Revision Class of Uncle on Clomiphene Citrate.- Selection of cases: - Anovulatory PCOS with normal
oestradiol levels who clinically exhibit irregular periods or absent periods (anovulation).
The commonest cause i s A) HP
dysfunction-i.e. WHO Group II anovulatory disorders. Absent or irregular
periods with normal serum oestradiol. Majority are of course PCOS women. This
resets the ovulation in order. It acts primarily on hypothalamusàthereby changes the pattern of pulsatile gonadotrophin-RH
in order.
Initial Dose: It does not matter whether one initiates on day
2/3/4 or day 5 of cycle. Most favour 50/100 mg dosage. The advantage of initiating
100 mg dosage is that by initiating with 100 mg one can diagnose which cases
are CC resistant by 3 cycles and thereby minimize the superfluous cycles.
When to move o to other
modality of treatment? One should wait at least for six ovulatory cycles before
switching over to complex modality of treatment e.g. Gonadotrophins/ IVF. By allowing six chances
of six ovulatory cycles-when one can almost be certain that CC will not work.
As a matter of fact as many as 75% of CC induced successful pregnancies occur
by third cycles. There are only few records where pregnancy has occurred after
seven ovulatory cycles. But if after one / two cycles repeatedly ET become thin
ie < 8 mm –it will be better to move on to gonadotrophins.
Results
& outcome: - In as many as 80% of cases there will be
ovulation and pregnancy will occur in 35-40% of women. Why so discrepancy
between ovulation rate and pregnancy rate? This is explained by the fact that
1) Thinning of endometrium 2) Thickening of cervical mucus in 15% of casesà may proceed for IUI. The chance of conception is poor
if ET s < 8 mm. Why there is thinning of ET is not clearly known but appears
to be unrelated to dosage & duration of Ry. May be it is idiosyncratic in
nature.
What to do if in first cycle there is
thinning of ET < 8 mm? It is
unlikely that in next cycles there will be improvement of ET. It is better to
switch over to gonadotrophins in second cycle
Prevalence of Cyst formation? In most cases the cyst formation after CC is due to
hyper response has to be halved. In such cases of extreme sensitivity àthe dosage may have to be halved.
Prevalence of CC Resistance? As
many as 20-25% of women with normal FSH (No DOR) - will be eventually CC
Resistant. CC resistance is more commonly seen in women with 1) IR, (metformin)
2) Obese women, 3) hyperandrogenic (Dexa). Those with 4) high LH (pretreatment
with Progesterone) also respond poorly to CC. Therefore one can add Metformin
to lower the hyperinsulinaemia / add Dexamethasone to curtail adrenal androgens
where hyperandrogenism is the cause / choose for pretreatment with micronised Progesterone if LH is very
high.
Multifollicular growth of Follicles in
CC induced cycles? : - As many as
60% do exhibit multifollicular growth as hypothalamus is blocked by CC. Therefore
rise of E2 in midfollice do not block the release of GNRH fro hypo-. As such
pulses will be there and FSH level will not be stopped as usually is the cases
in natural cycles where rising Serum E2 inhibits GNRH receptors.
When to ask for refraining from intercourse? If two follicles are above 14 mm then asking them to
use condom-otherwise multiple gestation will follow.
Prevalence of OHSS: _ never occurs with CC. But slight enlargement of
ovaries may ensue...
How to know that ovulation is occurring? –By simply performing day 21 (supposed midluteal phase) serum
progesterone assay. But serial USG is
better because if there are multiple follicles are coming up then multiple
pregnancy can be avoided by refraining
from intercourse.
Is USG necessary? Yes. The benefit of serial USG is that those who were
duly monitored and concerned doctor reacted according to variations in
follicular growth pattern, scheduling intercourse/IUI/ Inj
HCG- and poor ET-in
such cases the preg rate was slightly higher e.g. 48% rather than 35%
who were not monitored. The most
important benefit of USG monitoring that by careful monitoring one can quickly
move on to other modalities of Ry. This will reduce the total cost of
infertility Ry.
What about triggering with HCG? Many considerthat
it is beneficial even in CC cycles as it ensures definite LH surrogate surge if
administered after the follicle attains the size of 19-24 mm. What can be done
that one can proceed for LH surge is delayed, protracted or even absent in some
cases even when the Follicle is ready.
