pcos other than ART.pptx for mbbs and md

OVULATION INDUCTION
IN
PCOS OTHER THAN ART
DR REJI MOHAN,MD,DNB,FELLOW in RM
ASSISTANT PROFESSOR
DEPT. OF REPRODUCTIVE MEDICINE AND SURGERY
SREE AVITTOM THIRUNAAL HOSPITAL
GOVT MEDICAL COLLEGE
THIRUVANANTHAPURAM.dtd 05.10.2019
12/25/2023 drrejimohan@gmail.com 9447044485 1

My sincere gratitude
Almighty
Teachers
Colleagues
Students
Well wishers
Family
My patients
Organizers

OUTLINE
History and
Epidemiology
Recent advances
in diagnosis and
investigations
Ovulation
induction for
TI/IUI
Ovulation
induction for IVF
ICSI
Conclusion

HISTORY “But those women whose
menstruation is less than three
days or is meagre, are robust, with
a healthy complexion and a
masculine appearance; yet they
are not concerned about bearing
children nor do they become
pregnant.”
Hippocrates (460 BC-377 BC)
Young married peasent women
moderately obese and infertile with
two larger than ovaries bumpy
shiny and whitish just like pigeon
eggs .
Vallisneri 1721
“They saw in 7 women with
amenorrhoea, hirsutism, and obesity
found to have a polycystic
appearance to the ovaries”
Irving Freiler Stein & Michael Leo
Leventhal described as the “Stein-
Leventhal syndrome” in 1935

History
1935:Stein Leventhal syndrome
1980:Insulin resistance described later by Burghen
1990 NiH CRITERIA
2003 ROTTERDAM CRITERIA (two out of three are required for diagnosis)
2006-Androgen Excess Society-(hyperandrogenism plus one out of remaining two are
required for diagnosis)
2018 International evidence-based guideline for the assessment and management of
polycystic ovary syndrome

Epidemiology
Polycystic ovary syndrome is the most common endocrinopathy affecting
reproductive aged women
Prevalence of between 8% and 13%
36% of women in India suffer from PCOS
Infertility is a prevalent presenting feature
It’s prevalence among infertile women is 15% to 20%.
~75% of these women suffers infertility due to anovulation

• According to the Health Care-Related Economic Burden of the
Polycystic Ovary Syndrome, they stated,
 Mean annual cost of the initial evaluation to be $93 million
 Hormonally treating menstrual dysfunction/abnormal
uterine bleeding to be $1.35
 Providing infertility care to be $533 million
 Pcos-associated diabetes to be $1.77 billion
 Treating hirsutism to be $ 622 million.
• The total cost of evaluating and providing care to reproductive-
aged PCOS women in the United States is $4.36 billion
BURDEN
$4.36
billion

WHO ANOVULATION

Importance of making the diagnosis
Avoid IVF by treating well
beforehand
Diagnosis

PCOS
OA
~
Oligo-Anovulation
HA~Hyper-
androgenism
PCOM
~
Polycystic Ovarian
Morphology
Requires the presence of two out of the following three criteria.
Other causes of hyperandrogenism should be excluded
A raised LH/FSH ratio is no longer a diagnostic criteria for PCOS owing to its inconsistency

Oligo-Anovulation **** CCR
Irregular menstrual cycles are defined as:
When irregular menstrual cycles are present a diagnosis of PCOS
should be considered and assessed according to the guidelines
normal in the first year post menarche as part of the pubertal transition
> 1 to < 3 years post menarche: < 21 or > 45 days
> 3 years post menarche to perimenopause: < 21 or > 35 days or < 8
cycles per year
> 1 year post menarche > 90 days for any one cycle

Hyperandrogenism
PCOS
CLINICAL
Hirsutism
Acne
Alopecia
Virilisation
BIOCHEMICAL
modified Ferriman Gallwey score (mFG) with a level ≥ 4 - 6 indicating hirsutism
The Ludwig visual score is preferred for assessing the degree and distribution of
alopecia. **** CCR
Calculated free testosterone, free androgen index or calculated bioavailable
testosterone should be used to assess biochemical hyperandrogenism in the diagnosis
of PCOS. **** CCR

