POLYCYSTIC OVARIAN SYNDROME

Polycystic Ovarian Syndrome -
PCOS
Dr Sai Lakshmi Daayana
MBBS, MRCOG, MD, Sub-specialty
training in Gynaecology Oncology
(UK)
Consultant in Surgical Gynaecology
Oncology
Apollo Cancer Institutes, Hyderabad

Abbreviations used
AFC – Antral follicle count
AMH – anti-Mullerian hormone
BMI – Body mass index
GDM – Gestational diabetes mellitus
GTT – Glucose tolerance test
HC – Hormone contraception
IGT – Impaired glucose tolerance test
IVF – Invitro fertilisation
OCP – Oral contraceptive pill
PCOM – Polycystic ovarian morphology
PCOS – Polycystic ovarian syndrome
HA - Hyperandrogenism

What is PCOS?
A multifaceted disease
Involves:
u  Uncontrolled ovarian steroidogenesis
u  Aberrant insulin signaling
u  Excessive oxidative stress
u  Genetic/environmental factors

PCOS
Most common metabolic and reproductive disorders
among women of reproductive age
At increased risk of multiple morbidities, including
obesity, insulin resistance, type II diabetes mellitus,
cardiovascular disease (CVD), infertility, cancer, and
psychological disorders.
Also referred to as hyperandrogenic anovulation (HA)
Stein–Leventhal syndrome

Definition of Polycystic Ovary
Represents a condition in which an estimate of 10
small cysts of a diameter ranging between 2 and 9 mm
develop on one or both ovaries and/or the ovarian
volume in at least one ovary exceeds 10 ml.

Who gets PCOS?
Although it was previously considered as a disorder
of adult women, recent evidence suggests that PCOS
is a lifelong syndrome, manifesting since prenatal age.

Common Symptoms of PCOS
Women suffering from PCOS present with a
constellation of symptoms associated with
menstrual dysfunction and androgen excess.

How to diagnose PCOS?
The Androgen Excess Society defined PCOS as -
hyperandrogenism with ovarian dysfunction or polycystic
ovaries.
Androgen excess is a central event in the
development and pathogenesis of polycystic ovary
syndrome, and established that androgen excess
should be present and accompanied by
oligomenorrhea or PCO or both of them.

When to test for PCOS?
Stop medication around 1 month prior to testing,
along with testing near the luteal phase of the
menstrual cycle for more accurate results.
Testing should include:
BMI
Fasting lipid panel
2-h glucose challenge test
Screening for thyroid disorders

What is clinical hyperandrogenemia?

PCOS - Oligomenorrhoea
Oligo/amenorrhea cycles are defined as 8 or less cycles per
year.
To be diagnosed with PCOS, biochemical androgen
measurements should be fulfilled in the follicular phase in
patients with preserved menstrual cycles.

Causes / triggers for PCOS
Heterogeneous condition
Several factors, such as genetic factors, nutritional
condition in the uterus, prenatal androgen exposure,
insulin resistance, exaggerated adrenarche, and body
weight changes influence the condition.
PCO is the result of different interactions between
genetic and multiple environmental factors.

How to diagnose PCOS in
adolescents?
The main findings at present which indicate
diagnosis of the syndrome at this age are
biochemical hyperandrogenism or clinical
hyperandrogenism with hair excess.

Prevalence of PCOS
Varies according to diagnostic consensus
used, with estimates ranging from 9%
according to National Institutes of Health
consensus, up to 18% with the Rotterdam
consensus.

adolescents?
Early diagnosis in adolescent age group would allow
us for earlier treatment and even prevention of PCO-
associated morbidity
Premature diagnosis carries risks of psychological
distress and unnecessary treatment
The sign of polycystic ovary syndrome during the
post pubertal period overlap with normal physiologic
changes in puberty

adolescents?
A high rate of menstrual and anovulatory cycles could be
observable in this age group
A very common complaint is acne during adolescence
But alopecia is one of the rare phenomena in girls.......

Differential diagnosis of PCOS
§  Non-classical congenital adrenal
hyperplasia (NC-CAH)
§  Cushing’s syndrome
§  Androgen-secreting tumors
§  Hyperprolactinemia
§  Thyroid diseases
§  Drug-induced androgen excess
§  Other causes of oligomenorrhea or
anovulation

PCOS & AMH
Serum AMH is synthesized by small antral follicles,
which are precisely the ones seen in ultrasound.
Antral follicle count (AFC) on ultrasound as one of
the diagnostic criteria. Day by day technology of
ultra-sonography improves and accuracy of
ultrasonography devices increases, so the number of
follicles seen in ultrasonography increase too, but
remain dependent on the specific equipment....
It can be difficult to count antral follicles trans-
abdominally in virgins or obese.

