Semen analysis

Counselling for semen Analysis

In 40-50 % of couples presenting with fertility problems male factor is responsible either partially or completely . In our social set up even today males do not accept this   fact and  therefore  they do not agree  for examination or investigations . This  problem is more  prevalent  in people who are less educated Proper  counselling is a must with   the male partner before  subjecting the female  partner  for treatement   of infertility.

The  couple must be explained that according to the recent  WHO criteria 2012 , 15 million sperms / ml  motility and   4%  sperms with normal  morphology  are considered as normal physiological semen criteria . in spite  of this even  today  we read  several  labs quoting 60 million count   as normal    in their reports  Because   of this wrong   information  and ignorance  of laboratory   officials  and clinicians   several  patients   take medicines  for long periods  to increase  their sperm  count Remember  when sperm  count is 15 million / ml or more no treatment is required . Up to 86 % abnormal sperms is normal and physiological and even patient with 4 % - 14 % normal sperms can conceive either naturally or by intrauterine insemination . Only when < 4% of serms are normal , IVF / CSI may be required.

 When the sperm count is < 15 million / ml semen  analysis must be done at least  three times – 2 weeks apart  and 2 months  apart to confirm  the diagnosis . These patients should directly not be subject to IVF or ICSI . Instead we must try medical treatment for these males to improve the sperm count  so that they conceive   naturally  or with IUI. The whole  moto of  medical management of a subfertile   male is not to increase   the sperm  count 5-10   times or to achieve excellent semen parameters  . The moto is to increases  the count by a few million so that ICSI  can be converted to IVF  , IVF  to IUI  and perhaps   IUI  into natural  conception  . Medical  management  has been discussed in the chapter on male infertility .

Counselling for  cervical  factor

The  cervical   factor  of infertility is rare at present as surgeries  are not often done on cervix  Frequent  D & Cs may damage   endocervical    glands and epithelium Cauterization of cervix   should be discouraged.

I believe  that even   today  post coital test is very useful in infertility management   When  more than seven  motile sperms  are seen per high  power field  of microscope  , 10-12  hours  after intercourse it is an excellent PCT  according  to WHO  standards

What  information  we get from a normal  PCT

1.                      Preovulatory  cervical  mucous  is normal

2.                      Sperm  count  is normal

More over when the patient  is shown  these moving sperms  under  microscope  even after  12 hours  of intercourse it gives  them confidence   that both  the partners  are normal  and that helps  them  to conceive.

Patient is explained that these  sperms may remain alive  for 48-72  hours  in most of the patients  and in few they  have also been seen after seven  days. There is  a misconception  in majority  of the couples  that sexual   relations  must be kept when ovulation occurs.  Showing PCT  to patient   removes  this misconception. Cervix   acts  as a reservoir  for sperms so after the sexual   relation   even if  ovulation  occurs  in 2-3  days conception can occur. We can  therefore   explain  the patient that if for conception  the intercourse  was needed  exactly  when ovulation  occurs no raped girl would conceive. Couple should therefore  be advised intercourse at least once  in 2-3  days during  10-20  days  of 28-30 days cycle. The couple should be clearly  told that abstinence  of more  than 3 days  is not advisable during this  period in natural cycle as well as in stimulated  cycles for IUI.

Majority   of the couples believe  that if IUI is to be done it is  better to have abstinence before   to get good   sperm count But  this is not true  an abstinence of more than 3-4  days does  not increase  the count  instead the percentage  of dead sperms   in this semen   increases  . therefore  intercourse should not be    planned  it should be  absolutely  voluntary and  can be done  irrespective   of the day of IUI.

Abstienence is one of   the couses for failed IUI   Let me explain why and how In majority of gyneac clinics where    there is  n IVF  set up the semen preparation is suboptimal and so chances of conception are less  . Moreover   patient keeps   abstinence  before IUI  so the chance  of natural  conception  also is denied. As a result  patient  does not conceive  when she is on treatment    but conceives   spontaneously when she abandons  treatement . Remember  therefore  intercourse  at regular  intervals  in the fertile  period is absolutely essential

Majority of couples with  long tern infertility have lost  the charm of their  marital relations. Their  sexual  relations  are only planned  and compulsory  only targeted for child bearing They  must be  explained  that child is only a by product Main thing is  the love and affection intercourse   is just an expression of this feeling  and results  in conception. Counselling can help  them regain the charm of their marriage. All myths regarding   intercourse must be discussed and sorted out e. g. posture  position  timing washing etc.

