IVF Calculation of dose of Gonadotrophiuns by basal scan and oter parameters-Many methods to prognosticate the outcome of IVF

 

What is the relevance of basal scan, more so in prposed IVF Cycles ??  Ans: This scan is done on days 2-3 of the menstrual cycle    because at this phase of cycle    ovarian hormonal    levels   are at their baseline. The ovaries    are silent and have no active follicle     or corpus    luteum at this stage. The scan   is done using   B mode ultrasound preferably with color Doppler,    if facilities exists then may please add  pulse Doppler,  three  dimenstional  ultrasound and 3D   power Doppler   .

This scan   assesses   the ovarian     reserve(AFC)  and response   . Earlier it was though that such scan is

  also a key scan for ultrasound diagnosis of   polycystic ovaries but more reliance is pad in clinical signs of hyperandrogenism/hyperinsulimia and endocrine markers.

 Can we forecast the possible response of ovaries to gonadotrophin stimulation?? Ans:  There are many indices to prognosticate the outcome of IVF so far as retrieval oocytes are concerned?? AFC, AMH, Her age, Level of basal FSH, previous dose used are still the most common parameter used to prognosticate the  kind of response by gonadotrophin , initial and maximum dose in particular .

 

 Method No 1: What is Bologna criteria??  Assessment of ovarian reserve  and response   has been   tried by several workers   Bologna criteria also   defines poor  responders as those with A)  age  more than 40 years   B) less than   three follicles per   ovary and C)  anti Mullerian   hormone  less than 0.5 -1.1   ng/mL . In 1988 in Bellagio (Italy) a conference was held to reach a consensus statement to define Lactation amenorrhea method as a method of contraception and it was stated that, a postpartum woman has at least 98 percent protection from pregnancy for six months when she remains amenorrheic and fully or nearly fully  We are aware that it is this city where Breast Friendly Hospital program was formulated and accepted by most of the nations.    

. One of the  earliest  studies  by Ravhon et al  has   used  dynamic assessment of  inhibin B   and estradiol after  Buserelin acetate   as predictors   of ovarian   response    and have found  these to be highly  correlating   with the ovarian   response in IVF   patients  . The two    major drawbacks of this study  are that this  required several  blood tesis   at different times and the study sample  was pretty small .

Method No 2:: There are many indices to prognosticate the outcome of IVF so far as retrieval oocytes are concerned ??     Can we use 3D  ultrasound for assessment   of ovarian  response in IVF cycles?? Yes. Very much. For instance      In 2002   Kupesic  et al used 3D  ultrasound for assessment   of ovarian  response in IVF cycles. A) The antral   follicle   count    and  B) ovarian stromal flow   parameters        on the baseline  scan were shown   to be most   predictive of the ovarian  response   after pituitary  downregulation in this study   followed by total  ovarian   volume ovarian   stromal   areas and age. This   study could predict   favorable IVF   outcome   in 50%   of patients and poor   outcome in 85%    of patients   . Using this nomogram for dose calculation was   evaluated by the same   group in another    study. The results of this study   were in absolute   favor of individualizing   dose according to the dosage   nomogram   proving   the reliability of ultrasound   parameters and  age    and body  mass  index for decision   on stimulation  doses.

 

There are many indices to prognosticate the outcome of IVF so far as retrieval oocytes are concerned ??   Method No 2:  Can we use 3D  ultrasound for assessment   of ovarian  response in IVF cycles?? Yes. Very much. For instance      In 2002   Kupesic  et al used 3D  ultrasound for assessment   of ovarian  response in IVF cycles. A) The antral   follicle   count    and  B) ovarian stromal flow   parameters        on the baseline  scan were shown   to be most   predictive of the ovarian  response   after pituitary  downregulation in this study   followed by total  ovarian   volume ovarian   stromal   areas and age. This   study could predict   favorable IVF   outcome   in 50%   of patients and poor   outcome in 85%    of patients   . Using  this nomogram for dose calculation was   evaluated by the same   group in another    study. The results  of this study   were  in absolute   favor of individualizing   dose according to the dosage   nomogram   proving   the reliability  of ultrasound   parameters and  age    and body  mass  index for decision   on stimulation  doses.

 

There are many indices to prognosticate the outcome of IVF so far as retrieval oocytes are concerned??   Method No 3 :  a study  by Ng et al  showed basal  follicle  stimulating    hormone to be   the most  reliable  parameter   for assessment  of ovarian   response   followed by AFC and BMI  . Where   AFC was predictive of   number  of follicles   on the day of human   chorionic gonadotropin and BMI  was predictive of gonadotropins dosage .An  ultrasound based  study on prediction of ovarian response  in  2007   by Merce   et al   evaluated ovarian volume AFC  and 3D   power  Doppler  indices    vascularization index flow  index   and vascularization flow   index for their   reliability  to  calculate the number of    follicles grown   oocyte  retrieved embryos   transferred      . This study   clearly  showed the relevance of ovarian volume  and AFC   to the number of   follicles  matured and oocytes   retrieved. It  also mentioned  that 3D   power  Doppler   indices made the assessment of  ovarian response   to stimulation   protocols  easier.

