birth
defects
• Developmental delays

• When the goal is to minimize IVF complications, multiple embryo transfer

(MET) does not necessarily translate to a superior outcome.
• The goal of infertility treatment should be the delivery of a healthy single
baby, with fewer twin and higher-order births.
• The new guidelines promote single embryo transfer (SET).
• The voluntary transfer of a single high quality embryo, elective single
embryo transfer (eSET), has significantly reduced multiple gestation rates
and maximised the rate of singleton pregnancy without compromising
overall success rates.
• Thus reduces the risk of iatrogenic twins and higher order pregnancies.

56
 Live Birth Rates with Single- and Multiple Embryo Transfer

Triplets or more Twins Singletons

60 57%
(<0.1) (1.2)
50%
50 47%
(7.2) 45%
(2.0) (41.4)
40
Live births (%)

(35.1) (47.6)
30
(98.0)
20
(57.4)
(57.7) (52.4)
10

0
1 2 3 4
No. of embryos transferred

Desired Treatment Outcome (a) Before education (b) After education

a Triplet pregnancy b Twin pregnancy

Twin pregnancy

Singleton pregnancy
Singleton pregnancy

• A mandatory single blastocyst transfer policy with educational campaign in

a United States IVF program reduces multiple gestation rates without
sacrificing pregnancy rates as shown in the figure above.2
• SET is an effective method for reducing MP resulting from IVF and should be
consistently encouraged for the majority of patients to improve the likelihood
of delivering a healthy baby.
• A multi-faceted approach incorporating patient education and counselling,
reimbursement offers or other financial incentives, and IVF success
prediction tools can be used to improve eSET rates in clinical practice.1

57
Monitoring OI Cycles can Improve Outcome
Patient’s initial parameters
• Base line scan: to rule out ovarian or uterine pathology, AFC
• Base line hormonal profile: ovarian reserve, FSH:LH ratio, androgen excess,
thyroid profile and hyperprolactenemia
• Choose appropriate stimulation regime to prevent OHSS, multiple
pregnancy and predict responses to ovarian stimulation

Ovarian responses to OI
• Confirmation of down-regulation after GnRH agonist
• Determine response to drug
• Determine the dose and length of GT treatment
• Determine optimal time for hCG administration
• Detect ovulation
• Time ova-reduction
• Identify poor responders and women at risk of OHSS

Completion of therapy
• Diagnose complications of OI
o Premature lutenisation
o Lutenised unruptured follicle (LUF)
o Endogenous LH surge
o Retention/functional cysts
• Confirm pregnancy
• To rule out MP
• To rule out latest onset OHSS

Holisitc View of IVF Management

• Physician advice • Predict IVF cycle
• Nurse counselling • Predict risk of multiples
• Follow-up phone calls
Provide independent
Emphasize: Counselling Prediction
• Cumulative PR and advice tools
• Heath risks, financial
implications, emotional
stress with multiple
embroyotransfer
Patient Financial aid
• Educational DVDs education • Reimbursement
• Educational brochures offers and incentives
• Testimonials from parents
of twins/multiples
Relieve financial constraints

58
• Patient’ initial parameters such as base line scan, AFC, AMH, hormonal
profile help in choosing the appropriate regimen with successful outcomes
and fewer complications.
• Monitoring is necessary for confirming the down regulation, determining
response to drugs used for OI, determining the optimal time for hCG
administration, detecting ovulation, timing ova reduction and identifying
poor responders/ women at risk of OHSS.
• It is important to diagnose complications and treat them promptly if they
occur and confirm pregnancy and provide adequate support to the
pregnancy.1,2
References:
1. Tobias T, Sharara FI, Franasiak JM, et al. Promoting the use of elective single embryo transfer in
clinical practice. Fertility Research and Practice. 20162:1.
2. Ryan GL, Sparks AE, Sipe CS, et al. A mandatory single blastocyst transfer policy with
educational campaign in a United States IVF program reduces multiple gestation rates without
sacrificing pregnancy rates. Fertil Steril. 2007; 88(2):354–60.

In vitro Fertilisation
2. Egg pick up 6. Embryo transfer

4. Egg fertilisation

Cannula

1. Ovarian stimulation 3. Sperm 5. Embryo development

hormone therapy preparation

• IVF is a reasonable option, to limit the number of MP by transferring

small numbers of embryos
• The optimal stimulation protocol is debatable
• Implantation is not compromised in PCOS
• The increase in the cycle cancellation rate in women with PCOS
appears to be due to absent or limited ovarian response or due to
increased OHSS

59
• IVF is a reasonable option, because the number of multiple pregnancies can
be kept to a minimum by transferring small numbers of embryos.
• The optimal stimulation protocol is still under debate.
• It is reassuring that in the published data the pregnancy rates in women with
and without PCOS is similar. This observation suggests that implantation is
not compromised in PCOS.
• The increase in the cycle cancellation rate in women with PCOS appears to
be due to absent or limited ovarian response or due to increased OHSS.1
• Use of GnRH agonist vs antagonist and various other protocols for ART are
beyond the scope of this module.
• Further patients needing IVF need to be referred to the infertility specialists
for further management.

