Tamoxifene:-
There
are two important advantages of Tamoxifen over CC. These are a) No anti-estrogenic
effects of CC on genital tract b) No recorded neurological abnormality as is
observed very occasionally in CC cycles. Abnormalities of vision, the rare occurrence depression, grand mal epilepsy
and hallucinations are not heard of with TMX.
Ae
you worried about persistent thin Et , She is young ?? Thin ET ?? Tamoxifene is
the solution.
Tamoxifen: - The theoretical advantage of TMX over 1)
CC is that it (TMX) does not exhibit any antiestrogenic effect on cervical
mucus or endometrium. As such, many specialists use this drug (TMX) in cases of CC failure (sometime in CC
resistant too) - where there is a persistent thin endometrium in previous CC
cycles.
2) As an alternative
to Gonadotrophins as a treatment modality of thin ET:-Honestly
speaking, TMX, so far my belief goes, is occasionally used where couple can’t
afford for gonadotrophins.
Tamoxifen
is a SERM. Like Clomiphene this drug too was initially used for breast cancer. Tamoxifene has never been approved till date by any agency for
Ovulation induction. (Source: Hum. Reprod 2005; 29:1511).
It is claimed
that it (TMX) is as effective as CC in ovulation induction. It is initially used as 20 mg OD schedule. After two
failed cycles with TMX (if there is no evidence of ovulation) -the dose of
Tamoxifene can be increased in a stepwise fashion up to 60mg OD.
It is more
probable that endogenous hormones become near normal in pre-induction phase.
If ET is more than 5 mm, better to induce
withdrawal bleeding before ovulation induction.
Late
start of TMX-When?? The other alternative option is if on day 3 - ET is > 5
mm. then one can possibly reschedule evaluation of ET after 48 hrs...In some
cases, however, on day 4 /5 ET may shrink down to expected 5 mm by waiting for
48 hrs. Therefore, one can possibly gainfully utilize that cycle too by
initiating CC/tamoxifen/i.e. on day 5. ET may regress to 5 mm.
Tamoxifene: - The theoretical advantage of TMX over CC is that it (TMX) does
not exhibit any antiestrogenic effect on cervical mucus or endometrium. As
such, many specialists use this drug (TMX) in cases of CC failure (sometime in
CC resistant too) - where there is a persistent thin endometrium in previous
CC cycles.
Tamoxifene
has never been approved till date by any agency for Ovulation induction.
(Source: Hum. Reprod 2005; 29:1511). It is claimed that it (TMX) is as
effective as CC in ovulation induction. It is initially used as 20 mg OD
schedule. After two failed cycles with TMX (if there is no evidence of
ovulation) -the dose of Tamoxifene can be increased in a stepwise fashion up to
60mg OD.
Tamoxifen when? Scope & Indications
of Tamoxifen as Ovulogens:-:- In present day the main and possibly the
only indication of prescribing TMX is when there are side effects with CC
particularly visual /neurological side effects . Scintillating.scotoma.
Tamoxifen
is the second choice in CC resistant cases. Better option will be still Gonadotrophins. Gonadotrophins are quite
effective in CC resistant cases but costly and requires rigorous monitoring.
Such facilities may not be available in rural settings. There remains a
scope of TMX in selected cases of CC failure/ resistance cases.
CC has
failed after couple of cycles. Now, what are the practical options open to
young women in Indian perspective? Once counselling done after several cycles
of failed CC, many Indian couple (even uneducated couple) do realize that
gonadotrophin is badly needed for them but repent because they are simply
unable to afford for G cycle. Put in such a situation (after CC resistant
cases) the option remaining to the treating physician to prescribe TMX (as an
alternative to Gonadotrophin) and make some compromise. Doctor feel-“Watch-
what happens”-.
