Posted 1-5-19
A quick review on
a common drug i.e clomiphene citrate-Its
Indications and rational use and some kind of trade Off use
Clomiphene citrate is indicated for the treatment of anovulation in
women with ovulatory dysfunction(WHO Class II) in women desirous pregnancy.
Q. 1 Can
it be prescribed in males?? There are no adequate or well-controlled
studies that demonstrate the effectiveness of in the Clomiphene citrate
treatment of male infertility. In addition, testicular tumors and gynaecomastia
have been reported in males using clomiphene. The cause and effect relationship
between reports of testicular tumors and the administration of Clomiphene citrate is not known with certainty.
Q,.2: What tests should ideally precede prior to prescribing CC in women
who can afford proper investigations, noninvasive in particular ?? Ans; zuclomiphene
(cis) has a longer half-life than enclomiphene (trans). Enclomiphene
is claimed to be more potent and responsible for Ovulation induction
effect. Besides life time is also short.
Other impediments to achieving pregnancy must be excluded or adequately treated
before beginning CC therapy. But if the female partner is young
say < 23 yrs of age and trying time is less than 1 yr then tubal patency tests
or some invasive tests may be omitted for couple of cycles of CC . H semen analysis and few basic tets for
fitness of pregancy like STI, Viral Screen, basal scan should be considered as
an initial step.
Q3 . Who are most likely to respond?? Ans: Those patients most likely to achieve success with
clomiphene therapy include patients with polycystic ovary syndrome ( WHO class II anovulatory disorders) where
anovulation/ infrequent ovulation ( oligoovulation/ delayed ovulation) is due to hypothalamo pituitary ovarian
dysfunction with near normal gonadotrophin level. But in WHO class I anovulation gonadotrophins
are low as is serum oestradiol.
Q4: who may not respond well but there is no harm in
trying 1-2 cycle of CC as trial basis?? Ans:
It s a trade off and occasionally ovulation may ensue. For instance CC can
rarely of help in women 1) who had hyperstimulation with gonadotrophins, 2) amenorrhea-galactorrhea
syndrome, 3) psychogenic amenorrhea, 4) post-oral-contraceptive amenorrhea, 5) certain
cases of secondary amenorrhea of undetermined etiology. 6) Reduced estrogen
levels,(Low ET on basal SCAN) . All such
cases , while less favorable, do not preclude successful therapy specially in
young couple.
Q 5 : What Lab tets must precede prior to commencing CC?? Ans:-a) LFT, b) A day 3 Pelvic scan(better still in previous cycle
which is often termed as Evaluation cycle) to exclude myoma, Ovarian cysts. A conscientious
sonologist and high quality scan machine can pick up
endometrial polyp, synechiae, adenomyosis, congenital abnormalities of uterus (either septal diosrder or duplication
disorders-) c) TSH, d) PRL .Besides other genital tract impediments
to conception like gross PID or systemic
diseases like (renal, hepatic, DM, Hypothyroid etc) to achieving pregnancy must be excluded or
adequately treated before beginning Clomiphene citrate
therapy.
Q.6: What
may go wrong during CC ? What may be side effects?? Ans:-There are some rare risks which
are : 1)Ovarian Hyperstimulation Syndrome 2) very rarely reversible eye changes
as is observed in few cases of eclampsia.
Q. 7 .What spl
advice to offer to couple ??
Properly timed coitus in relationship to ovulation is important. An urinary LH
kit may be of help so that the patient and her physician realizes that drug has
responded by causing ovulation .Once ovulation has been established, each
course Clomiphene citrate of should be started on
or about the 2 -3rd day of the cycle so that the ill effects of CC on Endometrium
is lessened by the time blastocyst is supposed to be ready for implantation
(window of implantation).
Q.8 : Warning:-
Ans :Long-term cyclic therapy is not recommended beyond a total of about
six cycles (including three ovulatory cycles). How many cycles of CC is permitted?? Ans. Long-term cyclic therapy is not
recommended beyond a total of about six cycles (including three ovulatory
cycles
Q.9 . PRECAUTIONS. In prescribing Clomiphene citrate
Ans: CC is indicated only
in patients with demonstrated ovulatory
dysfunction who meet the conditions described below .Properly
timed coitus, as mentioned above in
relationship to ovulation is important. Occasionally in cases of unexplained
subfertility CC is used empirically if not tried earlier.
.
Q. 10: Where CC is contraindicated? . Ans 1 Persistent Ovarian cyst
:--Pelvic examination is necessary prior to the first and each subsequent
course of Clomiphene citrate treatment to
exclude any cysts. But honestly speaking this is often omitted for patients inconvenience
to travel a long distance o reach the clinic
and wait long hours for examination
and Pelvic USG( Basal scan as we call
it) . Many of us do one Full cycle monitoring 4-5 times in a cycle( usually second
cycle) for convinces of all concerned as the drug is relatively innocousos.
2. Patients with ovarian cysts
(day 3 pelvic USG will pick up such residual cyst). Any residual cyst > 10
mm goes against prescribing CC in that cycle or serum progesterone > 1.1
ng/ml . However a delayed star of CC may be done if F cyst disappears after 3-4
days, then day 6-7 initiation of CC may be done .