LH urine test may replace HCG in such cases.
What pretreatment can be done? What are the
ill effects of CC? CC forces
hypothalamus to release the GnRH pulse frequency from hypothalamus. This action
on hypothalamus and pituitary not only increase the FSH but LH too which is
already raised. To curtail the raised basal LH one can prescribe micronised
progesterone as pretreatment.
What about Metformin
pretreatment? Though theoretically seems to be sound combination but in
practice it has been evidenced that addition / pretreatment with metformin do
not increase the ovulation rate or preg rate too much. But may be tried in CC
resistant women. Some believe metformin should be given a fair trial along with
CC before we proceed for more costly HMG therapy in CC resistant women.
How metformin does exert
its action in PCOS women? It is needless to mention that most women who are
selected for CC are cases of anovulatory PCOS with some degree of IR. Metformin
lowers the serum insulin levels. Metformin also causes decrease of serum
Testosterone, LH, & increase in SHBG...l
What is the prevalence of absent LH surge
despite presence of good follicle? Not known.
What about adding
Dexamethasone 0.5 mg at bedtime? It may be used when there is evidence if
hyperandorgenism or proven raised value of serum DHEASO4. But many believe that
it should only be reserved for proven CAH
cases. As it causes weight gain and
increase in appetite it should better be reserved for CC resistant women.
Is there any rationality of prescribing
CC in unexplained subfertity: In
cases of unexplained infertility IVF is better option? If CC is used then per
cycle the preg rate is only 5.6% (slightly superior to TI) but increase
slightly to 8.3% f IU is added in combination. Nowadays nobody treats such
unexplained infertility women with CC.
What should be ideal flow chart for anovulatory PCOS women? 1) Weight
reduction & Metformin 2) CC 4-6 ovulatory cycles 3) Clomiphene Failure: Add metformin if not added. à Low dose FSH alone for 4-6 ovulatory cycles: Thereafter
either advises for IVF or LOD if age is < 30yrs.
Letrozole vs Clomiphene: - Pregnancy rate was 27.5% vs only 25% by CC alone.
But twining rate was 7.4% but in letrozole group it was 3.2% with no added risk
of cong malformation...
Clomiphene
Citrate.-Roy Homburg.
Selection of cases: -
Anovulatory PCOS with normal oestradiol levels who clinically exhibit irregular
periods or absent periods (anovulation). The commonest cause i s HP
dysfunction-i.e. WHO Group II anovulatory disorders. Absent or irregular
periods with normal serum oestradiol. Majority are of course PCOS women. This
resets the ovulation in order. It acts primarily on hypothalamusàthereby changes the pattern of pulsatile gonadotrophin-RH in
order.
Initial Dose: It does
not matter whether one initiates on day 2/3/4 or day 5 of cycle. Most favour 50/100
mg dosage. The advantage of initiating 100 mg dosage is that by initiating with
100 mg one can diagnose which cases are CC resistant by 3 cycles and thereby
minimize the superfluous cycles.
When to move o to
other modality of treatment? One should wait at least for six ovulatory
cycles before switching over to complex modality of treatment e.g. Gonadotrophins/ IVF. By allowing six chances
of six ovulatory cycles-when one can almost be certain that CC will not work.
As a matter of fact as many as 75% of CC induced successful pregnancies occur
by third cycles. There are only few records where pregnancy has occurred after
seven ovulatory cycles. But if after one / two cycles repeatedly ET become thin
ie < 8 mm –it will be better to move on to gonadotrophins.
Results & outcome:
- In as many as 80% of cases
there will be ovulation and pregnancy will occur in 35-40% of women. Why so
discrepancy between ovulation rate and pregnancy rate? This is explained by the
fact that 1) Thinning of endometrium 2) Thickening of cervical mucus in 15% of
casesà
may proceed for IUI. The chance of conception is poor if ET s < 8 mm. Why
there is thinning of ET is not clearly known but appears to be unrelated to
dosage & duration of Ry. Maybe it is idiosyncratic in nature.
What to do if in
first cycle there is thinning of ET < 8 mm? It is unlikely that in
next cycles there will be improvement of ET. It is better to switch over to
gonadotrophins in second cycle
Prevalence of Cyst
formation? In most cases the cyst formation after CC is due to hyper
response has to be halved. In such cases of extreme sensitivity àthe dosage may have to
be halved.