Ours
is a resource poor country: Not to speak of cost of purchasing Gonadotrophins:
Many Indians even cannot afford common low cost fertility tests (PRL,) that
usually should precede CC therapy (tests for medical fitness of pregnancy- IgG
rubella, hepatitis Viral Screen, TSH, etc). Not to speak of tests prior to
initiation of Gonadotrophin—which is the preferred agent most commonly used
after CC failure/ Resistance. Not all such tests are done free of cot in
Govt/Municipal Hospitals.:--Unfortunately, many Indian couple cannot afford for
usual tests at this juncture - so as to why CC failed in their case.
Such tests, if not carried out earlier are 1)
AMH .2) AFC, 3) Insulin Resistance, 4) high D2 LH & testosterone 5) DHEASO4,
& 6) PRL --not to speak of other costly tests. In such cases further tests
so as to find the etiology of CC resistant in particular women. We, Indian
doctors have to make many compromises at every step of clinical practice not
only in the discipline of reproductive medicine.
Like
CC TMX is also an competitive estrogen Antagonist –TMX ,like CC also competitively block the estrogen
binding sites at the level of actuate nucleus of hypothalamus, and stimulate
GnRH receptors located at Pit for accentuated release of pit FSH & LH.
Is
there any differential expression of LH over FSH –particularly in CC failure
cases? In fact there is about 3-4 fold
rise of FSH & LH while someone is on CC.
But the differential expression FSH & LH
in the aforesaid two types of oral Ovulogens is still under study. I have a
feeling this part of CC /TMX have not been adequately explored. It is hoped by
many researcher that CC failure is due
possibly to over expression of LH in fair number women and is a major cause of
CC failure poor oocyte quality.
Those who
are biased for TMX they claim such disproportionate
rise of LH on cycle days 8-11 is not the case with YMX.
But many
researcher believe that CC in fair no. of cases more rise of LH during the cycle
days of Day 8-Day 10thereby interfering the oocyte quality. Similarly in some
cases of CC induced cycle serum E2 remain at supraphysiological levels –explain
partly the reasons of failure of CC cycles.
In such women one can use TMX as an iterative
if the age of the female partner is< 25 yrs or she cannot afford for
gonadotrophin cycle. Some also have claimed that LUF is more than TMX.
Why oral Ovulogens in lieu of
gonadotrophins in CC resistant/Failure cases??- The advantages of CC/
Tamoxifen are low incidence of multiple gestations, OHSS, low cost, minimal
monitoring, .But we are all aware of the fact that whatever agent we use in
fair number of subfertile women CC/TMX become resistant despite appropriate
dosage e.g. Ov insufficiency, Hyperandrogenism, Insulin resistance, Elderly
women and women with BMI> 30 Kg/M2. In such cases one prescribes oral
Ovulogens mostly CC but the doctor concerned is sceptical right from the
beginning that CC/TMX may not work.
Miscarriages
rate and multiple pregnancy:--Such rates are more or less same with CC and
Tamoxifen :- e.g. 10% & ABOUT 22% RESPECTIVELY DEPENDING ON OTHER
ASSOCIATED FACTORES LIKE Age of female partner, BMI, ANDROGEN EXCESS DISORDERS,
Hyperinsulinemia, serum testosterone etc etc.
But for the
oral Ovulogens to be effective the D2 serum E2 should be ideally> 50 pg/ml
and not less.
Additionally, Women why are contraindicated for CC may also be a given few
cycles of TMX RY after due counselling. Such contraindications of CC are
impairment of hepatic enzymes.
Tamoxifene:-
There are two important advantages of Tamoxifen over CC. These are
a)
No
anti-estrogenic effects of CC on genital tract b) No recorded neurological abnormality as seen very occasionally in
CC cycles. Abnormalities of vision, the rare occurrence depression, grand mal
epilepsy and hallucinations are not heard of with TMX.
Additionally, researchers working with TMX and CC: - also claim that the very
rare threat of Auditory nerve changes in CC induced cycles is nonexistent in
TMX cycles.Moreover use of TMX in Ov induction is an “off-level use .