IVF Tools for Selection of Best Embryo

Polar body Blastomere Trophectoderm

Cell division Fluroscence Comparative Quantitative

timings Post-cleavage in situ genome polymerase
Atypical stage dynamics hybridisation hybridisation chain reaction
phenotypes (FISH) (CGH) (qPCR)

Progression to Embryo assessment Aneuploidy assessment

Embryo morphology
blastocyst by embryoscope by PGS

PGS: Preimplantation genetic screening

• Advancement in embryo cryopreservation, extended embryo culture with

blastocyst selection, and preimplantation genetic screening supports the
successful outcomes of elective single embryo transfer.2
• Preimplantation genetic screening (PGS), including comprehensive
chromosomal screening (CCS) technologies, allows clinicians to assess
embryos for aneuploidy (i.e., an abnormal number of chromosomes) prior to
transfer.
• CCS is highly predictive of the reproductive potential of human embryos.

60
 The Choice of Treatment will Depend on

germ
cell

is
ptos Proliferation
po

Differentiation
A

Apo
pto Oocyte
sis

Meiosis

• Presence of other infertility factors

• Available resources
• Risk tolerance

Success of OI in an ART Cycle Depends on

Age and
ovarian
reserve
Duration and
Financial
causes
support
of infertility

• Gonadotropin type
• Gonadotropin dose
Risk of
• GnRH analogue Lab quality
complications
• Trigger for final

ES S oocyte maturation

S UC C Physical and
psychological
Embryo
transfer
stress policy
Cryo
program
GnRH: Gonadotrophin relasing hormone

• Success of OI in an ART cycle depends on several factors as mentioned above

References:
1. The Thessaloniki ESHRE/ASRM-Sponsored PCOS consensus workshop group consensus on
infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23(3):462–477.
2. Lee AM, Connell MT, Csokmay JN, et al. Elective single embryo transfer- the power of one.
Contraception and Reproductive Medicine. 2016;1:11.

61
 Emotional Well-being

16
NIH PCOS

Hospital anixiety and depression

14 non-NIH PCOS
12 Controls
10
8
6
4
2
0
Anxiety Depression
PCOS: Polycystic ovary syndrome; NIH: National Institute of Health

Women with PCOS when compared with those without PCOS showed
• Worse anxiety
• Higher rate of depression
• Worse health related quality of life

• Women with PCOS had worse anxiety (P = 0.007) and depression (P = 0.048)
compared with women without PCOS.
• Both PCOS phenotype displayed higher rate of depression and anxiety than
controls
• They had worse health-related quality of life (HrQOL) compared to controls1
• Obese and hirsute women had worse HrQOL
• Reduced sexual self worth, and inability to conceive with existing desire to
conceive are the important factors that influence emotional well being.2
• OCP normalised the hormones but did not improve the distress symptoms
among women with PCOS.3
• Appropriate interventions by experts to improve psychological function in
all women with PCOS must be employed.
• Education plays an important role in help reduce the likelihood of depression
and anxiety among women with PCOS.
• Psychopharmacotherapy may be considered for modifying influence of
psychosocial function in women with PCOS.3
• Multidisciplinary team must be utilised for holistic treatment of women with
PCOS.2, 3

62
References:
1. Moran LJ, Deeks AA, Gibson-Helm ME, et al. Psychological parameters in the reproductive
phenotypes of polycystic ovary syndrome. Hum Reprod. 2012;27(7):2082–2088.
2. Tan S, Hahn S, Benson S, et al. Psychological implications of infertility in women with polycystic
ovary syndrome. Hum Reprod. 2008;23(9):2064–2071.
3. Rowlands IJ, Teede H, Lucke J, et al. Young women's psychological distress after a diagnosis of
polycystic ovary syndrome or endometriosis. Hum Reprod. 2016;31(9):2072–2081.

Conclusion

Presumed case of PCOS

Rule out any other health related and

infertility concerns in the couple Anovulation confirmed

Preconception counseling regarding weight management, smoking and alcohol consumption

? Bariatric surgery
CC Aromatase inhibitors

Tamoxifen

GT LOD

IVF

? Insulin sensitizers

CC: Clomiphene citrate; PCOS: Polycystic ovarian syndrome; GT: Gonadotrophin ; IVF: In vitro fertilisation; LOD: Laparoscopic ovarian drilling

