Minor causes of Unexplained subfertility

PROPOSED FOR SUBFERTILITY

 Subtle causes of subfertility that have  been proposed   as underlying  unexplained infertility   many of such defects  are also observed  in couples of normal   fertility

A)      Ovarian   and endocrine  factors

1)    Abnormal   follicle  growth 2)Luteinised  unruptured   follicles   and 3) functional ovarian cysts 4) Hypersecretion    of luteinising  hormone 5)Hypersecretion of prolactin  in the presence  of  ovulation 6) Reduced  growth hormone secretion / sensitivity  

B)      Cytological  abnormalities    in oocytes

C)      Genetic  abnormalities  in oocytes

D)     Antibodies  to zona  pellucida

E)       Peritoneal  factors

F)       Altered macrophage   and immune  activity

G)     Mild  endometriosis

H)     Antichlamydial antibodies

I)  Now the question arises can the couple  afford for such all testing in  a  given case?.

Tubal    factors

1)       Abnormal peristaltic or cilial  activity 2) Altered macrophage   and immune activity

Endometrial factors

1)    Abnormal   secretion of endometrial proteins(genetic/ inflamm) 2) abnormal   integrin / adhesion molecules 3) Abnormal  T cell   and natural  killer   cell activity  4)Secretion  of embryotoxic   factors 5)

Abnormalities in uterine  perfusion  and contractility

Cervical   factors

A 1) Altered cervical   mucus increased  immunogenicity  , 2)

General   immune factors 3) Altered cell  mediated immunity

Male factors

Reduction in motility acrosome reaction oocyte   binding  and zona   penetration ,Ultrastructural abnormalities  of head  morphology .Embryological   factors . Poor  quality   embryos

Reduced progression  to blastocyst in vitro

Abnormal   chromosomal   complement -  increased  miscarriage   rate

 It  appears that  the most   important prognostic factors  are the duration of infertility and   the age of the female  partner . Of   course the rate of progression to treatment  through   the various therapies  that are used  to boost fertility will  depend   upon the  age of the couple and their levels  of anxiety  together  with the available  resources.  The management  of unexplained infertility is usually empirical but couples   undergoing  treatment   should always be treated   as individuals.

Management  of Unexplained Infertility

. Doctors biasness about one on different uncommon tets which is common,  cause for unexplained subfertility!!!  Ans: Many centres have their own highly specialised    areas of interest   and research that they then promote   as the missing cause of unexplained   infertility    . Thus it  is possible    to draw long   lists    of putative   and subtle cause  of infertility many  of which cannot be  proven with certainty   and few of which    are actually amenable     to a corrective remedy    that has been shown to enhance    fertility    . One also    should remember    that couples with normal   fertility can  have abnormal test results. Once the well known   and obvious   causes of infertility have been excluded   the treatment   of couples  with unexplained  infertility should   follow clear   protocols.

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How best to treat U subfertility??  Ans: There are several    approaches  have been   used in the management    of unexplained  infertility ? Some of the therapies  that have  been used are discussed  here and we  propose   a stratified   protocol  used in practice. Therapy should  aim to boost  the monthly  pregnancy    rate above  the natural rate  of 1.5% -3%   that is expected  for couples who have been  trying  to conceive   for over a year

The relevance of  Clomifene   Citrate

In Unexplained subfertility: It used to be   though that clomifene enhanced fertility by  correcting   a subtle defect  in ovarian  function  - either   of follicular    development  or of  luteal phase   defect    . It  appears   more likely however that stimulation   of ovulation achieves  its effect by increasing   the number  of follicles    that develop  and consequently the oocytes   that are released  When  using clomifene  citrate one should  always   remember the side    effects   of multiple   pregnancy and   the possible   association between   its prolonged  use  and the putative   risk of ovarian    cancer  . Over the years many studies   have been published  and systematic  reviews have fluctuated in and out    of favour for the  use of clomifene  for the management of  unexplained   infertility. The latest   Cochrane   review of data relating   to 1159    participants    from seven randomised trials   reports  no  evidence   that  clomifene   was more   effective   than no  treatment   or than placebo   for liver  birth   or   for clinical pregnancy   both with intrauterine   insemination   without   and without   IUI  but   using human chorionic   gonadotropin.  

Superovulation  with IUI is the best option for Unexplained subfertility.

Gonadotropin therapy   requires   careful  monitoring   with   serial   ultrasound  scans   to minimise   the risks of  ovarian  hyperstimulation syndrome and multiple   pregnancy   .