Additionally, researchers working with TMX and
CC: - also claim that the very rare threat of Auditory nerve changes in CC
induced cycles is nonexistent in TMX cycles.
·
These are the advantages for choosing
TMX over CC. At least such plea has been put forward by different researches in
last four decades. But by convention, globally,
(including myself) CC is most popular
agent for Ovulation induction. Moreover use of TMX in Ov induction is an
“off-level use “ –as I mentioned at the outset. Tamoxifen (TMX) –Where are we??
What is TMX?? Are we under using Tamoxifen?? There is no fool gynecologist in Te
world that will lose time on discussing on TMX, except Prof S Pal of
Kolkata-who is a retired man!!! Tamoxifen, as we are all aware that is basically
an anticancer drug (breast cancer) but is occasionally used to promote
fertility, especially when thin endometrium is becoming a recurrent annoying
problem in CC induced cycle. ET as we all knows ideally be 9-10 mm in Ov
induction cycles. Mind you dear members, I am not referring desired or optimum
ET in IVF cycles.
·
·
Tamoxifen-When?? What are the
Indications? TMX is usually offered after couple of cycles of CC failures(
documented ovulation wit CC i.e. clomiphene but no pregnancy) or CC resistance(
no ovulation despite CC of 3-5 cycles more so
in young couple-female partner is
< 25 yrs and trying time is 3 yrs). Tamoxifen when? Scope &
Indications of Tamoxifen as ovulogen:-:- In present day the main and
possibly the only indication of prescribing TMX is when
there are side effects with CC particularly
visual /neurological side effects .
Scintillating Scotia are the main contraindications of CC. Though, in
such situation both the drugs (CC & TMX) are to be withheld forthwith
but one can use either agent at a lower dose after a gap
of 3-6 cycles couple of months
·
·
Point 3:-Well, there are many reasons
are there why CC fails to achieve preg despite documented Ovulation. Again
coming back to CC –The common reasons why CC fails despite ovulations are 1) Thin
ET 2) LUF 3) too much E2 in peril-ovulatory phase produced by more than 3 growing follicles àspoils te game at endo level or too much E2 induced by CC may lead
to impaired maturation of oocytes 4) Premature LH in CC cycle even in CC cycles (little discussed by teachers,
Admittedly, I must confess that I was
not aware that premature LH surge is a problem even with an apparently benign drug i.e. CC. his happens
due to surge of sudden production of E2
synthesized by too many follicles. This LH when acts on Oocyte which is underprepared
(not ready for meiotic division). However, we will later discuss in details about
dynamics of CC failure and CC resistant in evening hours today as these are
common phenomenon and little discussed in Practical MD class. Many a times I
was not allowed by the local Internal Examiner not to ask on such tough
Questions in MD & was stopped on
many occasions not to ask tees complicated problems while putting a SG plate in
Gynae Viva table at DNB/MD examinee.
·
·
Point 5:-A tip for young girls /boys.
Always keep vermillion pkt at your purse if you want to learn reproductive
biology at slaughter house: A tip from Grand-pa.
·
The next issue is where from we
collect so many information on human reproduction?? Not from mousse/ rabbits’/ rabbits or guinea pigs as we commonly come across at our
Physiology Pact class or Pramacolgy Lab.
