Polycystic Ovarian
Syndrome and
Response to
Stimulation
Introduction
Polycystic ovary syndrome (PCOS) is a polygenic, multifactorial
heterogeneous disorder of uncertain etiology.
It is one of the most common endocrine disorders affecting females.
The prevalence of PCOS is around 6–8 % in reproductive age group
females
Stein and Leventhal in 1935 described a symptom complex associated
with anovulation. They reported a subset of patients having
amenorrhea, hirsutism, and enlarged ovaries who resumed
menstruation after bilateral wedge resection of ovaries
Etiopathogenesis of PCOS
In patients of PCOS, there is a steady state of hormone levels with no
fluctuation as compared to normal fluctuations observed in normal
menstruation cycle.
The level of FSH is usually low or normal due to increased inhibition
by estrogen and inhibin B levels. Also, the level of LH is raised. It is the
frequency, not amplitude, that is increased, but there is no cyclic
variation as seen in normal menstrual cycle. The bioavailability of LH
is also increased due to glycosylation, which causes more basic
forms leading to increased bioactivity. Also there is abnormality in
GnRH pulse generator and sensitivity of GnRH to progesterone is
decreased There is decreased dopamine neuronal activity because
of lack of progesterone
Since level of LH is increased, there is increased production of
androgen which does not get converted to estrogen, and there is
increased intraovarian androgen. So, new follicles are recruited
each cycle, but due to lack of estrogen dominance, no dominant
follicle is selected. Anovulation and multiple small follicles of 2–10
mm are present in the ovary giving the PCO morphology on
ultrasound (USG)
Around 40–50 % of PCOS females suffer from insulin resistance and
hyperandrogenemia. Insulin resistance is a condition where
endogenous and exogenous insulin has less than normal effect on
the muscle, fat, and liver. Hyperinsulinemia causes increased
androgen by two mechanisms. It acts through its receptor in ovarian
theca cell and IGF-1 receptor in ovarian theca cell. Also it acts on
the liver and causes decreased production of SHBG leading to
increased level of free androgen
Definition of PCOS
NIHCD (1990)
1) Hyperandrogenemia or hyperandrogenism
2) Menstrual dysfunction
3) Exclusion of other known disorder having a similar clinical presentation
ESHRE/ASRM (2003) 2 of 3 criteria
1) Oligo/anovulation
2) Clinical or biochemical sign of hyperandrogenesim.
3) PCO (12 follicle,2–10 mm,vol 10cc or more) on USG also excluding other causes
of androgen excess
AEPCOS
1) Hyperandrogenism (hirsuitism)
2) Ovarian dysfunction (oligo/anovulation,PCO)
3) Exclusion of other androgen excess related disorder
Clinical Presentation
The features of PCOS can be seen in early childhood as premature
adrenarche, adolescent PCOS, hirsutism, and acne. In a
reproductive age group female, PCOS can present as menstrual
irregularities like amenorrhea, oligomenorrhea, infertility, hirsutism,
and and in postmenopausal women, endometrial hyperplasia
metabolic syndrome
In PCOS women AMH levels are often raised
due to increased number of follicles and
granulosa cells. Women with
hyperandrogenemia tend to have higher
AMH levels. It is found that high AMH levels
inhibit folliculogenesis.
Management
the first line of management in the case of PCOS is weight loss and
more important is the maintenance of the weight loss. Even a loss of 5 %
weight can lead to decrease in irregularities of period and in some
cases resumption of menstruation
Weight loss leads to decrease in free testosterone levels by increasing
SHBG levels
1. Diet calorie restriction of 500 kcal/day is presently recommended
for PCOS female
2. Exercise weekly exercise for 150 min/week along with dietary
restriction with the goal of 5–7 % weight loss leading to decrease in
SHBG and insulin resistance.
3. Pharmacological treatment orlistat which acts by decreasing
intestinal absorption of fatl, Appetite suppressant like sibutramine acts
by decreasing the appetite and has dose-dependent action, Statins
act by inhibiting HMG-CoA reductase enzyme, which is the rate-limiting
step in cholesterol pathway
4. Behavioral treatment increased chances of having depression due
to obesity and infertility.
5. Bariatric surgery obese women with BMI of >35 kg/m
Insulin Sensitizers
Metformin increasing the peripheral uptake of glucose in the muscle
and intestine, starting with a minimum dose of 500 mg per day along
with meals to a maximum level of 1500–2000 mg per day
Thiazolidinediones include rosiglitazone and pioglitazone. They are
less effective than metformin in decreasing insulin resistance and lead
to weight gain and are category C drug in pregnancy
Myoinositol and D-Chiro-Inositol Myoinositol positively modulates
insulin sensitivity in nonobese PCOS patients without compensatory
hyperinsulinemia, improving hormonal parameters.
Ovulation Induction
Problems in Ovulation Induction in PCOS
1. Disturbed folliculogenesis leading to poor response to induction
2. Large number of antral follicles sensitive to FSH leading to multiple
follicular development, OHSS, and multiple pregnancy
3. Tonically elevated serum LH levels leading to premature
luteinization, low pregnancy rates, and high miscarriage rate
Standard therapy: clomiphene citrate is started from
day 2 to day 5 after onset of spontaneous
menstruation or progesterone- induced
menstruation, for 5 days.
case of lean PCOS, the dose is as less as 25 mg/day.
The maximum response is obtained with 150 mg/day.
Combined Therapy : Metformin was prescribed
along with clomiphene citrate in cases of PCOS.
Glucocorticoids Some of the women with
PCOS show involvement of an adrenal
component with raised DHEAS. In these
women glucocorticoids may be given.
Alternative Therapy
Tamoxiphen started with a dose of 40 mg per day from day 2 to
day 6 of cycle and can be increased to 80 mg per day
Aromatase Inhibitor Letrozole is an aromatase inhibitor. It acts by
inhibiting the action of the aromatase enzyme, which converts
androgens to estrogens. The drug is started with 2.5 mg from day 2
of menses for 5 days
Second Line of Treatment
1 Laparoscopic Ovarian Drilling (LOD)
Gonadotrophin and GnRH Analogues
ART will be required in around 20 % of the patients. In vitro
fertilization is a reasonable option for prevention of higher-order
births especially in PCOS patients who are prone for multiple
pregnancy. Patients can start with simple treatment like IUI with
gonadotrophins and then proceed to IVF.