PCOS & AMH
Serum AMH is synthesized by small antral follicles,
which are precisely the ones seen in ultrasound.
There is a need for objective parameters, and the
serum AMH level could be useful for diagnosis of
PCOS.

PCOS & AMH
There is a problem to solve; the absence of a
worldwide standard for serum AMH assay and
inability to define thresholds make application of
serum AMH level more difficult.

What is AMH?
AMH is a member of transforming growth factor-beta (TGF-
β) superfamily. It is secreted by the granulosa cells of small
antral and pre-antral follicles to regulate early follicular
development.
AMH expression starts around the 25th week of gestation
and continues until menopause.
AMH also has minimal inter- and intracycle variability.
AMH serum levels are closely correlated with the number of
early antral follicles in both healthy women and women with
PCOS and it is mostly produced by granulosa cells of follicles
from 2 to 9 mm in diameter (60%) precisely the ones seen in
ultrasonography.

What is AMH?
Serum AMH level has more sensitivity than the AFC because
it also reflects pre-antral and small antral follicles (< 2 mm)
which are hardly seen in ultrasound, therefore it is a deeper
vision for growing follicular pool than the AFC.
So AMH could be noticed as a suitable hormonal marker of
the ovarian follicular count and we can assume that serum
AMH level is an indirect reflection of ovarian reserve. So
serum AMH level could be replaced by AFC and PCOM.

Facts about AMH
Plasmatic level of AMH is quite stable from one cycle to
another
AMH level is independent from the hypothalamus-pituitary
axis
AMH can be influenced by some factors. Obesity is
sometimes associated with a significantly lower level of
serum AMH

Facts about AMH
A positive correlation between serum androgen and AMH
levels has been reported and the production of androgens
could be on intrinsic defect of thecal cells in PCOS.
Most researchers agree that AMH should be considered as a
marker for increased ovarian reserve.
Impaired folliculogenesis may cause excess accumulation of
pre-antral and small antral follicles, which may ultimately
cause the increased AMH levels associated with PCOS.

Metformin Therapy for the Management of Infertility in
Women with Polycystic Ovary Syndrome (Scientific Impact
Paper No. 13)
Published: 23/08/2017
Metformin inhibits the production of hepatic
glucose, decreases lipid synthesis, increases fatty
acid oxidation and inhibits gluconeogenesis resulting
in a decrease in circulating insulin and glucose.

Metformin Therapy for the Management of Infertility in
Women with Polycystic Ovary Syndrome (Scientific Impact
Paper No. 13)
Published: 23/08/2017
Metformin enhances insulin sensitivity at the cellular
level and also appears to have direct effects within
the ovary. Therefore, it would seem logical to
anticipate that insulin lowering and insulin-
sensitising treatments, such as metformin, should
improve symptoms and reproductive outcomes for
women with PCOS.

Ovarian hyperandrogenism
In women of normal weight, ovarian
hyperandrogenism is driven primarily by luteinising
hormone.
In women who are overweight, insulin may augment
the effects of luteinising hormone by amplifying the
secretion of androgens by the ovaries.

Insulin resistance in PCOS
Insulin also suppresses the secretion of sex hormone‐binding
globulin by the liver, leading to increased levels of free
circulating testosterone.
Women with PCOS are more insulin resistant than weight‐
matched women who do not have the syndrome.
Insulin resistance (IR) is seen in approximately 10–15% of
slim and 20–40% of obese women with PCOS, and women
with PCOS are at increased risk of developing type II
diabetes.

Insulin Resistance & Weight
The more overweight an individual the greater the
degree of IR. Maternal weight can have a profound
effect on both natural and assisted conception,
influencing the chance of becoming pregnant and
the likelihood of a healthy pregnancy.
Studies have demonstrated higher rates of preterm
birth, miscarriages and low birth weight in babies
born to obese versus normal weight women with
PCOS.

Facts about metformin
The use of metformin is consistently associated with
more adverse effects compared with clomiphene
citrate or placebo, particularly nausea, vomiting and
other gastrointestinal disturbances.
Large proportion of women in the metformin group
discontinue treatment because of adverse effects.
The use of long‐acting preparations may help to
reduce gastrointestinal adverse effects.