is commonly though. But most of the Informations of human reproduction including
details of spermatogenesis at diff stages, what happens at Epididymis, in vas,
Seminal vesicles, Prostate etc can be derived killed bulls. So far information’s
on Females similarly details of F repro tract are deveined from nonhuman vertebrates upper
class woo mimic more like unman males & unman females including response to
gonadotropins endocrines except that tees cow, seep don’t menstruate. I as=all
discuss otter 3 animals woo menstruates but nonhumans?? primate
Commonest cause as suggested by Repro endocrinologist and biologists
after feeding Cato seeps, Cows and ten collecting ovaries & uteri from
slaughter use offers us many information’s
to persons who are performing P D course in genl Sc colleges? university level, In fact slaughter house is
te ans Garden for reproductive biologist, many information’s aver been receive
from removed from removed uteri, Cx
virginal canal , Tubes and Ovaries after mating on the previous night
with a bull-so that sperms can be traced add effect of CC cane documented in
under of cows
·
Once I entered at te age of 24 yrs with
my girl friend to collect ovaries from dead cow as my girl friend didn’t have vermillion mark on her forehead we were
refused to enter in a semi-dark room where dead cows were lying and pieces are
made. ?!!! Thereafter whenever I visit any place be it Paris or Goa with any
girl friend I put vermillion marks an arrival at all resorts. Do you get me??
·
Point 7:-Why CC fails to achieve
preg? Quite often there is persistent antioestrogenic effect at endometrium
level resulting into suboptimal growth (should I call it as unreceptive
endometrium). Thin ET may range from 4-7 mm which is not uncommon in normal
cycles too but more commonly observed in CC cycles thereby preventing cross
talk between blastocyst and endometrium. (Unresponsive or hostile endometrium).
·
·
Point 8:-This (thin ET is not the only
peculiar for CC only but thin Et may be due to many other causes like Kochs,
Synechiae Hyperprolactinaemia, numerically poor E2 receptors at endo levels
(less population of receptor density). or genetic mutation of E2 receptors at
endo levels and many other about one
dozen causes or pleomorposim of genes. All such adverse factors may lead to
either in isolation or in combination barrier
to achieve preg despite documented
ovulation.
·
·
Point 9:-Final success is not achieved in
about 40=60% cases with CC alone in India (Hyperinsulinaemic country-many young
women with PCO or without PCO have abnormal GTT –with interferes with normal
actions or dynamics of CC):: It is presumed that thin ET is the cause of CC
failure and though it is doing the
trusted primary job of ovulation but at the cost of poor or adverse effect on
ET. Thus goal don’t result in spite of good “dribbling” & “football pass”. The other causes of failure to achieve preg
despite documented ovulation are 1) undiagnosed
/ unsuspected Tubal block 2) Good endo
thickness but poor receptivity 4) LUF 6) LPD 7)Transient Hyperprolacunaemia
6) Minimal endometriosis not detected by history or palpation / Kochs in peritoneum or even at
endo/tubes undiagnosed high normal DHEASO4 from adrenal androgens etc . I
shall will come to these in detail to moor, if I remain alive.
·
·
Point 11:- How best to know whether
someone is ovulating or not while one is consuming Ovulogens (CC/Letrozole/
Tamoxifen)?? There is a long debate whether to monitor or not to monitor in simple
cc induction cases where thousands of Indian women are taking it daily. This
also applies to Letrozole cycles. TMX- i.e. whether to monitor
by Foll monitoring which is bothersome & costly for poor couple (daily wage
loss & bus expenses).
·
·
However, if you ask distinguished ART
specialists most of them will answer in favour of “NO MONITORING IN CC or
Letroz cycles “--more so if couple is young. But, I have a feeling that the
balance is more in more in favour of monitoring as I was personally in favour
of monitoring since 1992. .I have trained in that way and I feel guilty if I remain
blind what is happening inside te ovaries, Follicle s & endo in particular
after taking CC/ letrozole. This is more easy to insist on monitoring if woman concerned is staying close to our hospital
so that I can formulate my plan in next
cycle (say switching over to MG/ letrozole
/Adding E2 orally or suppl E valerate at te beginning of next cycle or
adding Decadron or Bromocriptine for
first 15 day) . Know many of you
may differ with my poilosdopy as many atopic are debatable in Medical Science.
·
·
Point 12:-My logic is unless we
monitor by F M ten we miss many tings watt is apprehending at Foll level particularly
one many follicles are cofirm asynchronous growth of follicles(evidence of hyperinsulinaemia)
or poor ET, Fluid in Endo cavity etc.