But these studies   do not have   a precise dose  calculation  strategy.

There are many indices to prognosticate the outcome of IVF so far as retrieval oocytes are concerned??   Method No 4 : Yet another predictive model for dose calculation  prognostication of IVF ??   Few researchers in 2003   combined age,   BMI,  cycle length  and smoking  status   and ultrasound   features of the ovaries   also to design    a dosage  nomogram of recombinant   follicle    stimulating hormone   for IVF/ intracytoplasmic   sperm injection   patients. This   was   a prospective study    and also had a larger   sample volume than the    previous   two studies   . According to this  study total number of   antral follicles   and ovarian stromal   blood  flow were the two most significant   predictors of ovarian response  and ovarian   volume   was highly     significant   predictor of number of   follicles   and oocytes   retrieved. Few researchers have also shown   that daily    FSH dose may be   calculated on the basis of age AFC and serum  AMH   levels  in a patient.

Another    landmark study   by Olivennes  and Howles  et al  - The CONSORT   study used  basal FSH.  BMI .  age and AFC for individualizing   FSH dose  for ovarian stimulation . A dose   calculator was developed using these  factors  as predictors and    was evaluated   in a  prospective  clinical   trial .

The only study that worked  on the dose   calculations  for IUI patients  was by    Freiesleben NL et al in 2008   with 159   patients.  They  evaluated    age , spontaneous  cycle length, body     weight,    BMI    smoking   status total   ovarian  volume   AFC   total Doppler   score  of   ovarian stromal  blood flow  baseline FAH and  estradiol  as possible  predictive factors   of ovarian  response. This study   concluded  that body weight   and AFC    may be used      to achieve     appropriate    ovarian response  for IUI   in ovulatory patients  . Study     by the  same investigators for IVF   and ICSI  patients concluded that AFC   and age  could predict   the low  response    better  whereas  to predict  hyper response  AFC and   cycle   length were   better   parameters.

The parameters that we  have used  to calculate   the dose for  gonadotropins stimulation   protocol  for IUI cycles in our   study  are AFC  ovarian   volume   stromal  resistance   index and   peak systolic  velocity  and age and BMI . Before  proceeding  to the actual dose calculation   protocol  a short   justification     for each   parameter     used would be considered    relevant . As AMH   has been already   established  as a reliable   parameter   for assessment of ovarian  reserve   the AFC  and  ovarian volume the are considered for the assessment of   the ovarian   reserve would the compared with AMH. 

Anti  Mulleirna hormone and AFC both have reflections of   primordial   follicles  and both are stable between cycles  . Serum   AMH    levels have been shown to strongly correlate  with the number of antral follicles and have appeared to   by   cycle independent. In   a meta analysis by Broer et al it has been shown that   AMH  has at least the same level    of accuracy   and clinical   value for the prediction of poor   response   and non pregnancy as AFC. Both AMH  and AFC  are  accurate   predictors of excessive  response to ovarian   hyperstimulation. Difference   of correlation  co efficient     between   AFC and AMH  for ova retrieved on ovum pick up is minimally significant in PCO   group. Therefore  for both   groups AFC alone may suffice as a test for estimation of ovarian  reserve.

Doing   AFC   assessment alone would  be more   cost effective for predicting   the ovarian    reserve in patients undergoing  controlled ovarian    stimulation with gonadotropin    releasing hormone   antagonist AFC had  the  highest accuracy  for predicting  ovarian  response in patients with    abnormal   ovarian   reserve   test and was    statistically    significant   than significant  than AMH  in predicting    ovarian  response . For prediction of poor  ovarian  response a model  including    AFC+  AMH  was found   to be almost  similar  to that of using AFC  alone.

Precise   calculation of AFC therefore  can help in predicting  the ovarian   response. This can be done  on two dimensional ultrasound   or by 3D  with inversion  mode rendering  and Sono  AVC a specialized 3D ultrasound   software   for calculation of antral follicle   number   and   volumes    jayaprakasan    et al have shown   that calculation of follicle  number   per ovary    with 2D  or 3D have given   identical   results. Though 3D with   sono AVC may be more  precise in cases  with AFC   being more   than 12-15  . There  is least    chance of follicles being missed   or being    counted   twice  because     of color coding   when Sono AVC   is used for   calculating   the AFC But  post processing  is required     for   accurate   calculations . It takes longer   to perform   because of the   need for  post processing  and obtains  values that are   lower than   those obtained by the 2D  and 3D MPV  techniques   as it does   not over count.