Modified FG score 0-4 max 36 The Ludwig visual score

PCOM: Polycystic Morphology
The definition of PCOM in the Rotterdam criteria is 12 or more follicles
measuring 2 - 9mm throughout the entire ovary or an ovarian volume ≥ 10cm
Using endovaginal ultrasound transducers with a frequency bandwidth that
includes 8MHz, the threshold for PCOM should be on either ovary, a follicle
number per ovary of ≥ 20 and/or an ovarian volume ≥ 10ml, ensuring no
corpora lutea, cysts or dominant follicles are present

Recommendedminimumreportingstandards
• Last Menstrual Period
• Transducer Bandwidth Frequency
• Approach/Route Assessed
• Total Follicle Number Per Ovary Measuring 2-9mm
• Three Dimensions And Volume Of Each Ovary
• Reporting Of Endometrial Thickness And Appearance Is
Preferred
• Other Ovarian And Uterine Pathology, As Well As Ovarian Cysts,
Corpus Luteum, Dominant Follicles ≥ Equal 10mm
In patients with irregular menstrual cycles and hyper androgenism, an ovarian
ultrasound is not necessary for PCOS diagnosis; however, ultrasound will identify the
complete PCOS phenotype

Phenotypes

DD and investigations

PRENATAL
FACTORS
Aromatase
inhibitors (AI’s)
Clomiphene
citrate (CC)
Insulin lowering
medications
Laparoscopic
ovarian drilling Gonadotropins
Treatment OPTIONS -anovulatory infertility

Healthy
Eating
Regular
Physical
Activity
-Achieve and/or maintain healthy weight
-To optimize hormonal outcomes
-Restore ovulation and fertility
-General health
-QOL across the life course
Lifestyle modification or prenatal care

SPECIFIC
MEASURABLE
ACHEIVABLE
REALISTIC
TIMELY
 Achievable goals such as 5%
to 10% weight loss within six
months
 A variety of balanced dietary
approaches
 An energy deficit of 30% or
500 - 750 kcal/day (1,200 to
1,500 kcal/day)
 150 min/week of moderate
intensity physical activity or
75 min/week of vigorous
intensities or an equivalent
combination of both
 Behavioral strategies to
facilitate adherence to diet
and activity
recommendations
GOALS –SMART-REALISTIC
Daily, 10000 steps is ideal
Self-monitoring including with fitness tracking
devices and technologies for step count and
exercise intensity, could be used as an adjunct

1.Selection of appropriate treatment
2.Induce monofollicular development
3.Start with least invasive and simplest treatment option
4.Maximize rate of singleton pregnancies
5.Minimize risk of OHSS
6.Exclude pregnancy
Points to consider beforeOvulationInduction

Points to consider beforeOvulationInduction
7.Total motile sperm count of at least five million/ejaculate.
8.Advice on weight control (gain/loss to achieve a BMI of <30kg/m2 or
>20kg/m2)
9.Adequate counselling of women regarding the risks of treatment
10.Ensure adequate monitoring facilities (ultrasound and laboratory) are
available, together with protocols with clear guidelines for reducing risks,
which would include cancellation of treatment cycles

PRENATAL
FACTORS
Aromatase
inhibitors (AI’s)
Clomiphene
citrate (CC)
Insulin
lowering
medications
Gonadotropins
Laparoscopic
ovarian drilling

• Letrozole and anastrozole, with letrozole being the most widely
used.
• Start from day 3–7
• Doses of 2.5–7.5 mg per day in 2.5mg increments
• Adverse effects include gastrointestinal disturbances, asthenia,
hot flushes, headache and back pain
Aromatase inhibitors (AI)Letrozole
AI INHIBITS E
biosynthesis
no oestrogenic
negative feedback
on the HP axis
FSH INCREASED
FOLLICULAR
GROWTH

Letrozole should be considered first line pharmacological
treatment for ovulation induction in women with PCOS with
anovulatory infertility and no other infertility factors.
JUSTIFICATION
Letrozole more likely both to ovulate and to have a live birth
compared to clomiphene
The likelihood of live birth is increased 40–60% with letrozole
compared to clomiphene
Failure to ovulate (letrozole resistance) is lower
Multiple pregnancy rates appear lower
Hot flushes, generally the least desired side effect of any
antioestrogen, is less common with letrozole than clomiphene,
but still present.
Others:GI disturbances, asthenia headache back pain