·
Point 13;-“Three –in-One philosophy “
(many Informations –like Foll growth, ET growth, development of asynchronous
follicles—Fluid collections and imaging modality can also forecast the date of imminent ovulation. Thereby
enabling husband to come to home if he is employed a bit away from home town as
happens often say 100-20 km away. .
·
·
: Point 14:-“Do it yourself principle”:--As
we know ovulation can be proved by serum Prog assay on late luteal phase or day
21 of cycle. But as of now in non IVF cycles the choice is more in favour of
documentation of ovulation by F M meted:-is “serial monitoring by even 2-D USG
by the Gynae herself/ himself) –say on day 3, day 8, and then depending on
growing full dia every 2-3 days after
day 8 scan . By and large 4 times scans will suffice to interpret about what is
going on at Follicles or at Endo level .One can omit Doppler studies of
Peri-follicular or Subendometrial flow studiers (PI, RTI) aim non IVF cycles. Thereby
too can do it yourself and eater at no cost or token money for salary of attendant,
RT??
·
·
Point. 15: Pl do remember ET ≠ is not endometrial
Receptivity(receptive or embryo friendly endo):
·
·
Point 16:-: To avoid thin ET what can
be done in CC cycles”:-Policy 1:-That is why most people for last 3 decades
after the advent Foll monitoring by USG has sifted te day of initiation of CC
on day 2(instead of day 5 as was the protocol earlier-even up to 1988) with the
idea that adverse effect of CC will peas of early by the time Ovulation occurs.
But we should remember at the same breath that ET Receptivity of endo is more
relevant, so far pregnancy is concerned, than” USG measured thickness” near fundal
level at periovulatory period.. And sadly we are till date can’t a very any
easy-to-use lab test to quantify Endometrial Receptivity except ERA which has
come in last decade. Policy 2:-Add E2 (orally), Sildenafil ( Viagra / Viagra
/ Viagra / Penagra)-2 mob TDS & 25 mg (vaginally) TDS. These drugs can be
started as soon as lagging of Et is noticed on day 8/day 9 scan but many prefers
to suppl such drugs in next cycle from day 3 along with day of initiation of CC
.How best to overcome tin Point 17:-ET?? Policy 3: Brest and most accepted
policy is to swum over to gonadotropin induction (after excluding Kochs &
PRL disorders) &n IUI which offers excellent results in cases with rec thin
ET.
·
·
Point 18:-Is a problem and concerned
doctor considers that CC is causing the entire nuisance at endometrial level,-What
is the usual scenario?? By and large gynecologists use Clomiphene citrate as
initial choice in cases of subfertity problem. Honestly speaking most of us
initiate CC (a common drug) without investigating & confirming that Te
concerned women sire; u suffering from anovulatory disorders or oligo ovulatory
disorders, Owner, admittedly, many a times in unexplained subfertility cases-
CC or letrozole is used knowing full well that the woman is really ovulating.
Why then people use CC in an ovulating women?? Why? What is their back of
mind”” Reasons thereof?? It has been
documented by RCT that by some beneficial
modification(facilatimg effects ) induced by CC as an adjunct work on tissues (
paracrine factors & coenzymes )
promoted better quality of eggs, AS such these facilitating effaces wick are
not visible or demonstrable by te Gynae spl can do te magic. As a result oocytes
which were so long imperfect or less fertilizable are now become 100% ready,
well dressed and ready to meet sperm(not sperms) - so as that CC induced
Oocytes are as fresh as fruits from your own garden . These in favourable
women, results in excellent oocytes
which are full of youth with good
nucleus, chromatin & full quota of
mitochondria -à synthesis of best possible fertilizable or ova with no possibility of
developing post fertilization errors in development.