63
 Key Points

• While examining women with presumed polycystic ovarian syndrome

desiring pregnancy any other health issues or infertility problems in the
couple should be excluded.
• Before any intervention is initiated, preconception counselling should be
provided emphasising the importance of life style, especially weight
reduction and exercise in overweight women, smoking and alcohol
consumption.
• Bariatric surgery may be considered in those with body mass index 35 kg/m2
and when lifestyle therapy fails.
• The recommended first-line treatment for ovulation induction remains the
anti-oestrogen clomiphene citrate.
• For cases where clomiphene citrate fails, recommended second-line
intervention is either exogenous gonadotrophins or laparoscopic ovarian
drilling. Both carry their own advantages and drawbacks. Treatment needs
individualisation. Exogenous gonadotrophins are associated with higher risk
of multiple pregnancies and intense monitoring of ovarian response is
necessary. Laparoscopic ovarian drilling is usually effective in <50% of women
however further ovulation induction may be required.
• Overall, ovulation induction is highly effective with a cumulative singleton live
birth rate of 72%.
• In vitro fertilisation is the recommended third-line treatment as it is effective
in women with polycystic ovarian syndrome and may significantly reducing
chances of multiple pregnancies by restricting to single embryo transfer.
• Metformin alone has limited benefits in improving live birth rate
• Metformin should be used for women with glucose intolerance.
• If a gonadotrophin relasing hormone agonist protocol is used, metformin as an
adjunct may reduce the risk of ovarian hyperstimulation syndrome.
• Health professionals should be aware of the potential psychosocial needs
among women with polycystic ovarian syndrome and infertility, particularly
women with polycystic ovarian syndrome who are obese and provide
appropriate interventions.
• Even singleton pregnancies in polycystic ovarian syndrome are associated
with increased health risk for both the mother and the foetus which will be
discussed in our next module on polycystic ovarian syndrome and pregnancy.

64
Suggested Readings

1. The Thessaloniki ESHRE/ASRM-Sponsored PCOS consensus workshop

group consensus on infertility treatment related to polycystic ovary
syndrome. Hum Reprod. 2008;23(3):462–477.
2. Frank S, Stark J, and Hardy K. Follicle dynamics and anovulation in polycystic
ovary syndrome. Hum Reprod Update. 2008;14(4):367–378.
3. Practice committee of ASRM. Prevention and treatment of moderate and
severe ovarian hyperstimulation syndrome: a guideline. Fertility and
Sterility. 2016;106(7):1634–1647.
4. I.J. Rowlands, H. Teede J. Lucke, et al. Young women's psychological distress
after a diagnosis of polycystic ovary syndrome or endometriosis. Hum
Reprod. 2016;31(9):2072–2081.
5. Emekçi-Özay Ö, Özay AC, Çaðliyan E, et al. Myo-Inositol administration
positively effects ovulation induction and intrauterine insemination in
patients with polycystic ovary syndrome: a prospective, controlled,
randomized trial. Gynecol Endocrinol. 2017;33(7):524–528.

65
Notes

66
Notes

67
Notes

68
 PCOS and Infertility

POST-TEST
1. The commonest infertility issue with PCOS is:

a. Tubal infertility

b. Unexplained infertility

c. Anovulatory infertility

d. All the above

2. The prevalence of PCOS has been reported as_____% in women with

infertility.

a. 40%

b. 50%

c. 60%

d. 70%

3. Infertilty in PCOS is due to:

a. Ovarian dysfunction

b. Hyperandrogenemia

c. Hyperinsulinemia

d. All the above

4. Leptin is one of the peripheral signal that forms the link between
adiposity and dysregulation in the gametogenic and steroidogenic
potential of an ovary.

a. True

b. False

5. For checking ovarian reserve following test must be done:

a. AMH

b. AFC

c. Both (a) and (b)

d. None of the above

6. Which of the following is incorrect about hormonal testing in PCOS?

a. Hormonal testing is necessary for evaluating every case of PCOS

b. Few tests are done to rule out other possible dysfunctions before
treating for PCOS

c. Any one hormone test such as FSH/ LH/ AMH/ Oestrogen/ Testosterone
is sufficient

d. All of the above

7. AMH is biomarker for PCOS. Which of the following is correct?

a. AMH is raised in PCOS women

b. AMH levels fall in PCOS

c. AMH does not influence FSH

d. It has no role in anovulation of PCOS

8. Management of infertility in PCOS starts with:

a. Gonadotropins

b. IVF

c. Clomiphene citrate

d. Weight loss

9. In an obese woman with PCOS and anovulatory infertility, living in the

interiors who needs to travels three hours to reach the clinic and has
failed to conceive on clomiphene citrate protocols, what would be your
next step?

a. Gonadotropins

b. Laparoscopic ovarian drilling

10. For IVF in PCOS women with infertility. Which of the following is
incorrect?

a. It is recommended as the third step of intervention

b. It can help restrict to singleton pregnancy

c. It has poorer results among PCOS women

d. All of the above

Answers: 1. c; 2. a; 3. d; 4. a; 5. c; 6. c; 7. a; 8. c; 9. a; 10. c
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