Unexplained subferility

.1: Causes of subfertility: Studies   of populations  infertility  20 %-30% revealed  that  A)     ovulatory dysfunction   20%-35% B)   tubal damage 10% -50%  C) sperm dysfunction , 5%-10%   D) endometriosis-10%      E) 5% cervical  mucus   problems   and  F)  5% coital   dysfunction.. Its couples problem.

. Q.2: It is one person’s diseases!!!  A degree of subfertility  is found in both partners    in 30 %  - 50%  of couples  as usually  a couple’s  subfertility   is a relative  rather  than an absolute  barrier  to conception. It should be   remembered that the greater the   prevalence of a condition the greater the predictive value of its screening test. So everyday   tests are of most   value in detecting   the commonest   causes of subfertility.

Q.3: : Unexplained  infertility’ ---Why not to wait for detailed costly investigatios and further complex treatement  ?? Is there any clear protocol when we should  initiate  detailed investigastins in a case of  Unexplained subfertility.  What is known to us about    Unexplained  infertility ?  It has   been defined    as the inability  to conceive  after 1 year in the absence    of any abnormalities.  But fortunately, A)  the natural   pregnancy  rate in couples  with unexplained  infertility has been reported   as between  2%  and 4%  per menstrual  cycle. One study reported B) spont   conception   rates of 15%   of couples  with unexplained infertility within 1 year   and  C) 35%  within 2 years  . And   the D) cumulative chance   of pregnancy   over 3 years   has even been   reported as being   80% . Therefore   it has been suggested that treatment   should be deferred until the couple  has been   trying to conceive  for 2-3 years and age of Female parter is < 32 yrs. as before   this time   therapy   may not   confer any benefit   over the   natural   chance of conception  .

 Q.4: What are the limitations of tests designed for subfertility??  Ans: The   limitations of the various tests    however also should be appreciated .For instance A)  tubal patency   does not necessarily equate  with normal   function  and  B) an elevated   luteal phase    progesterone   concentration does not confirm   that an oocyte has been released  from the follicle.  

  Q.5 : If one decides for tests then what tests to do?? : It is presumed that the couple had had schedule tests  like  assessment    of ovulation.,  routine seminal analysis ,  and tubal patency  . Now the  question that comes are   supplementary investigations such   as  1) follicular   scanning  for entire cycle unstimulated,  2) laparoscopy  / hysteroscopy  with endometrial    biopsy       and  3) complex    sperm function  tests  are  useful  in helping  to predict  the chance  of conception  but they may not   influence  th outcome  of treatment.

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Q.6 :  Etiology of Unexlained subfertility ::  POSSILE  SUBTLE CAUSES  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 et afford dfor such all tetsung in  agiven cvase?.

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 .Embyological   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

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. Q.8: Doctors biasness about one spl 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.

Clomifene   Citrate

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

There are few  prospective   randomised studies  involving the use of  gonadotropins  alone in  the treatment of unexplained   infertility   and most of the studies   that have   evaluated   gonadotropins   with IUI are  retrospective analyses. 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. 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.