Facts about metformin
The optimal regimen for metformin has not been
determined; doses of between 500 mg/day and
3000 mg/day have been used, with the most
common regimens being 500 mg three times daily
or 850 mg twice daily.
It is also not clear whether the dose should be
adjusted for body weight or other factors.

Metformin for PCOS
related obesity
Lifestyle improvement and supporting women with
individualised assessment, setting goals and using a
combination of diet and exercise remains the first‐
line approach.

Metformin for Ovulation
Induction
Metformin compared to clomiphene in women
with a BMI under 32 kg/m2 reported no
difference between metformin and
clomiphene citrate in terms of ovulation,
pregnancy, live birth, miscarriage and
multiple pregnancy rates.

Metformin in Pregnancy
Metformin appears to be safe in pregnancy,
however the usual advice is to discontinue
post conception with the exception of those
with diabetes.

Failure to Clomiphene
Ovulation Induction in PCOS
Women with PCOS who have not responded to
clomiphene citrate may be offered one of following
second‐line treatments:
•  Laparoscopic ovarian drilling
•  Combined treatment with clomiphene citrate and
metformin, if this has not already been given as a
first‐line treatment, or
•  Gonadotrophins

Metformin with IVF in PCOS
Women on long GnRH protocol - significantly
reduced risk of ovarian hyperstimulation syndrome
(OHSS) when metformin is used.
The short GnRH antagonist protocol is
recommended for women at risk of OHSS, for which
the role of metformin is unclear.

Women with PCOS are at increased risk of
pregnancy‐related complications, including
gestational diabetes, pregnancy‐induced
hypertension, pre‐eclampsia and neonatal
morbidity. In view of the favourable effects of
metformin on metabolic, cardiovascular and
thrombotic events in the diabetic population,
it would seem feasible that outcomes could be
improved in PCOS pregnancies with
metformin.

No improvement in these complications with continued use of
metformin throughout pregnancy was found, although there
appeared to be a nonsignificant trend toward reductions in
late miscarriage and preterm delivery rates, which is now the
subject of a large ongoing randomised controlled trial.
Metformin has a good safety profile in pregnancy, with no
evidence of teratogenicity.

Other insulin‐sensitising
drugs
There is insufficient evidence to recommend
the use of other insulin sensitisers, such as
thiazolidinediones (glitazones), d‐chiro‐
inositol and myo‐inositol, in the treatment of
anovulatory PCOS.
Newer insulin‐sensitising agents, such as
glucagon‐like peptide 1 (GLP‐1) analogues
(e.g. exenatide and liraglutide), are currently
under investigation.

Role of Metformin in PCOS
Metformin appears to have a limited role in
improving reproductive outcomes in women
with PCOS, although there may be a benefit to
using metformin in specific patient groups,
for example in obese women when combined
with clomiphene citrate, those with
clomiphene citrate resistance, and those who
have been found to have either IGT or type II
diabetes.

1. Age at which PCOS is commonly diagnosed is
q  18 to 44 years
q  Less than 13 years
q  More than 50 years

2. A positive family history and excess insulin
secretion by the pancreas are thought to play a role
in the etiology of polycystic ovarian syndrome.
q  True
q  False

3. Which of the findings listed below that occur in
PCOS are attributable to hyperandrogenism
(elevated testosterone levels)
q  Weight loss in spite of increased appetite
q  Excess body and facial hair
q  Tall stature

4. PCOS was first described by
q  Louis Pasteur
q  Stein and Levinthal
q  Pavlov

5. The major reason for women with PCOS to suffer
from infertility is
q  Obesity
q  Anovulatory menstrual cycles
q  Excess insulin levels

6. Women suffering from PCOS are at an increased
risk of developing
q  Diabetes
q  Dyslipidemias (elevated cholesterol and lipid
abnormalities)
q  Endometrial (uterine) cancer
q  All of the above

7. Diagnostic imaging tests done in suspected
PCOS include
q  Pelvic ultrasound
q  Transvaginal ultrasound
q  MRI
q  All of the above

8. The diagnostic criteria employed for the
diagnosis of PCOS is termed
q  Framingham criteria
q  Nottingham criteria
q  Rotterdam criteria

9. The choice of treatment for symptoms of
androgen excess such as excess body and facial
hair, is which of the following?
q  Thyroxine
q  Oral contraceptive pills
q  Metformin

10. The drug of choice to treat PCOS associated
infertility is
q Clomiphene citrate
q Metformin
q Letrozole

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