Counselling for  uterine  factor

This  is to be discussed with the patient  after a 3D ultrasound  as this is a good standard for congenital  uterine  malformations  and endometrial pathologies. Patient also can see and understand  these  3D pictures and the optimum management then can be easily explained. Fibroids less than 4-5  cms in size and not touching the endometrium  do not require removal . Patient can also be convinced  and explained this by explaining them how  the embryo  comes from the tube to the uterus  and implants in the endometrium

Majority of the patients have a wrong concept  that D & C   is helpful  for conception. This is a myth  and should be  clarified D & C  should not be   done in modern infertility  practice. The only  role  today of D & C is to exclude   endometrial  sample D & C whether  the endometrium  is  in proliferative phase  or secretory  phase.

Counselling  for tubal  factor

Patient  must be explained that fertilization occurs in fallopian  tube and after  4-5 days embryo comes to settle  in the uterus. This explanation  is also useful tos counsel if the patient gets  an ectopic  pregnancy Tubal  evaluation is very important    in infertility practice RT should be  discarded Laparoscopy   is the gold  standard    for evaluation  of the tubes.

Patient   should  be explained that at the time of ovulation Fimbrial end of the tube  covers  the ovary  a negative pressure of 1 mm of  H g is created  due to movements of the  cilia this sucks  the  ovum from the follicle  into  the tubal lumen so ovum  does not separate and release  from the follicle to  roll into the tubal lumen  but tube is vital and instrumental Therefore  it is  important  that  tubo ovarian    relation should   be healthy a patent tube is not  sufficient . HSG gives   us only incomplete  information  only about   the patency of the tube . This can be replaced by sonosalpingography.

Now  microsurgery   is almost replaced  by ART for pathological  tubs Results  of microsurgery  are very good in tubo tubal  anastomosis in patients   with tubal  ligation especially  laparoscopic   tubal ligation. Therefore   in young  patients   where TL  is done microsurgery  should be offered as an alternative to ART   as it is a onetime procedure  and patient  gets a breathing time for  up to two years before ART.

Counselling for ovarian causes:

Patient should be counselled that ova is released from the ovary only once in a month and it survives for 6-8 hours . Sperms that are stored in the cervix can reach the ova and conception can occur. Ovulation can be confirmed by serum progesterone levels assessed on day 21-22 . Daily sonography is not required just to confirm whether ovulation has coccured or not . Basal body temperature record and cervical mucous does not help much in management.

Unexplained infertility :

About 5- 10% of patients are infertile in spite of everything being normal . They have normal semen analysis , normal endoscopy normal luteal phase and normal endocrinological reports. These are ideal patients for IUI . Six cycles of superovulation with IUI must be tried before subjecting these patients for ART IUI is the choice of treatment for idiopathic infertility rather than IVF.

Counselling for IVF

There are lots of misconceptions  prevailing for IVF  treatement   regarding three aspects

1.          Indications

2.          Results

3.          Cost

Indications

It must be clearly understood  that IVF is the first choice  in only those patients   who have bilateral tubal block severe endometriosis or severe male  factor  infertility . IVF  may be  done in  patients  with  unexplained  infertility   only  when  six well  tried  superovulation  with IUI  cycles  have  failed to give pregnancy  Dys ovulatory infertility  like PCO is not a primy  indication for IVF

Results

Patients  believe  that IVF is like a fast food and a sure  shot solution to infertility they have been misled about the same. They must be explained that  the results of IVF in the best  centres  of the world are

30%  in first cycle

40-45 % in second  cycle

50-55%   in three cycles

60-65%  in four cycles

65-70% in five cycles

70-73% in six cycles

Therefore  in patients  who  do not have absolute indications for IVF  should be given a chance  of IUI instead  of taking  them for  IVF  because    about  six  superovulation with IUI cycles  cost the same as one IVF  cycle with more chances  of success.