Letrozole for infertility treatment might be associated with a
higher risk of congenital cardiac and bone malformations in
newborns
• Multiple subsequent case series (Tulandi et al., 2006; Forman et al., 2007; Dehbashi et al.,
2009; Sharma et al., 2014; Tatsumi et al., 2017), multi-centre RCTs (Legro et al., 2014a,b;
Diamond et al., 2015) and a recent systematic review and meta-analysis (Wang et al.,
2017), all failed to note an increased congenital anomaly rate, with prevalence of
anomalies with letrozole orclomiphene under 5%(the expected anomaly ratein
thispopulation is 5–8%) (Davies et al., 2012)
• Multiple subsequent case series , multi-centre RCTs and a
recent systematic review and meta-analysis, all failed to note
an increased congenital anomaly rate with prevalence of
anomalies with letrozole or clomiphene under 5% (the
expected anomaly rate in this population is 5-8%)
LETROZOLE IS BACK

PRENATAL
FACTORS
Aromatase
inhibitors (AI’s)
Clomiphene
citrate (CC)
Insulin
lowering
medications
Gonadotropins
Laparoscopic
ovarian drilling

 Nonsteroidal triphenylethylene derivative introduced in 1961,
 A selective oestrogen receptor modulator with both
oestrogenic and anti-oestrogenic properties .
Clomiphene citrate

• Start with 50 mg
• Empirical incremental titration
• FDA appproved maximum dose is 100 mg/day
• Beyond 6 cycles- undesirable
Clomiphene citrate

 About 80% ovulate with cc treatment,only about 30%-40%
conceptions occur.
 Discrepancy is mainly due to the anti-oestrogenic effects on
the endometrium and cervical mucus.
 Twin pregnancy and triplets with CC are 5–7% and 0.3%,
respectively and OHSS is less than 1% .
 The potential for borderline increased risk of ovarian tumours
with 12 cycles or more has been noted.
 Day 2-5 start

COMMON SIDE EFFECTS
Mood swings -64 TO 78%
Hot flashes -10%
Visual disturbances-<2%
Breast tenderness
Pelvic discomfort
Nausea-2-5%
OHSS -<1%

Letrozole vs clomiphene
• OVULATION RATE
Significantly higher with Letrozole
• CUMULATIVE LIVE BIRTH
27.5% vs 19.1%
• PREGNANCY LOSS
Similar
• SINGLETON PREGNANCY
Significantly higher with Letrozole
• MAJOR CONGENITAL ANOMALIES
No difference
RCT by Legro et
al NEJM 2014

PRENATAL
FACTORS
Aromatase
inhibitors (AI’s)
Clomiphene
citrate (CC)
Insulin
lowering
medications
Gonadotropins
Laparoscopic
ovarian drilling

Insulin lowering medications
THIS HAS LED TO INSULIN-SENSITIZING DRUGS USE IN OVULATION INDUCTION.
PREMATUREFOLLICULAR ATRESIA AND ANOVULATION
EXCESS LOCAL OVARIAN ANDROGEN PRODUCTION AUGMENTED BY HYPERINSULINAEMIA
INCREASED BIOAVAILABILITY OF FREE ANDROGENS.
OVARIAN ANDROGEN BIOSYNTHESIS
INSULIN RESISTANCE

• Metformin is a biguanide currently used as an oral
antihyperglycemic agent
• Dose to start with 500mg daily with food. After 1 week,
increase to 1000mg for another week and then to 1500 mg
daily.
• The target dose is 1500–2550 mg/day (500 or 850 mg three
times daily)
Insulin sensitisers

 Metformin improves the
ovulation rate and clinical
pregnancy rate compared with
placebo or no treatment, but
not the live birth rate.
 Compared with CC, metformin
gives lower ovulation rate and
clinical pregnancy rate
 Metformin could be
recommended in adult
women with PCOS, for the
treatment of weight,
hormonal, and metabolic
outcomes. esp BMI> 25
 Improves the ovulation rate
and clinical pregnancy rate
in obese patients but not in
non-obese patients
 Improves live birth rates
inclusive in CC resistant
women only
 With long term use low
vitamin B12 levels.
• Metformin monotherapy
• Metformin co-treatment with
CC
Insulin sensitisers