According   to one study    ovarian  volume less  than 3 cc was significantly     predictive  of higher IVF  cancelation rates more than 50%  and ovarian    volume  can be used in decision   making for stimulation  protocol for ovarian induction .   Moreover   it is also    known that the patients   who  have   larger ovaries   and are
PCOS   have a higher risk of     developing  OHSS. AFC and ovarian volume provide  direct measurements   of ovarian  reserve. The mean   ovarian diameter   significantly correlated with age  day 3 FSH  day 3 Lh  and day 3   estradiol . but  another study  shows  that ovarian   volume  is a poor predictor of number  of  oocytes obtained  in an IVF  cycle as compared   to AFC.

Inclusion  of stromal  blood flows   as one of the decision   making parameters  is also considered. It has been shown   that measurement  of ovarian stromal   flow in early  follicular   phase  is related to subsequent   ovarian response in IVF  . Ovarian   stromal blood flow velocity    after 2-3 weeks of  pituitary   suppression is a true   representative   of baseline ovarian  blood flow  and predictive  of ovarian responsiveness and outcome of IVF  treatment.

The ovarian stromal blood flow was   found to be   negatively  correlated  with age. Ovarian    blood flow  predicts ovarian   responsiveness and hence    provides a  noninvasive  and cost effective  prognostic   factor of IVF  outcome.

 

Ovarian   stromal PSV   after pituitary   suppression is predictive of ovarian  stromal PSV   was the most important  single   independent predictor of ovarian response   inpatients with normal basal   serum   FSH levels. Patients   with   PSV  more than or equl  to 10 Cm/s  had significantly higher median  number     of mature   oocytes   and higher   clinical pregnancy    rates. Ovarian   stromal blood   flow velocity  after 2-3  weeks of  pituitary  suppression is a true   representative  of baseline  ovarian   blood flow  and predictive of ovarian responsiveness   and outcome of IVF  treatment.

 Considering  the 3D power Doppler   indices that are representation of global vascularity of the organ   of interest   it has been demonstrated that VI, FI  and VFI of the   ovary were significantly    related to ovarian response  to stimulation.

Kupesic  has shown    correlation   between the ovarian   stromal FI and  number  of  mature oocytes  retrieved in IVF   cycles and pregnancy rates. This study    has shown    that stromal   FI < 11 indicates   low responder , 11-14 indicates   good and > 15  has a high  risk of ovarian   hyperstimulation  syndrome   . Women   with polycystic ovary  syndrome had higher   AFC   ovarian volume         stromal  volume   and  stromal  vascularization   . Though 2D power Doppler   indices were not higher  in PCOS    than in controls.

Total  ovarian   VI and VFI  were  significantly     lower in  women aged more than   or equal  to 41 years . Quantification   of ovarian stromal  blood flow by 3d power Doppler Us in women  with endometriosis    may provide   an important   prognostic indicator   in those undergoing   IVF.  Undertectable basal ovarian   stromal blood  flow     in at  lest one   ovary  is related to low  ovarian    response in infertile women   undergoing IVF   embryo  transfer.

The role of the ovarian   stromal  flow in variable ovarian   response can be  explained  by a simple understanding  . If the   blood flow to the ovary is abundant more percentage of the   gonadotropins   loaded  into the patient’s  system will    reach the ovary and        therefore  total    amount of gonadotropins   to be used for the    patient may be   less and vice   versa. Therefore   if blood   flow to the ovary is more   the patient  is a good   responder     but if the flows  to the ovaries   are less   she is a poor   responder.

Total   number of  antral follicles  achieved        the best predictive  value for  favorable IVF  outcome  followed by ovarian   stromal Fi, total      ovarian    stromal  area and total ovarian volume. AFC ovarian   volume and ovarian 3D     power  Doppler    flow indices did not significantly   change after  a short term   treatment   of GnRH   agonist  for pituitary  downregulation.

And    therefore   these parameters can be used as reliable   parameters for  assessment   of the ovarian reserve  and response   to decide the stimulation    protocol in non down  regulated IUI cycles as well as in agonist and antagonist      down   regulated IVF  cycles   also .The    ovarian    stroma flow is less in obese   patients require   higher doses  for  stimulation Elevated    luteinizing  hormone levels  may be responsible    for increased   stromla vascularization   due to neoangiogenesis catecholaminergic stimualiton    and leukocyte   and cytokine  activation. Does  this    mean that    when the LH   is low ovary   may show   less flow  and it is in these  patients  that there is  a need  to add Lh to their   stimulation.