Cost 

IVF  is a very  expensive  procedure its cost includes  charges  for gonadotrophins  and  medicines  which comprises the largest  amount  nearing  Rs 60,000  to 80,000   depending  on the consumption by the patient. The second  highest  cost is  of disposables  and media. This also  about Rs 10,000 -15,000 . Over and  above  this  the cost also includes  that of the IVF  consultant   embryologist anaesthetist etc. Therefore  it must be understood  that when   we try to cut off the cost  one has to compromise on drug  quality  and disposables This  would definitely compromise with the results  also

Carry Home Message

Councelling plays very impotant role in  management

15 million count with 305  motility with 4% normal  sperms  are new  WHO  2012 criteria.

7 motile sperms  / HPF is excellent  PCT 

D & C is done only to  rule out  TB 

Laparoscopy is gold  standard

S Projesterone  on day 21    indicates  ovulation 

6 cycles  of IUI should be tried in unexplained  infertility  before  ART.

For ART results  and cost  must be counselled.

Clomiphene citrate

Clomiphene  citrate is  a mixture of two  isomers enclomiphene 62%  and zuclomiphene  38%  zuclomiphene is more potent   more oesrogenic  and responsible  for ovulation   inducing actions . IT is in clinical use since 1967  for dysovulatory infertility   The efficacy of th drug  varies  in clinical  practice  if the proportion of enclomiphene and  Zuclomiphene  is not maintained.

Mechanism of Action

It acts purely   as antagonist  or antioestrogenic  agent. It binds with oestorgen   receptors at hypothalamus signaling lack of oestrogen  to hypothalamus. This is turn releases GnRH  which causes  pituitary to secret more FSH and LH. This   stimulates the ovarian   follicular   development.  As the duration  of action is longer  it allows  more and more FSH and LH  secretion  and so causes  multifollicular development . Clomiphene   has direct effect on ovary to stimulate  follicular   oestradiol  synthesis. It increases  the GnRH  pulse  frequency  in ovulatory  patients  and pulse  amplitude   in anovulatory  patients  like PCOS  . clomiphene   does not display  progestational corticotrophic androgenic  or antiandrogenic properties.

Indications of clomiphene  citrate

WHO group II  patients

It is  extremely effective in anovulatory  patients  in whom hypothallamo pituitary  ovarian  axis is normal . normal  thyroid   function tests and prolactin should be confirmed  before starting  the treatment . It is not effective  in hypogonadotrophic hypogonadism i. e. WHO group I, as there is negative feedback mechanisms of oestrogen,.

Luteal phase  defect

Short  luteal  phase  is associated  with  low  levels  of FSH  in follicular   phase  causing LPD. Clomiphene citrate will increase FSH and LH in follicular phase develop good follicle and correct the abnormality in luteal phase . So clomiphene citrate is the drug of choice in LPD due to short luteal phase.

Unexplained infertility

The rationale of using clomiphene citrate in unexplained infertility is that it corrects subtle defects due to deficiency of FSH and LH . It increases the number of follicles available for fertilization and corrects LPD. Cochrane database supports the use of clomiphene citrate in unexplained subfertility . Former belief of cervical dysmucorrhoes and decreasing endometrial receptivity with CC is not accepted and instead of contraindication unexplained infertility is the indication for clomiphene citrate in modern era.

Contraindications

1.                      Large ovarian cyst > 5 cms in diameter. The cycle can be started when size of the cyst < 5 cms on day 5 of the cycle.

2.                      Liver disease

Treatment Regimes

1.                      Clomiphene citrate is given as 50 mg dose daily between day 2 and day 5 for 5 days after spontaneous or induced bleeding Ovulation conception and pregnancy rates are same independent of the day when clomiphene citrate is started . But day 5 is the most accepted day for starting the treatment .

2.                      Most women   respond to clomiphene  with maximum 100 mg  daily dose. Higher  doses have very poor  pregnancy  rate. Prof  Bruno Lunenfeild  and Prof  Roy  Homburg have recommended only one dose to start with and maximum 100 mg daily . The advantage of using this dose is that it can  diagnoses  clomiphene  resistant cases earlier  and will cut down  superfluous cycles of treatement   till ovulation occurs.

