Ayodda Ram Temple
solved :-How many of Indian Gynaecologits believe :-1) Weight loss reduces 30 % of visceral fat , this regains
reproductive functions in 60-100 % of
cases but
it is equally important to remember that that a normal weight
PCOS patient may not
benefit from weight loss. 2) Findings
of two RCTs indicated that metformin does not increase live birth rates above
those observed with CC alone and
There as no clear evidence that addition of metformin to CC as a primary therapy for
induction of ovulation has a
beneficial effect. (ESHRE/ASRM 2007 consensus).: 3) When metformin is used as
the only drug for ovulation induction
in PCOS patients the live birth rate is only 7.2% as compared to that with CC which is 22.5% .4) Mwetformin :-Its
action is gradual and within
six months it establishes ovulatory cycles by decreasing
insulin and androgen level 5) Its
action is gradual and within
six months it establishes ovulatory cycles by decreasing
insulin and androgen level
PCO:: Principles of
treatment :
Treatment Modality
in PCOS:
1.
Weight loss is
always the first line of treatment. Central obesity is more
common to cause metabolic changes.
In PCOS
waist: hip ratio is 0.7-0.8 : Normal BMI :--(Normal
: 20 -24.9 kg/ m2, Overweight : 25-29 kg/ m2 ,Obese : > 30 kg / m2 )
. An even a meager 5-10% of weight loss is important to improve metabolic
abnormalities & also induce
ovulation when married . Weight loss reduces 30 % of visceral fat , this regains
reproductive functions in 60-100 % of
cases. Weight loss
reduces hyperinsulinemia, hyperandrogenemia and increases the SHBG. It improves
the sensitivity for ovulatory drugs.
It reduces clomiphene resistance
and therefore cost of treatment.
Weight loss decreases the rate of
abortions.
2.
Insulin
lowering drugs :
Combating:-Insulin resistance in
PCOS patients causes hyperinsulinemia
which in turn stimulates theca cells of the ovary to secret more androgen. More than
50-80 % of PCOS patients have insulin resistance. Insulin sensitizers
like metformin are therefore used in PCOS patients. Earlier metformin was thought to be a useful drug for
ovulation induction in PCOS
patients . But recent
reports indicate that when metformin is used as the only
drug for ovulation induction in PCOS patients the live birth rate is only 7.2% as compared to that with CC which is 22.5% . It has also been
proved that metformin does not lower the dose of
CC required when it is used in combination with CC. CC therefore
is the most appropriate first line
of treatment for ovulation induction in PCOS patients. Metformin for young patients : These patients
with PCOS have a long timeline to achieve pregnancy . it is a drug of choice in PCOS patients
who do not want to conceive immediately . Its action is gradual and within six months it establishes ovulatory cycles by decreasing
insulin and androgen level.
Other advantage of metformin is that it decreases the incidence of multiple
pregnancies with ovulation induction drugs. If the patient does not conceive when on metformin option of CC remains open for her. Its action is gradual and within
six months it establishes ovulatory cycles by decreasing
insulin and androgen level Its action is gradual and within
six months it establishes ovulatory cycles by decreasing
insulin and androgen level Metformin alternatives :
Insulin sensitizers pioglitazone and rosiglitazone and
other drugs like acarbose
or D chiorinositol have not found to be
superior over metformin and so
their routine use for infertile patient
has not been established. Findings of two
RCTs indicated that metformin does not increase live birth rates above
those observed with CC alone.
ESHRE/ASRM 2007 consensus:
a.
There as no clear evidence that addition of metformin to CC as a primary therapy for
induction of ovulation has a
beneficial effect.
Metformin use in PCOS
should be restricted to
women with glucose intolerance
and frank type II diabetes.
Aim: Ovulation
induction in PCOS requires careful assessment of patient and specific therapy
to induce ovulation and decrease LH which is detrimental to ova. Reduction in
circulating insulin is also required in some patients to get better ovulation.