Prevalence of CC Resistance?
As many as 20-25% of women with normal FSH (No DOR) - will be
eventually CC Resistant. CC resistance is more commonly seen in women with 1) IR, (metformin)
2) Obese women, 3) hyperandrogenic (Dexa). Those with 4) high LH (pretreatment
with Progesterone) also respond poorly to CC. Therefore one can add Metformin
to lower the hyperinsulinaemia / add Dexamethasone to curtail adrenal androgens
where hyperandrogenism is the cause / choose for pretreatment with micronised Progesterone if LH is very
high.
Multifollicular
growth of Follicles in CC induced cycles? : - As many as 60% do exhibit
multifollicular growth as hypothalamus is blocked by CC. Therefore rise of E2
in midfollice do not block the release of GNRH fro hypo-. As such pulses will
be there and FSH level will not be stopped as usually is the cases in natural cycles
where rising Serum E2 inhibits GNRH receptors.
When to ask for
refraining from intercourse? If two follicles are above 14 mm then asking
them to use condom-otherwise multiple gestation will follow.
Prevalence of OHSS:
_ never occurs with CC. But slight enlargement of ovaries may ensue...
How to know that
ovulation is occurring? –By simply performing day 21 (supposed
midluteal phase) serum progesterone assay.
But serial USG is better because if there are multiple follicles are
coming up then multiple pregnancy can
be avoided by refraining from intercourse.
Is USG necessary?
Yes. The benefit of serial USG is that those who were duly monitored and
concerned doctor reacted according to variations in follicular growth
pattern, scheduling intercourse/IUI/ Inj HCG- and poor
ET-in such cases the preg rate
was slightly higher e.g. 48% rather than 35% who were not monitored. The most important benefit
of USG monitoring that by careful monitoring one can quickly move on to other
modalities of Ry. This will reduce the total cos of infertility Ry.
What about
triggering with HCG? Roy Homburg considers that it is beneficial even
in CC cycles as it ensures definite LH surrogate surge if administered after the
follicle attains the size of 19-24 mm. What can be done that one can proceed
for LH surge is delayed, protracted or even absent in some cases even when the
Follicle is ready. LH urine test may
replace HCG in such cases.
What pretreatment
can be done? What are the ill
effects of CC? CC forces hypothalamus
to release the GnRH pulse frequency from hypothalamus. This action on
hypothalamus and pituitary not only increase the FSH but LH too which is
already raised. To curtail the raised basal LH one can prescribe micronised
progesterone as pretreatment.
What about
Metformin pretreatment? Though theoretically seems to be sound
combination but in practice it has been evidenced that addition / pretreatment
with metformin do not increase the ovulation rate or preg rate too much. But
may be tried in CC resistant women. Some believe metformin should be given a
fair trial along with CC before we proceed for more costly HMG therapy in CC
resistant women.
How metformin does
exert its action in PCOS women? It is needless to mention that most
women who are selected for CC are cases of anovulatory PCOS with some degree of
IR. Metformin lowers the serum insulin levels. Metformin also causes decrease
of serum Testosterone, LH, & increase in SHBG...l
What is the
prevalence of absent LH surge despite presence of good follicle? Not known.
What about adding
Dexamethasone 0.5 mg at bedtime? It may be used when there is evidence
if hyperandorgenism or proven raised value of serum DHEASO4. But many believe
that it should only be reserved for proven CAH cases. As it causes weight gain and increase in
appetite it should better be reserved for CC resistant women.
Is there any
rationality of prescribing CC in unexplained subfertity: In cases of
unexplained infertility IVF is better option? If CC is used then per cycle the
preg rate is only 5.6% (slightly superior to TI) but increase slightly to 8.3%
f IU is added in combination. Nowadays nobody treats such unexplained
infertility women with CC.
What should be the
ideal flow chart for anovulatory PCOS women?
1) Weight reduction &
Metformin 2) CC 4-6 ovulatory cycles 3) Clomiphenee Failure: Add metformin if
not added. à
Low dose FSH alone for 4-6 ovulatory cycles: Thereafter either advises for IVF
or LOD if age is < 30yrs.
Letrozole vs Clomiphene:
- Pregnancy rate was 27.5% vs only 25% by CC alone. But twining rate was 7.4%
but in letrozole group it was 3.2% with no added risk of cong malformation...
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