3.                      RCOG  guidelines  with ACOG  recommendations is  that  clomiphene citrate  can be used  maximum   for 12  months in life  time and maximum for  6 months  continuously  therefore  monitoring for evidence  of ovulation  is a must when  patient  is on clomiphene citrate.

Monitoring

1.                      Serum progesterone in mid luteal phase if if > 3ng/ml it  is an evidence of ovulation

2.                      LH  detecting kit can help to know the LH  surge  normally  LH  surge  occurs after 7 days of the last dose of clomiphene citrate.

3.                      Serial  sonography just for documenting ovulation   is not justified. It does not help  to change  the line  of treatement . It is  very  inconvenient   to the patient  as compared to  s progesterone levels  being assessed a week  before  expected date of menstruation .

4.                      If LH on day 8-9 is > 10 iu/ ml success rate is very low   because  of poor quality  ova and embryo

5.                      EB  should not be   done to know  the proliferative or secretory  phase as it is an invasive test

Monitoring during  clomiphene  citrate  treatement  is must because   it can be used only for 3-6 months Majority  of conceptions occur within first three months.

Results

1.          Clomiphene  citrate  will induce ovulation in approximately  75-80 5 of cases.

2.          Upto  70-75% of cumulative  pregnancy rate can be achieved in 6-9 months

3.          In many  series only upto  405  pregnancy  rates  have been  achieved because  of antioestrogenic  effect on cervical  mucous  endometrium  ova and embryo 

4.          75 % of conceptions occur in the first 3 months  so in clinical practice many consultants use it only for 3 months . After 6 months of therapy , only few pregnancies are recorded in literature.

5.          So if the patient has not ceceived within 3-6 months with clomiphene citrate re evaluation of the  patient  and switching over to further   management is required

Side effects

1.          Serious  side effects are extremely rare

2.          Transient   hot flushes  mood  swings  breast  tenderness nausea and pelvic  pain may occur.

3.          Visual disturbances may occur which  are reversible after  cessation of treatment   . Alternative  methods  are tried  if patient  complains   of visual  disturbances.

Antioestrogenic  effects   of clomiphene  citrate.

Antioestrogenic effect  on cervix  endometrium ovary  ovum  and embryo  have been  described but there  is no objective evidence  that these effects occur  or have  clinical consequences  Endometrial  thickness is within   normal   range   in majority  of cases. Very   rarely  endometrium suppression  is observed  which is  less than  6 mm  inspite of a good mature   follicle clomiphene  citrate is not given instead this patient is to be   shifted over to other therapy Usually  same endometrial  suppression is repeated  in subsequent  cycles. Cervical   dysmucorrhoea  can be  overcome by  intrauterine   insemination   . In these  patients having antioestrsogenic  effect  even though ovulation rate is 805  conception  rate is only 40%  Exogenous oestrogen  supplementation   has no effect. It should not  be used to correct cervical  dysmucorrhoea  or increase   endometrial  thickness  Tamoxifen and letrozole  can be used  to overcome  these side effects.

Risks of clomiphene  citrate

1.                      Multiple  pregnancy

2.                      Miscarriage  : It does not increase  spontaneous  miscarriage   rate

3.                      Congenital  anomalies

There is no substantial evidence   that clomiphene   citrate  causes any particular birth  defects. It does not increase  open  neural tube defects as was previously suggested

Ovarian   hyperstimulation syndrome Mild  OHSS   may occur  in a few  case of PCOS  which requires only conservative management  Severe  PHSS is rare and 1 have  not seen  any in my  practice of  30  years .

Breast  and ovarian  cancer previous  studies suggested  that if clomiphene  citrate is used for more than 12  months  it  can increase  the incidence of ovarian malignancy But  subsequent   studies have proved  that fertility drugs  are not associated   with any invasive cancers Clomiphene   citrate  does not increase  the risk of breast  cancer.

Women   on clomiphene   therapy must be counselled that no causal  relationship  has been established between ovulation  inducing  drugs   and breast   or ovarian cancer . However  prolonged  treatement   with   clomiphene   citrat3e   is futile and should be avoided because   it has little  success. 