1.
Weight loss
2.
Clomiphene
3.
Letrozole
4.
Insulin lowering drugs
5.
Glucocorticoids
6.
Gonadotrophins
7.
GnRh antagonist
8.
GnRh agonist
9.
Ovarian drilling
10.
IVF/
IVM
3.
Weight
loss :
It is extremely difficult for the patient to lose weight. So
it should always be emphasized in each meeting. The treatment
for weight loss includes diet exercise
group therapy behavioural counseling pharmacological treatment and bariatric surgery. So it is a
team work that is required to help
the patient to loose weight.But it
should be remembered that a normal
weight PCOS patient may not benefit from weight
loss.
4.
Clomiphene
citrate:
CC induces ovulation in 70-% to 80% of cases with
30-40 % pregnancy rate
and gives 30% cumulative live
birth rate. The main advantage is that
70-80 % of patients may conceive in 3 cycles. Pregnancy
rates are the same whether CC is
started on day 2-3-4-5 . The dose
of > 150 mg has only 10
% pregnancy rates
and Prof Bruno Lunenfield recommends a dose of only 100 mg / day for 5 days.CC acts on hypothalamus to secrete
GnRh which in turn gives FSH and LH. In PCOS patients LH is otherwise also high. Therefore CC is continued after first cycle only if on day 8-9 of the cycle LH < 10 iu, in the first cc cycle. This is because high LH
reduces the conception rate and increases the abortion rate. CC only in women who have
LH values of < 10 IU on day 8/day 9 of cycle.
5. Letrozole
This is a very good alternative to CC. It causes hypooestrinism and hyperandrogenism. Because of fall in oestrogen levels it leads to rise in FSH and LH levels
that stimulates follicular development.
The resultant rise in oestrogen has negative
feedback mechanism and it
reduces FSH and LH thus allowing monofollicular development. Hyperandrogenism caused by
letrozole increases the sensitivity of the follicle to FSH .
therefore letrozole with
gonadotrophins is a synergistic
combination,.
The indications of letrozole are :
a.
CC
resistant cases
b.High baseline E2
c.
Anti
oestrogenic effect of CC on endometrium
d.
High day 8-9 LH, > 10 iu
e.
With gonadotrophins
There are several
reports which indicate that letrozole is better than CC for ovulation induction in PCOS and some reports
that have shown that letrozole is at least
as effective as CC for ovulation
induction . All in all the advantages of letrozole are monofollicular development
lesser
incidence of multiple pregnancy lesser
risk of OHSS and lower abortion rates due to fall in LH levels.
6.
Insulin lowering
drugs :
Insulin resistance in PCOS patients causes hyperinsulinemia which in
turn stimulates theca cells of the
ovary to secret more androgen. More than 50-80 % of PCOS
patients have insulin resistance . Insulin sensitizers like metformin are therefore used in PCOS patients. Earlier metformin
was thought to be a useful drug
for ovulation induction in
PCOS patients . But recent reports indicate
that when metformin is used
as the only drug for ovulation induction in PCOS patients the live birth rate is only 7.2% as compared to that
with CC which is 22.5%
It has also been proved
that metformin does not
lower the dose of CC required
when it is used in combination
with CC.
CC alone is therefore is the most
appropriate first line of treatment
for ovulation induction in
PCOS patients.
Findings of two RCTs
indicated that metformin does
not increase live birth rates above
those observed with CC alone.
ESHRE/ASRM 2007 consensus:
b.
There
as no clear evidence that addition of metformin to CC as a primary therapy for
induction of ovulation has a
beneficial effect.
c.
Metformin use in PCOS
should be restricted to women
with glucose intolerance and frank type II
diabetes.
Metformin + Gonadotrophins
Addition of
metformin to gonadotrophins has no advantage
in improving ovulation rates pregnancy rates live birth
rates multiple pregnancy rates or
incidence of OHSS.