Q.11: Contraindications of CC:-1)
Clomiphene citrate
should not be used in patients with ovarian enlargement except those with
polycystic ovary syndrome.
2) Past history of OHSS
however mild.
3. Patients with abnormal
vaginal bleeding. If abnormal
vaginal bleeding is present, the patient should be carefully evaluated to
ensure that neoplastic lesions are not present, in such suspected cases endometrial biopsy
warranted . Polyp is a common cause of metrorrhagia in addition to endometrial
hyperplasia due to excess oestrogen.
4. Patients with abnormal liver function.
5. Hypoestrogenic
women: Ans:-
Oestrogen Levels should be normal which may be reflected by ET thereby
avoiding blood tests. . If persistently thin ET then a review of the case be
made to exclude 1) Kochs 2) synechiae 3) H H (hypothalamic Hypo pituitary disorders) .The
other way of assessing adequate endogenous estradiol is subjecting the concerned woman for bleeding in
response to progesterone in cases of sec amenorhoea(progesterone challenge
test) .But it is equally true that reduced estrogen levels, while less
favorable, do not preclude successful therapy.
Q. 12: Where
suboptimal response is likely?? Clomiphene citrate therapy cannot be expected to substitute for specific
treatment of other causes of ovulatory failure A) like Primary Pituitary or
Ovarian Failure.. B) . Endometriosis
.C) Possible Endometrial Cancer: Endometrial
Cancer though very very rare at the childbearing age group but we should remember
that the incidence of endometriosis and endometrial carcinoma increases with
age as does the incidence of ovulatory disorders.
Endometrial biopsy should
always be performed prior to Clomiphene citrate
therapy in population with excess ET > 10 mm at early proliferative phase
with menstrual disorders.
D) Other Impediments to Pregnancy. Impediments to
pregnancy can include thyroid disorders, adrenal disorders, hyperprolactinemia,
and male factor infertility.
E) . Uterine Fibroids. Caution should be exercised when using Clomiphene citrate in patients with uterine fibroids due
to the potential for further enlargement of the fibroids.
.
Q, 13 : Can we coprescribe
Gonadotrophins / Bromocriptine /
oestrogens along with CC to promote folliculogenesis?? Ans:
Although the medical literature suggests various methods, there is no
universally accepted standard regimen for combined therapy (ie., Clomiphene citrate in conjunction with other
ovulation-inducing drugs. Coprescription 1:-Many ART specialist do coprecribe
HMG 75 IU on day 3 with the idea it will recruit more no of follicles and also
another dose of HMG on day 8 with the idea that this second dose
will speed up any follicles which is lagging behind (late bloomers) .This picking up of slowly
growing will hopefully increase serum Oestrgen and there will be no
blunting of LH surge and hopefully avoid
LUF. Coprescription 2; Low cost IVF:- Similarly,
there is no universal agreement or standard
protocol of using Clomiphene citrate
regimen for ovulation induction in preplanned In vitro fertilization programs to
produce ova for fertilization and Embryo
transfer.
Q. 14 :-CONTRAINDICATIONS
of Clomiphene citrate
1)
Hypersensitivity
2) a known hypersensitivity or allergy to clomiphene citrate or to any of its
ingredients. 3)
3)
Pregnancy . But point is if she has consumes CC
unknowingly will it cause harm? Ans: research has shown that 4.5 mg/kg/day for various periods during
pregnancy did not have any abnormal offspring. 4) hepatic diseases :-
Q. 15: Contraindications: Clomiphene citrate therapy is contraindicated in patients with 1)active liver
disease or a history of liver dysfunction ,2) Abnormal Uterine Bleeding. Clomiphene citrate is
also contraindicated in patients with 3) abnormal uterine bleeding of
undetermined origin.4) Ovarian Cysts. CC is contraindicated in
patients with ovarian cysts or enlargement not due to polycystic ovarian
syndrome .
5) CC is contraindicated
in patients with uncontrolled
thyroid or adrenal dysfunction or 6) in the presence of an organic
intracranial lesion such as pituitary tumor
q 16:
What near life threartening compl may
occur ?? Visual Symptoms
Patients should be advised
that blurring or other visual symptoms such as spots or flashes (scintillating scotomata) may occasionally occur during
therapy with CC. These visual
symptoms increase in
incidence with increasing total dose or therapy duration and generally disappear
within a few days or weeks after CC is discontinued. Patients should be warned
that these visual symptoms
may render such activities as driving a car or operating machinery more
hazardous than usual, particularly under conditions of variable lighting.
These visual symptoms
appear to be due to intensification and prolongation of afterimages. Symptoms
often first appear or are accentuated with exposure to a brightly light
environment.
While measured visual
acuity usually has not been affected, a study patient taking 200 mg CC daily
developed visual blurring on the 7th day of treatment, which progressed to severe
diminution of visual acuity by the 10th day. No other abnormality was found,
and the visual acuity returned to normal
on the 3rd day after treatment was stopped.