Treatment alternative

A  Extended clomiphene  treatment

1   . Clomiphene citrate is given for 7-10 days

2 150 mg of clomiphene   citrate  is given   for 8 days

3.                      50 mg / day  is given   for 5 days   and increment  of 50 mg/day is  done every  5 days  to reach  250 mg/day

No factors   have been  identified that can predict  which   patient will respond  to extended regime . Such extended  regimes   have extremely  poor  pregnancy  rates  and are  not much  helpful  in clinical   practice. 

Clomiphene   citrate +  Glucocortiocids

This  combination  is very useful in chronic anovulatory   patients  . It is also given  to those patients    who have high DHEA-S . It can be given  to all the patients  who show increase in adrenal androgen    production . It  has given good  results even  with normal  DHEA-S  and unselected   population   having clomiphene   resistance   due to increased androgen . Those  patients    who are resistant to 100-150 mg of clomiphene  citrate  start ovulating   when glucocorticoids  are added glucocorticoids  are given  in the form  of dexamethasone 0.5  mg daily or prednisolone 5 mg daily contiuously for 30 days at bed time. It can  be given   continuously for 3-6 months No  serious  side effects  are seen  though water   logging  and weight  gain  have been   documented. The dose  can be  reduced  to 0.25 mg / day  or can be stopped in 2  phase   of the cycle. As the  drug is very  cheap  and effective and does not have   any major  disadvantage  it should be tried  in chronic  anovulatory  patients   &  resistant PCOS patients.

Clomiphene  citrate + Oestrogen

Oestrogen   was tried to improve  cervical  mucous and endometrial   thickness  but  these effects  are not due  to the dosage   and duration     of treatement    of clomiphene citrate. It is   ideisyncratic  response   in a subgroup of patients   on clomiphene citrate  which may reduce  conception   rate. So its   combination  with oestrogen    is not  of any help and  should not be used in clinical   practice.  Empirical  treatment   with oestrogen  has no role.

 Clomiphene  + Bromocryptine

Bromocriptine is given  to the patients   with hyperprolactinemia But  there are two definite indication even  with normal prolactin level.

Galactorrhea with normal prolactin  level. In  these  cases galactorrhoea  must be confirmed  by presence  of fat globules under the microscope   in the secretions expressed   from the breast. It must be differentiated  from simple mucoid  discharge that does not have   fat globules.

There are  patients   who are known  as spikers  In  these patients    prolactin is increased  in the first half  of the cycle when  clomiphene   citrate is used for  ovulation  induction These patients  are given  bromocyrptine .   in first half  of the cycle . It is  not to be  continued in 2  half of the cycle as normal  level of prolactin is required  for maintenance  of corpus  luteum. Clinically  these  patients  show poor endometrium even though there is no local  cause and follicle  is very good and meet all parameters on b mode  and colour Doppler  for optimum follicle maturity. Bromocryptine can be tried in these patients and if  endometrium improves  it can  be continued for 3-6 months. `

Clomiphene citrate + hCG

Routine  use of hCG  for rupture  of the follicle is no justified  if the follicle is mature it will reflect  as serum oestradiol  level of >  150 pgm/ml. This  will initiate   the LH surge  which in turn will course rupture   of the follicle   and exogenous hCG  is to required . But if the follicle is not mature  and if hCG  is given as a trigger  for ovulation. It will  lead to premature luteinization or atresia. Therefore hCG musts not be  given  just to cause  a follicular  rupture 

But hCG  can be combined with clomiphene when IUI  is to be done hCG  in these cases  is done to time IUI as follicle ruptures   34-36   hours after hCG  injection , hCG can also be  given  in patients   proved    to have absent   inadequate  or  delayed  LH surge  This is a common occurrence  in endometriosis hCG  therefore   must be used for timed intercourse  to time IUI and din cases of delayed LH surge.

Clomiphene  citrate + gonadotrophin

Gonadotrophins  are often combined  with clomiphene with  the idea that it would decrease  the requirement of gonadotrophins Clomiphene citrate  by its  direct effect on ovary increases the sensitivity  of ovary to gonadotrophins  This  combination has risks of ovarian   hyperstimulation and multiple pregnancies

Personally I am never  convinced by this combination and would never use it . It does not  increase  the pregnancy  rate. The argument  is that   clomiphene  citrate increases FSH and LH both. The poor  pregnancy  rate with   clomiphene  citrate is  because of high   LH  which will remain inspite   of adding  gonadotrophins. The effect of high LH  will decrease   the implantation  and pregnancy   rate. So even though  we get a follicle after   adding gonadotrophins  in many of these patients   the follicular   quality is not good and pregnancy  rates  are only comparable to clomiphene citrate  alone and much les than gonadotrophins alone. Instead  letrozole   is a better drug to be  combined   with gonadotrophins. This will be discussed elsewhere.

