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 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. CC Resistant cases: - What other instigations?
Primary infertility with pcod. Did not respond to 100mg of clomiphene. Don't
forget to get 1) AMH 2) What is her age, 3) baseline FSH, 4) LH 5) e2? 6)
What’s the tubal status?
Before going for hmg
is there any other protocol. She is also taking tab. Metformin, &
Myoinositol, N- Acetylcysteine combination for 2-3 months and then tries
induction with 200mg of cc.
For PCOS FSH is
better than hmg..; Cc+metformin or cc+ steroids: As she is already taking
cc+metformin, one may start with cc+inj r-FSH ,to do follicular monitoring and
accordingly add r-FSH/HMG
·
Initial Dose: Treatment with CC is effective only in
patients with sufficient serum estradiol levels After correction of underlying
problems, including those related to stress, exercise and eating disorders,
treatment with gonadotropins is effective in patients with low FSH levels, but
it must be started at a low dose because of the possibility that ovaries
unaccustomed to FSH will be hyperstimulated 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 (see Roy Homburg –p.
76).
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 ideal flow chart for
anovulatory PCOS women? 1) Weight reduction & Metformin 2) CC 4-6
ovulatory cycles 3) Clomiphen e 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. (see Roy Homburg-pp. 80).
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
c m.
Salient
Features of FM.
1)
Per follicle E2 level should be about
150-300pg/ml. per follicle.
2)
Dipstick urine test(home monitoring)-
second morning sample is best, 7 am to
10 am best
3)
FM- when? - Better to commence on day
9.
4)
Doppler Velocimetry- Perifollicular
blood flow- 50-75% wit RI of 0.4 – 0.48
5)
Midluteal P- 1) above 3ng/ml=
evidence of Ovulation. B) IF ABOVE 10NG/ML= ADEQUATE P= Expected to be adequate
luteal LENGTH.
6)
What
is clomiphene check+-- t means after each cycle of failed CC- on subsequent Day
3 USG is done to note Evidence of Cyst. (Residual cyst).
7)
If no conception after 30-4 cycles ten one
may proceed for MG.
8)
If recurrently serum P on Day 21 is < 10
ng.
9)
/ml ten= Vag P must.
10)
Poor
ET- Go for MG/Letroz.
.
Pharmacology:-CC was synthesized in 1956 but therapeutic use in 19961
by Greenblatt. FDA approval in 1967.Trade ratio between En and Zu are 62% and
38%.Chemically CC is drug with contains both estrogen agonist and antagonist
activity. But its main action is estrogen antagonist. But Zuclomiphene is
absorbed slowly and is retained in body for prolonged timeout 85% is excreted
in stool. After administration the enclomiphene is absorbed first and
disappears more rapidly.
A) Mode of Action:-Structural similarity
with estrogens molecule cause competitive occupation of nuclear receptors
naturally designed for estrogens- present in the hypothalamusàCC binds with the
nuclear receptorsàultimately
depletes causes “interference with development/ synthesis of new nuclear
receptorsà
depletion of ERà The
very process of ER replenishment is interfered with”.
B)
Action
at Hypothalamus: - More pulsatile rise of LHRH from Hypothalamusàmore release of
gonadotrophins from Pituitary. Therefore, in summary, GNRH pulsality is
increased after admistration of CC. The point is this in cases of PCOS the
pulse frequency is already highàAfter
CC administration the pulse amplitude is increased, not the frequency. After CC
administration both LH and FSH amplitude rise, but this raised secretion of LH
& FSH fall son after discontinuation of CC. The rise of LH causes more rise of P in the CC-induced cycle-as
such the drug may be used in cases of diagnosed LPD as an initial Ry.
C)
Clinical
Indications of CC: - 1) WHO type II anovulation: - PCOS type. 2) LPD as P
levels are typically higher in CC induced cycles ->which raises improved
preovulatory follicle and good functioning CL development.3) Unexplained
infertility.
D)
Side effects (K. Rao-pp 530). Vasomotor, Visual disturbances, Breast
discomfort,
E)
Adverse
effects of CC on reproductive tract: _ 1) it has some toxicity on ovum,
embryo, ovaries, and ET, Cx mucus that is not clinical significance. In most
cases ET is satisfactory and so also Cx mucus production.
F) What about level of LH level after CC administration?
There is marked increase of LH in proportion to FSH may occasionally
occur. This temporary change in FSH: LH ratio may alter proper growth of
Follicle. ( Source :Balasch J et al Hum Reprod 1995;10:1678-83.Administarion of
Cc for more than 5 days resulted in an initial rise of FSH levels, despite continuation of CC beyond 5
days, whereas LH level remained high throughout the entire treatment
period(Source: Soham Z. “The clinical therapeutic window for LH in COH” Ferti
Steril 2002;77:1170-7.
G) Questionable Indications: - 1)
LPD, 2) Unexplained infertility.
I)
Contraindications: - Ovarian Cysts, Liver diseases.
J) CC insensitive women-What to do?
1)
Add the
followings 1) metformin 2) Glucocorticosteroids 3) Gonadotrophins as an
added agent 5) Anti-oxidants/ ovum nutrients.
2)
Other
alternatives modes of OI: - AI/ Gonadotrophins and sometime ovarian
drilling.
3)
The prevalence of multiple pregnancy:-8%
4)
OHSS:-
5)
Spont. Abortions:-
6)
CM:-
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