TreatmentstrategiesforwomenwithWHOgroupIIanovulation:
Systematicreviewandnetworkmeta-analysis.RuiWangetal BMJ
2017;356:j138
Objective
• To compare the effectiveness of alternative first line treatment options for women
with WHO group II anovulation wishing to conceive.
• Of 2631 titles and abstracts initially identified, 57 trials reporting on 8082 women
were included
• All pharmacological intervention are more effective
than placebo or no drugs for achieving ovulation and
pregnancy
• Combination of CC+metformin and Letrozole alone
better in terms of ovulation and pregnancy, letrozole
superior to CC in LBR
• Metformin and Letrozole were associated with a lower
risk of multiple pregnancy in comparison with CC
Three
key
findings

PRENATAL
FACTORS
Aromatase
inhibitors (AI’s)
Clomiphene
citrate (CC)
Insulin
lowering
medications
Gonadotropins
Laparoscopic
ovarian drilling

• Utero-ovarian ligament is grasped by
atraumatic forceps moving the ovary
(towards anteriorabdominal wall & in
front of the uterus).
Laparoscopic ovarian surgery
LOS more effective in patients with high LH, and significant
reductions in LH and androgens following surgery.
LOD restores menstrual regularity in 63%–85% of women
Beneficial effects on reproductive outcomes lasts for several years
in many women.
Rule of 4
4 puncture
4 seconds
4mm
40watts
Monopolar/laser
Antimesentric border
Saline irrigation

Teede.Internationalevidence-basedguideline.
FertilSteril2018
• Laparoscopic ovarian surgery could be second line therapy for
women with PCOS, who are clomiphene citrate resistant, with
anovulatory infertility and no other infertility factors.
• Laparoscopic ovarian surgery could potentially be offered as
first line treatment if laparoscopy is indicated for another
reason in women with PCOS with anovulatory infertility and no
other infertility factors.
• Risks need to be explained to all women with PCOS
considering laparoscopic ovarian surgery.

• Where laparoscopic ovarian surgery is to be recommended,
consider
 Comparative cost
 Expertise required for use in ovulation induction
 Intra-operative and post-operative risks are higher in women
who are overweight and obese
 There may be a small associated risk of lower ovarian reserve
or loss of ovarian function
 Periadnexal adhesion formation may be an associated risk

PRENATAL
FACTORS
Aromatase
inhibitors (AI’s)
Clomiphene
citrate (CC)
Insulin
lowering
medications
Gonadotropins
Laparoscopic
ovarian drilling

• Greater sensitivity to gonadotropin stimulation
• Therefore, multiple (“explosive”) follicular
development
Gonadotropins

1.STEP-UP:
1.Conventional=Stan
dard
2. Low dose
3. Chronic low dose
2. Step-
down
3. Step-up,
step-down
GONADOTROPIN PROTOCOLS

• SEQUENTIAL increase in FSH {determine the FSH threshold for
follicular development} and dose is increased till an ovarian
response.
• CONVENTIONAL
• Starting dose: 75-150 IU/d:
• Dose Increased by: 75 IU if response is not seen
• Excessive follicle development
• Increased OHSS
• No longer recommended
Step up

 Stating dose: 37.5-75 IU/d
 Duration of starting dose: 5-7 d
 No follicle development: increase the dose by 100%
 Follicle growth: maintain same dose until follicular selection
is achieved.
LOW DOSE

 The principle is to find the “threshold” level of FSH which will
lead to the development of a single preovulatory follicle .
 Proposed mainly by the ESHRE and ASRM joint consensus
Thessaloniki group to prevent the OHSS
 Starting dose: 37.5 IU
 Duration of starting dose:14 d (90% target achieved)
 The weekly dose increment is by 50% or 37.5 IU
 Serum E2 levels are measured and USG is performed on day
7. If Serum E2 is >200 pg/ml or follicle size is above 10 mm,
the same dose is continued
CHRONIC LOW-DOSE

• Conceived 46%
• Multiple pregnancies34%
• Miscarriages 23%
• Severe OHSS 4.6%
• Results of Conventional Therapy:
14 Series, 1966-1984, WHO I & II
• Low-Dose Gonadotropins:
Summary of Results
Hamilton-Fairley & Franks, 1990