It is  reasonable    to expect   that the combination  of gonadotropins to induce   super ovulation   with the release   of two or three  oocytes with   insemination   of a prepared  sample sperm   into the uterine   cavity   should boost  fertility. There are  however contrasting    studies in the literature. A meta analysis in the Cochrane database   has  recently   published  the evidence of a benefit  of IUI alone with expectant management    but  when ovarian  stimulation   was used IUI   increased the Chance  of pregnancy compared  with timed intercourse . A  significant   increase in live birth rate was   found for women where IUI   with ovarian stimulation was compared  with IUI  in a natural   cycle . However   the trials provided    insufficient data  to investigate the    impact  of IUI  with or without   ovarian hyperstimulation    on several important outcomes  including live births multiple pregnancies miscarriage and risk of ovarian   hyperstimulation . There was   no evidence of  a difference in pregnancy  rate for IUI  with ovarian stimulation compared with timed intercourse  in a natural   cycle and interestingly   IUI in   natural   cycle was better   than timed  intercourse with ovarian    stimulation . In  summary there   is evidence   that  IUI with ovarian stimulation  increases  the liver birth   rate compared with  IUI compared with timed intercourse  in stimulated cycles. Overall   IUI with   ovarian    stimulation   appears  to have  a potential albeit   relatively  limited   role in the management   of unexplained  infertility  .

 Melis et al have reported  a large   prospective randomized study   comparing gonadotropin   therapy  and timed  intercourse   with gonadotropin therapy  and IUI .

Two  hundred  couples    with at least  3 years  unexplained  infertility  received  superovulation with follicle   stimulating   hormone to   produce at least two follicles. There was  no significant  difference  in the outcome  of the  two groups with a cumulative conception  rate of   approximately  43%  after  three  cycles and a multiple  pregnancy   rate of 10 %      

 . A similar    study from  Glasgow    randomised 100 patients to receive  ovulation  induction using   pituitary  desensitization  with     a gonadotropin  releasing hormone agonist followed by FSH    with   timed intercourse of IUI    group compared   with 18%  in the timed   intercourse  group.

Superovulation with IUI Protocols

The rationale   behind   superovulation   with IUI encompasses the deposition of a prepared or enhanced   preparation  of sperm as close   as possible to at least  one oocyte    sperm  can  be prepared in many ways  the most     common of which   includes simple sperm washing  swim up techniques and gradient separation techniques .  Sperm   washing  is achieved  by diluting a sample         of liquefied     sperm in culture  medium followed by  centrifugation  and resuspension in the  medium thereby  removing   seminal plasma   but leaving   bacteria and immotile spermatozoa in the   preparation .

Details of  Superovulation with IUI Protocols

IUI methodology 1 The swamp up method : The sample  is enhanced further  if the wash     is repeated and the sperm  then left   to swim up  to the surface  of the media   for 30-60  min .  Whence it is   recovered    leaving    debris bacteria   and  immotile   spermatozoa at the bottom    of the tube. The    supernatant should  now contain 80-100%   motile sperm   and a significantly  higher   percentage  with normal   morphology  . IUI methodology 2: gradient separation techniques: Alternatively sperm can be layered on an isotonic  Percoll column which provides   a density   gradient  for the separation     of morphologically   normal   motile  spermatozoa.

What protocol will be better in IUI procedure where aim is monofollicular growth??  Ans: Step Down !!! Ovarian    stimulation is optimally achieved  using gonadotropin injections  without prior   pituitary  desensitization  . We have   found a step  down protocol   follicles  using a starting   dose of 150 units and dropping   to 75 units  after  three doses. Treatment   is started on day 2 of the cycle and ultrasound  monitoring  is commenced   on day 8. Stimulation is  continued and the dose adjusted   as necessary   until   there are   tow follicles of 16 mm diameter or more  with the largest  follicle   having   a diameter   of at least   18 mm  and no more than and no  more than  three follicles   in total greater than 14 mm. With   this   approach   the monthly rat of conception   is approximately  15% -20%  and the  4 month cumulative conception rate is 40% . the risk   of twins is in the  region  of 20%   and the rate of  triplet  pregnancies is less than  1%.

The main  concern   is that ovarian    stimulation increases multiple  pregnancies  Nonetheless we   believe   that   with careful  ultrasound   monitoring   and strict  criteria  for cancellation if there  are more  than    two mature  pre ovulatory   follicles  the multiple pregnancy  rates     should be  able to  be kept to less than 5% .

How helpful is IVF in cases of unexplained subfertity?? Is it so or results of IUI with IVF are similar to Gonadotrophins and IUI (with either swim up/ gradient method) ? Let us see what Cochrane database analyzes.

. The Cochrane   database included six   studies  and showed  that the live birth rate per woman   was  significantly  higher with IVF   than expectant  management      . There was no   difference   in LBR   between IVF   and IUI alone    . In studies   comparing IVF   with IUI +  ovarian stimulation   LBR  per woman   did not   differ significantly between the groups  among  women who   had yet  to receive  any treatment     but was   significantly   higher in a large   RCT of women   pretreated  with IUI +   clomifene   citrate  who    had IVF    compared    with IUI   . There  was no   evidence   of a significant difference in multiple   pregnancy rate or ovarian   hyperstimulation    syndrome  between the two treatments.

We believe  that it seems    sensible to progress to IVF  in couples with unexplained  infertility   after initial  treatement with  superovulation / IUI . In women    more than 35  years of age we believe  that IVF  should be  offered  as first   line therapy .