Tamoxifene

·         Knowledge on 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.

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·         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 resitance( 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

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·         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.

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·         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 arecderveided from nonhuman vertebrates upper class woo mimic more like unman males & unman females inclufingffd response to gonadotropins endocrines except tat 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 xcollges?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).

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·          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.

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·          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.

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·         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).

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·         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.

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·         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 comimfm asynchronous growth of follicles(evidence of hyperinsulinaemia) or poor ET, Fluid in Endo cavity etc 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. .

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·         : 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??

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·         Point. 15: Pl do remember ET    ≠ is not endometrial Receptivity(receptive or embryo friendly endo):

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·         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 as come in last decade. Policy 2:-Add E2 (orally), Slidenafil (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.

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·         Point 18:-Is a problem and concerned doctor considers tat 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, Owevr, admiitedly, many a times in unexplained subfertility cases- CC or letrozole is used knowing fully 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  postfertilizatioin 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 Leyrozole 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 Letroze 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, ‘

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·         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.

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·         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?

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I never used this...what is d effect on endometrium?

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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???

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. 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..
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 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 ...See More

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 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 C_oax 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.