GnRH  agonist

GnRH  agonists are not used routinely in IUI cycles and are reserved only for IVF cycles. Agnoists are used  for down regulation in IVF  but this in IUI cycles only increases the requirement of gonadotrophins without increasing the pregnancy rate.

Clomiphene citrate + Antagonists

This makes a good  combination in thin  lean PCOS patients   where LH  is tonically raised. It improves the quality of ovum and also the conception rates. For patients on clomiphene  therapy  serum LH levels  are checked on day 8-9  of he cycle. If it  is > 10 iu/ ml it is  an indicator of poor   pregnancy  rates. These are the ideal   patients  to start  antagonists. Regular  use of antagonist  is not  justified because   it sharply decreases  LH  and quality of follicle  is changed and it causes  regression of follicle as well as luteal  phase  defects.

Clomiphene  citrate+ Metformin

Several  workers  have shown  that metformin is inferior to clomiphene   citrate   for ovulation   induction and metformin  alone should not be used for   ovulation  induction . but in CC resistant causes of PCOS when metformin is  combined with CC it improves  ovulation 4-9 times more   than clomiphene   alone. This shall be further discussed in the chapter    on PCOS   But  metformin  is a very useful  drug when   patient  does not want  to conceive  immediately if metformin  is take for 6 months  it will normalize  hormonal  milieu it will decrease  LH  decrease androgen so it  CC is given  when patient   wants to conceive   ovulation will occur  and will decrease  the incidence  of multiple  pregnancy  also.

Clomiphene  citrate  + drilling

It is done in CC resistant cases Drilling is also done before   switching over  to gonadotrophins.

Prior  treatments

Clomiphene   after prior treatment   with OC pills   The mechanism  of action of OC pills is to decrease  the LH surge High LH will cause    high androgen which   in turn will cause   anovulation  So OC pills  when given  for 2-3  months  will decrease the LH  and in turn decrease  androgen   and improves sensitivity to clomiphene  with the same  dose. Therefore  in PCOS  patients  prior treatment    with OC pills was given  routinely in CC resistant cases  and did show  good results

Micronised progesterone

If it is given for 5 days  it modulates LH  pulsatility reducing LH concentration and induces more  favorable  environment for CC  

Letrozole

Introduction

Letrozole is an aromatase  inhibitor  used for ovulation  induction . it is   the third  generation  of aromatase inhibitor. First  and second  generation of  aromatase inhibitors    are not used in  clinical   practice. The main  advantage of the drug  is that it is a  reversible  enzyme inhibitor It was for the first  time used by Mitwally  et al in 2001  for ovulation   induction.

Mechanism of induction of ovulation 

Aromatase a  cytochrome  P450  dependent  enzyme  acts as  ultimate step  in synthesis  of oestrogen  catalyzing the conversion of  androgen  to oestrogen . This conversion  occurs at  peripheral  sites  such as muscle  fat and liver  . Letrozole  inhibits   aromatase enzyme by completely  binding to the heme  to cyto 450  subunits   of enzyme  so that  androgen   is not converted to oestrogen .

The end    result is  low oestrogen   causing negative feedback at  hypothalamus   and pituitary   releasing FSH  and LH  releasing factors  resulting  in high FSH   and LH  causing     folliculogenesis.

As androgen  is not converted into oestrogen   there is  slightly higher level   of androgen which also causes folliculogenesis. Letrozole has no effect on oestrogen   receptors  and acts  on hypothalamus  so it has no deleterious effect on LH surge cervical  mucous   and endometrium

As FSH  and LH stimulates  folliculogenesis oestrogen  will rise  and will cause negative feedback  on Fsh  release so  FSH will decrease. This decrease  of FSH is responsible   for monofollicular  development as  other  follicles  will not grow. This is not the case   with clomiphene   citrate   which binds with  the oestrogen   receptors  and FSH  will go n rising inspite   of high oestrogen   leading to  multifollicular   development with CC. Another important   advantage  is that along  with FSH , LH  will not decrease  and so quality of an ova is not disturbed and does not affect  implantation.