·
Roving tat because of subfertility is
anovulation or oligo ovulation. But in all fairness every subfertile women
should aver a n evaluation scan Agreed, And if clomiphene becomes resistant (no
ovulation despite 150 mg OD 0ten most of us switch over to Letrozole, Went
letrozole was banned for about 8 yrs in our country on te plea that Letrozole
causes unacceptable rate of cog malformations Govt banned letrozole , however,
letrozole fortunately or unfortunately went Letrozole was again reintroduced te
people used as Letrozole as first cove, I don’t know wetter ties is appraise or
not, but so gear U am concerned I sell initiate letrozole as fist choice only went
serum E2 is > 80 pg /ml i=on day 2-3. But honestly speaking own many go so
estimate serum E2 bedsore sousing CC or Letroz or say Tamoxifen (TNX) or anastrazole??
Most of us don’t estimate E2 (day 2) and initiate CC (if E2cis< 80 pcg) or
letrozole if E2 > 80, ‘
·
·
Q.4. CC is not a panacea for
anovulation: It may not induce ovulation in as many as 30% cases and in such
case you may be challenged by Te couple-“Doc, Why did you offered CC as an
initial ovulation inducing agent? Why not some otter agent likes letrozole (as
my friend Rubin was prescribed Dr T K) or anastrazole as my friend emu was
suggested by Dr AB or say Sumangala who was prescribed Anastrazole as initial
dryad?? Who gave you Te authority to waste precious 4 mi=ants of our
subfertility?? Tate is no answer for this, We are not simply Gods, neither
angel.
·
·
Watt is te prevalence of CC
resistance cases went pre-induction evaluating by AM, Glycaemic profile,
Endocrine profile do not suggest any otter abnormality: CC resistance is common –as high as 30% PCOS
women. As we know Ovulation can be proved by serum Prog assay on late luteal
phase or day 21 or the more common use of documentation of ovulation is
“serial monitoring by 2-D USG by te Gynae herself/ himself) –say on day 3, day
8, and then depending on growing full dia
every 2-3 days. By and large 4v scans will suffice to interpret about
what is gang on at Follicles or at RT??
·
used Tamoxifen 20
mg OD from day 2- day 6 many times with results comparable to clomiphene
Sir can it be
used as a first line drug as ultimately we don't want an ovulatory only cycle
BUT AIM IS TO HAVE a fertile cycle is needed
Any advantages of
tamoxifen over clomiphene?
·
I never used
this...what is d effect on endometrium?
·
·
Theoretically
have read about tamoxifen use in cc non responders and apparently almost
comparable responses!
Not very
convincing
We use it
regularly- fine ova 40 mgs once a day from day 3 for 5 days
Which company is
it???
·
. Akumentis · 1
Not approved for
induction like letrozole. Comparable with clomiphene if not better.
I have used Tamoxifen.
Response is not
equivalent to cc.....but u need to add
hmg when using tamoxifen ....endometrium will 9 mm by day five or day six. ...
..Not that great unlike cc..
.
TMX
when clomiphene
and letrozole failures....seen pt ovulating with good endometrium....only one
pt was positive but then this was the last drug to resort after cc n letrozole....theoretically
results comparable as in cc....
Really good
results in PCOD patients, use from day4...can do wonders in attaining
monofollicular development!!
Tamoxifen when?
Scope & Indications of Tamoxifen as ovulogen:-:- In present day the main
and possibly the only indication of prescribing TMX is when there are side
effects with CC particularly visual /neurological side effects . Scintillating
Gonadotrophins
are quite effective in CC resistant cases but costly. CC has failed after
couple of cycles. Now, what are the practical options open to young women in
Indian perspective? Once counselling done after several cycles of failed CC,
many Indian couple (even uneducated couple) does realize that gonadotrophin is
badly needed for them but repent because they are simply unable to afford for G
cycle. Put in such a situation (after CC resistant cases) the option remaining
to the treating physician to prescribe TMX (as an alternative to Gonadotrophin)
and make some compromise. Doctor feel-“Watch- what happens”-.