• The step-down regimen is intended to reduce the incidence of OHSS,
but the long half-life of gonadotropin preparations makes it difficult
to judge the proper dosage for maintenance of a lead follicle without
risk of OHSS
Step-Down Protocol

• FSH dependence of leading follicle decreases as follicle grows.
• The 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.
• Start stimulation with low (37.5–75 IU/day) FSH dose, which is
increased by 50 % or 37.5 IU after 14 days if no ovarian
response.
• Thereafter, any further FSH increment is made by 37.5–75 IU at
weekly intervals to a maximum of 225 IU/day.
• Once dominant follicle emerges and reaches a diameter of 14
mm, the dose is reduced by 50 %.
Sequential Regime

In women with PCOS and CC resistance or CC failure, we found no
evidence of a difference in live birth,multiple preg CPR ,misc and
OHSS rates between urinary-derived gonadotrophins and rFSH .
Improvement uncertain between HMG/HP-HMG.
Suggest weighing costs and convenience in the decision to use one
or the other.

Teede.Internationalevidence-basedguideline.
FertilSteril2018.
• ***Gonadotrophins could be used as second line
pharmacological treatment
• ***Gonadotrophins could be considered as first line
treatment, in the presence of ultrasound
monitoring,following counselling on cost and
potential risk of multiple pregnancy, in women with
PCOS with anovulatory infertility and no other
infertility factors.

• ****Gonadotrophins, where available and affordable, should be
used in preference to clomiphene citrate combined with
metformin therapy for ovulation induction, in women with PCOS
with anovulatory infertility, clomiphene citrate-resistance and no
other infertility factors, to improve ovulation,pregnancy and live
birth rates
• ***Gonadotrophin induced ovulation is only triggered when there
are fewer than three mature follicles and needs to be cancelled if
there are more than two mature follicles with the patient advised
to avoid unprotected intercourse.
• STRICT CANCELLATION POLICY

Cost and availability
Expertise required for use in ovulation induction
Degree of intensive ultrasound monitoring required
Lack of difference in clinical efficacy of available gonadotrophin preparations
Low dose gonadotrophin protocols optimize monofollicular development
Risk and implications of potential multiple pregnancy
Teede. Internationalevidence-basedguideline.
Fertil Steril 2018
A low-dose regimen is the ASRM/ESHRE and WHO consensus recommendation
when using gonadotropins in women with PCOS.
Evaluation and Treatment of Polycystic Ovary Syndrome - www.ncbi.nlm.nih.gov LEGRO 2017
Where gonadotrophins are prescribed, considerations include:

O.I agents-- ovulation ,live birth rate.
multiple pregnancy
FSH 88%
Letrozole 86%
CC +
Metformin
75%
Clomiphen
e
51%
LOD 39%
Tamoxifen 36%
Metformin 26%
Placebo 1%
Letrozole 81%
FSH 74%
CC+Metfor
min
71%
Tamoxifen 48%
Clomiphen
e
36%
Metformin 30%
Placebo 10%
FSH 93%
Clomiphe
ne
70%
Placebo 50%
Tamoxifen 46%
CC+Metfo
rmin
44%
Letrozole 34%
Metformi
n
14%
Wang et al
Network
metaanalysis
2017
OVULATION LIVE BIRTH RATE
MULTIPLE
PREGNANCY

Algorithm

A gonadotrophin releasing hormone antagonist protocol is to reduce the duration of
stimulation, total gonadotrophin dose and incidence of ovarian hyperstimulation
syndrome (OHSS).
Human chorionic gonadotrophins is best used at the lowest doses to trigger final
oocyte maturation to reduce the incidence of OHSS.
Triggering final oocyte maturation with a gonadotropin-releasing hormone (GnRH)
agonist and freezing all suitable embryos could be considered with a GnRH antagonist
protocol
Selective freeze of all embryos.
Elective single embryo transfer
IVF

CONCLUSION
• Lifestyle intervention is recommended as the ﬁrst-
line management.
• Ovulation induction using letrozole is the NEXT-
line medical management.
• Gonadotrophins and laparoscopic surgery are
second line
• IVF therapy is the third-line therapy where other
treatments have failed.

THANK YOU FOR YOUR PATIENCE
AND
GOD BLESS YOU
9447044485
drrejimohan@gmail.com

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