This is  another advantage over clomiphene citrate  which causes  persistent high LH  along with FSH

Indication

1.                      CC resistant cases : when  100-150 mg of CC fails to induce  ovulation  letrozole should be tried

2.                     
PCOS : Here baseline E2 is elevated which blocks   hypothalamus causing an ovulation. Letrozole will reduce   oestrogen  and stimulate hypothalamus  to release  LHRH  to  secrete  more FSH   and induces  folliculogenesis.

3.                      It is useful in cases  where CC induces cervical  dysmucorrhea and  poor endometrium Letrozole  is devoid  of  antioestrogenic effect as it does not bind to oestrogen  receptors.

4.                      When LH is elevated   on day  8 or day  9 with  CC letrozole  should be tried.

Characteristics  of    letrozole

It causes total suppression of oestrogen   with does upto 5 mg /day  Maximum suppression occurs  between day 5-7

After  day 7 oestrogen level  will rise  due to folliculogenesis  because  of increasing FSH  after negative  feedback of oestrogen  due to letrozole.

This  rise of  oestrogen  will continue  for 5-7  days . This E2  peak will cause  LH surge  for ovulation  So LH surge   occurs  after 12 days unlike  CC where it  occurs early

Oestrogen rise   after 7 days will decrease FSH  which is responsible for monofollicular   development

It has no antioestrogenic effect on cervical  mucous or endometrium

Temporary  rise of androgen improves the sensitivity of follicle  to gonadotrophin it therefore requires  lower  dose of gonadotrophins when it is combined with  letrozole

Advantages  of Letrozole

1.It is  almost free from side effects

Monofollicular  development 

No anti oestrogenic  effect leading to higher  pregnancy rates

Low multiple pregnancy rate  due to monofollicular  development

Low abortion rate because  of no effect on endometrium

Higher  androgen   stimulates  follicle and so lower doses of gonadotrophins  are required

Doses

Recommended dose is 2.5 mg from day 3-7

Some  workers suggest 5 mg dose. Five mg dose as routine is not justified as  2.5 mg can suppress 97-99%  of oestrogen . 5 mg may suppress So it may not cause  monofollicular development As it is a chemotherapeutic agent it may be  toxic  to ovum   and embryo

20 mg on day 3 it has advantage   having short half life and reduces  embryotoxic  effect. But symptoms  of hypooestrinism may  develop

It is superior to anastrazole 1 mg from day 3-7

Side  effects

It increases  intra follicular  androgen   which may arrest the growth  of follicle . but optimum  level of androgen   is not yet decided.

As it is chemotherapeutic agent for  carcinoma  breast  it may be teratogenic to ovum  and embryo .

Future   uses :

Improves implantation  in IVF  some women   have high levels  of aromatase p450  in endometrium and is related   to poor IVF  results. It can be useful to these patients.

Decreased supraphysiological  oestrogen  and decreased  aromatase will improve  implantation

It stimulates follicles   for Invitro  maturation in PCOS

Author’s view

Should letrozole replace CC ?

Strongly believe that letrozole  should be used  as the first line of drug  . The argument is  that  it has comparable pregnancy rate with CC  and it does not  increase  congenital malformation . The main advantage is it has no antioestrogenic effect on cervical  mucous  and  endometrium and so it will cut down  superfluous  cycles  of treatment

Letrozole  +  gonadotrophins

We have  found letrozole +FSH a very useful combination for giving equivalent   pregnancy  rates like  gonadotrophins with advantage  that lower  number   of ampoules of FSH  are required. Apart  from this  it given lower rate  of multiple births it sensitizes  ovary by rise  in androgen  level &  an added advantage  is that  reduces  number of gonadotrophin  ampoules We have used this combination  routinely for superovulation with  IUI. So  letrozole is  superior in PCOS  and poor  responders  than CC

No anti oestrogenic  effect is the single most important  benefit with letrozole that prevents the use of CC