Metformin in IVF :
There are several papers that indicate no difference in
metformin and non metformin group in pregancy rate in IVF patients.
Metformin after conceptions :
Safety of
metformin in pregnancy has not been
established. A large
prospective randomised controlled
trial has shown that when
metformin is continued in
early pregnancy does not
decrease the miscarriage rate. Metformin crosses
the placenta and significant
level is found in fetal
serum , therefore metformins
should be stopped after the
pregnancy test until more
consistent data are available.
Metformin for young
patients
: These patients with PCOS
have a long timeline to
achieve pregnancy . it is a drug of choice in PCOS patients
who do not want to conceive immediately . Its action
is gradual and within six months
it establishes ovulatory cycles
by decreasing insulin and androgen level. Other advantage of
metformin is that it decreases
the incidence of multiple
pregnancies with ovulation induction drugs. If the patient does not conceive when on metformin option of CC remains open for
her A recent metaanalysis
revealed that metformin does not
result in weight loss among overweight
and obese PCOS patients.
Metformin alternatives
: Insulin sensitizers pioglitazone and rosiglitazone and
other drugs like acarbose or D
chiorinositol have not found to be superior over metformin and so their routine use for infertile patient
has not been established.
Clomiphene
citrate + glucocorticoids
50% of PCOS
patients have adrenal component
in hyperandrogenism which is
evidenced by increased DHEA-S which
is entirely from zona reticularis
of adrenal cortex. These are the patients who are
resistant to 150 mg of CC and
require higher doses of
goandotrophins. They respond well
with dexamethozone 0.5 mg daily for 3-6 months along with CC. Water
logging because of the
drug can be reduced by adding
diuretics once a week or decreasing the dose of
dexamethasone to 0.25 mg or one
may also discontinue the drug after ovulation . Serious complications are extremely rare and so this drug must be
tried on obese PCOS. `
Gonadotrophins
Gonadotrophins are indicated in patients with CC failure with high LH
and having antiestrogenic effect of CC.So the bioactivity of uFSH – HP
and rFSH is always higher than other
preparations and dose required
will be also less of these preparations. rFSH has advantages over uFSH . These are :
a.
FSH inhibiting
substances are absent in rFSH
b.
rFSH
has more basic isoforms
c.
rFSH has higher
consistency
d.
rFSH has only
10 % degenerated forms
e.
rFSH has less
batch to batch variations
f.
rFSH will
be released on basis of
mass.
g.
rFSH needs
lower dosage.
h.
rFSH gives
more embryos and allows for
cryopreservation which increases the
cumulative pregnancy rate.
i.
rFSH can be self
administered subcutaneously
rFSH
versus HMG :
In PCOS patients LH level is always on higher side. So by adding LH through HMG will increase the LH level which is
detrimental to ova &
fertilization. So in PCOS only
rFSH or FSH – HP should be used which
are without LH activity . Metaanalysis of eight
randomized controlled trials
conforming rFSH with HMG
has shown that rFSH has 50 %
higher pregnancy rates . The FINVAT report
1999 also showed that the pregnancy rates were higher with rFSH than
with HMG. The prospective
study of 24000 ART cycles from
Germany also showed higher
birth rate and lower dosage with rFSH than HMG.
So, we can conclude that rFSH
is always better for ovulation
induction than HMG.
rFSH / Highly
purified HMG
the process of purification is partially successful with specific activity
of 2000 iu / mg of protein for HMG – HP
. In many cases hCG has to be
added to maintain LH activity hCG
has longer biological half life. Presence of variable amount of
hCG may further increase variation between different batches of product and result in follicular
atresia. HMG- HP contains 30
5 extraneous protein including
leucocyte elastase
inhibitor protein C inhibitor and Zn- B2
glycoprotein apart form hCG. So rFSH is better than HMG
- HP in clinical practice 
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