Let us refresh our knowledge on Clomiphene
: Indications and usage of clomiphene
citrate
Clomiphene citrate is indicated for the treatment of anovulation in women
with ovulatory dysfunction in women desirous pregnancy.
Q. 1A: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 ?? Ans; 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
tets or some invasive tets may be omitted. for couple of cycles of CC .
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 oligoovulation 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. It is also causes Oligo ovulation (patients
with demonstrated ovulatory dysfunction in WHO class I anovulation.) but CC won’t
work -
Q4: Who may not respond well but there is no harm in
trying 1-2 cycle of CC as trial basis?? Ans:
1) who had hyperstimulation with gonadotrophins, 2) amenorrhea-galactorrhea
syndrome, 3) psychogenic amenorrhea, 4) post-oral-contraceptive amenorrhea, and
5) certain cases of secondary amenorrhea of undetermined etiology? 6) Reduced
estrogen levels,(Low ET on basal SCAN) while less favorable, do not preclude to try
for successful therapy.
Q 5 : What Lab tets must precede prior to
commencing CC?? Ans:-a) LFT, b) Pelvic scan to exclude myoma,
Ov cyst, Ovarian cysts. A good sonologist and state of the art scan machine can pick up
endometrial polyp, synechiae, adenomyosis, congenital abnormalities of
utters (either septal diosrder or
duplication disorders-) c) TSH, PRL .
Besides other genital tract impediments to achieving pregnancy must be excluded or
adequately treated . Such are (gross PID)
or systemic diseases like (renal, hepatic, DM, Hypothyroid etc) 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) very
rarely 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).
Q.9 . PRECAUTIONS.) Clomiphene citrate
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: 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. 13: Where CC is contraindicated? . Ans 1 Pelvic examination is necessary prior to the first and
each subsequent course of Clomiphene citrate
treatment to exclude any cysts, PID, Pelvic adhesive disease, Endometriosis.
2. Patients without ovarian cysts(day 3 pelvic USG will pick up such
residual cyst) may be initiated with CC/Letrozole. Any residual cyst > 10 mm
goes against prescribing CC in that cycle,
.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 without
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 .
4. Patients with abnormal liver function.
5. Is she hypo
oestrogenic?? Ans:- Oestrogen Levels should be normal which may
be reflected by ET . 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 to subjecting the concerned
woman from 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.
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) 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 basal scan reveal excess ET > 10 mm at early
proliferative phase with menstrual disorders.
4. Other Impediments to
Pregnancy. Impediments to pregnancy may include thyroid disorders, adrenal disorders,
hyperprolactinemia, and male factor infertility.
5. 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, 14: can we co-prescribe
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 avoid hopefully LUF. Coprescription 2; Low cost IVF:- Similarly, there is no
standard Clomiphene citrate regimen for
ovulation induction in vitro fertilization programs to produce ova for
fertilization and reintroduction. However many prescribes CC 100 mg dose from
day 3 for 10days and HMG 150 IU daily from day 8 . Alt day serum E2 and Foll
monitoring is must, Trigger and OPU(Ovum Pick Up) as deem necessary.
.
Q.
15:-CONTRAINDICATIONS of Clomiphene citrate
1)
Hypersensitivity
2) a known hypersensitivity or allergy to clomiphene citrate or to any of its
ingredients.
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 :-
Clomiphene citrate therapy is contraindicated in patients with liver
disease or a history of
liver dysfunction 6)Abnormal Uterine Bleeding.
Clomiphene citrate is contraindicated in
patients with abnormal uterine bleeding of undetermined origin
7) Ovarian Cysts. CC is
contraindicated in patients with ovarian cysts or enlargement not due to
polycystic ovarian syndrome .
8) CC is contraindicated in patients with uncontrolled thyroid or adrenal dysfunction
or in the presence of an
organic intracranial lesion such as pituitary tumor
q 12:
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 lit 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.
Ovarian Hyperstimulation Syndrome by Clomiphene Citrate.
:-
Part II ,
1)What it is? Pharmacokinetics
It is a SERM, Blocks
Hypothalamus Clomiphene (Nagori):- Zuclomiphene (cis form) is only 38% in
ordinary clomiphene. but zu-CLOM(TRANS
FORM 0 IS 62% AND VIRTUALLY .
Q.2. Which isomer to use? En
is more potent and responsible for OI. Besides life time is also short.
It is a raceme mixture of
two stereoisomer’s. CLOMID (clomiphene citrate tablets USP) 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. It is represented structurally as: .
CC is a mixture of two geometric isomers [cis
(zuclomiphene) and trans
(enclomiphene)]
Containing between 30% and
50% of the cis-isomer.
Each white scored tablet
contains 50 mg clomiphene citrate USP. The tablet also contains the following
inactive ingredients: corn starch, lactose, magnesium stearate, pregelatinized
Cornstarch, and sucrose. A
present 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. 5. what is the pregnancy rates?
Any clinical studies ?
In one study 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..
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. It is also reported
that 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.
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