Ophthalmologic ally
definable scotomata and retinal cell function (electroretinographic) changes have
also been reported. A patient treated during clinical studies developed
phosphates and scotomata during
prolonged CC administration, which disappeared by the 32nd day after
stopping therapy. Post
marketing surveillance of adverse events has also revealed other visual signs
and symptoms during CC While the etiology of these visual symptoms is not yet
understood, patients with any visual symptoms should discontinue treatment and
have a complete ophthalmological evaluation carried out promptly.
:-
Phramocopia of Clomiphene Citrate molecule : What it is? Pharmacokinetics
It is a SERM, Blocks Hypothalamus.
Clomiphene as we use it contains Zuclomiphene
(cis form) is only 38% but zu-CLOM(TRANS FORM 0 IS 62%.
Q.2. Which isomer to use? zuclomiphene
(cis) has a longer half-life than enclomiphene (trans). Enclomiphene is claimed to be more potent and responsible for Ovulation induction
effect. Besides life time is also short.
CC is there forte is a raceme mixture of
two stereoisomer’s. Clomiphene citrate tablets is an orally administered, nonsteroidal,
ovulatory stimulant designated chemically as
2-[p-(2-chloro-1,2-diphenylvinyl)peony] triethylamine Citrate (1:1). It has the
molecular formula of C26H28ClNO • C6H8O7 and a molecular weight of 598.09..
CC is a mixture of two
geometric isomers à cis form (zuclomiphene) and trans form -> (enclomiphene)]
Most of the trade preparations
Contain between 30% and 50% of the cis-isomer. . The tablet also contains the
following inactive ingredients: corn starch, lactose, magnesium stearate,
pregelatinized Cornstarch, and sucrose. The drug can be recovered in the feces 6 weeks after administration.
Subsequent single-dose studies in normal volunteers showed that zuclomiphene (cis) has a longer
half-life than
enclomiphene (trans).
Detectable levels of zuclomiphene persisted for longer than a month in these
subjects. This may be suggestive of stereo-specific enterohepatic recycling or
sequestering of the zuclomiphene. Thus, it is possible that some active drug
may remain in the body during early pregnancy in women who conceive in the
menstrual cycle during CC therapy.
1)
HOW CC ACTS? CC is a drug of considerable pharmacologic potency.
With careful selection and proper .Management of the patient, CLOMID has been
demonstrated to be a useful therapy for the .Anovulatory patient desiring
pregnancy.
Clomiphene citrate is capable of interacting with estrogen-receptor-containing tissues,
including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix.
It may compete with estrogen for estrogen-receptor-binding sites and may delay
replenishment of intracellular
estrogen receptors.
Clomiphene citrate initiates a series of endocrine events culminating in a
preovulatory gonadotropin
surge and subsequent follicular rupture. The first endocrine event in
response to a course of
clomiphene therapy is an increase in the release of pituitary
gonadotropins. This
initiates steroidogenesis and folliculogenesis, resulting in growth of the
ovarian follicle and an
increase in the circulating level of estradiol. Following ovulation, plasma
progesterone and estradiol
rise and fall as they would in a normal ovulatory cycle.
Available data suggest
that both the estrogenic and antiestrogenic properties of clomiphene may
participate in the initiation of ovulation. The two clomiphene isomers have
been found to have mixed estrogenic and antiestrogenic effects, which may vary
from one species to another. Some
data suggest that zuclomiphene has greater estrogenic
activity than enclomiphene. Clomiphene citrate has no apparent
progestational, androgenic, or antiandrogenic effects and
does not appear to
interfere with pituitary-adrenal or pituitary-thyroid function
Why En- clomiphene is better?
En & Zu clomiphene. En is more potent as OI. Half
life is short, But Zu last long in the body as many as 1 month after
stimulation. In obese women higher dose –no benefit.
Q.4. What is
the prevalence of CC resistance case & how do we treat that? About
20-25 % cases do not respond to CC. The options are further investigations
& treat with followings:.
Q.5. Is
there any Carry Over Effect?
Although there is no evidence of a “carryover
effect” of CC , spontaneous ovulatory
menses have been noted in some patients after CLOMID therapy.
1
Q.5. what is the pregnancy rates?
CLINICAL STUDIES
During clinical
investigations, 7578 patients received, CC some of whom had impediments to
ovulation other than ovulatory dysfunction (In those clinical trials,
successful therapy characterized by pregnancy occurred in approximately
30% of these patients.
There were a total of 2635
pregnancies reported during the clinical trial period. Of those
pregnancies, information
on outcome was only available for 2369 of the cases.
summarizes the outcome of
these cases.
Of the reported
pregnancies, the incidence of multiple
pregnancies was 7.98%: 6.9% twin, 0.5%
triplet, 0.3% quadruplet,
and 0.1% quintuplet. Of the 165 twin pregnancies for which sufficient
information was available;
the ratio of monozygotic to dizygotic twins was about 1:5.
reports the survival rate
of the live multiple births.
A sextuplet birth was
reported after completion of original clinical studies; none of the sextuplets
survived (each weighed
less than 400 g), although each appeared grossly normal. ectopic pregnancies, 4
hydatiform moles, and 1 fetus papyraceous.
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