Not to speak of Gonadotrophins:
Many Indians cannot afford further tests so as to why r CC resistance followed:--Unfortunately,
many Indian couple cannot afford for usual tests at this juncture - so as to
why CC failed in their case. Such tests, if not
carried out earlier are 1) AMH .2) AFC, 3) Insulin Resistance, 4) high D2 LH
& testosterone 5) DHEASO4, & 6) PRL --not to speak of other costly
tests. In such cases further tests so as to find the etiology of CC resistant
in particular women. We, Indian doctors have to make many compromises at every
step of clinical practice not only in the discipline of reproductive medicine.
Like CC TMX is
also an competitive estrogen Antagonist –TMX ,like CC also competitively block
the estrogen binding sites at the level of actuate nucleus of hypothalamus, and
stimulate GnRH receptors located at Pit for accentuated release of pit FSH
& LH.
Is there any
differential expression of LH over FSH –particularly in CC failure cases?
In fact there is
about 3-4 fold rise of FSH & LH while someone is on CC.
But the
differential expression FSH & LH in the aforesaid two types of oral Ovulogens
is still under study. I have a feeling this part of CC /TMX have not been
adequately explored. It is hoped by many researcher that CC failure is due possibly to over expression of LH in fair number
women and is a major cause of CC failure poor oocyte quality.
Da those who are
biased for TMX they claim such disproportionate rise of LH on cycle days 8-11
is not the case with YMX. I admit that I personally do not know about the
differential expression of FSH vs. LH in CC cycles against TMX cycles.
But many
researcher believe that CC in fair no. of cases more rise of LH during the
cycle days of Day 8-Day 10thereby interfering the oocyte quality. Similarly in
some cases of CC induced cycle serum E2 remain at supraphysiological levels
–explain partly the reasons of failure of CC cycles. In such women one can use
TMX as an iterative if the age of the female partner is< 25 yrs or she
cannot afford for gonadrophin cycle. Some also have claimed that LUF is more
than TMX.
Genetic
polymorphism of cytochrome P450 2D6 determines oestrogen receptor activity of
the major infertility drug clomiphene via its active metabolites
Clomiphene citrate is the most used
drug for the treatment of female infertility, a common condition in western
societies and developing countries. Despite dose escalation, up to 30% of women
do not respond.
Since clomiphene shares structural
similarities with tamoxifen, which is predominantly bioactivated by the polymorphic
cytochrome P450 (CYP) 2D6, we systematically explored clomiphene
metabolism and action in vitro and in vivo by pharmacogenetic,
-kinetic and -dynamic investigations.
Human liver microsomes were incubated with
clomiphene citrate and nine metabolites were identified by mass spectrometry
and tested at the oestrogen receptor for their antagonistic capacity.
(E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene showed strongest
inhibition of the oestrogen receptor activity with 50% inhibitory
concentrations of 2.5 and 1.4 respectively. CYP2D6 has been identified as the
major enzyme involved in their formation using recombinant CYP450 isozymes as
confirmed by inhibition experiments with CYP monoclonal antibodies. We
correlated the CYP2D6 genotype of 30 human liver donors with the
microsomal formation rate of active metabolites and observed a strong gene-dose
effect.
A healthy female volunteer study
confirmed our in vitro data that the CYP2D6 polymorphism
substantially determines the formation of the active clomiphene metabolites.
Comparison of the Coax of (E)-4-hydroxyclomiphene and
(E)-4-hydroxy-N-desethylclomiphene showed 8 and 12 times lower concentrations
in subjects with non-functional CYP2D6 alleles. Our results highlight
(E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene as the active
clomiphene metabolites, the formation of which strongly depends on the
polymorphic CYP2D6 enzyme. Our data provide first evidence of a biological
rationale for the variability in the response to clomiphene treatment.
`
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