Methodology of abdominal route of sonogrophay & Folliclular monitoring

How to measure a follicle in ovulation induction process and estimation of endometrial thickness? What is basal scan? Technology of vaginal route of sonography & abdominal route of USG Let us discuss about the types of endometrium

Why the A,B, & C  types of endometrial pattern which was quite popular in the late eighties and early ninties have become unpopular?? It is akin to unpopularity of POP-Q quantitive classification  of genital prolapse which never gained popularity.  Problem :-Endometrial     pattern  was frequently reported as  (initially described  in 1984 )-  any of three  patterns. These are namely   type A, a  multilayered triple line endometrium  consisting of a prominent outer   line or layer a central hyperechogenic   line and an inner hyperechogenic or   black    region , type B    an intermediate isoechogenic  pattern with the same reflectivity     as the surrounding  myometrium and type C   :-  a non   prominent   or absent central echogenic   line an entirely   homogeneous   endometrium without    a central   echogenic   line. But there was subsequently others reversed  the ABC   pattern and people had confusions!!! 

However, most present   day gynae spl   no longer use ABC   pattern. Why?? -What is the members view on not being popular method of classification of endometrium? By contrast people are now switched over to  previous terminology  i.e. in descriptive pattern . to avoid any ambiguity. However still some Sonologist at Kolkata still report in the format as ABC system of endometrial echogenecity & other adjectives .But we should be aware that any methodology is correct. One may follow either classification  system  .

Most present    day authors  no longer use ABC   classification but instead use  the terms A)   triple  line and homogeneous   to describe   the two most  common endometrial  patterns. A third term post ovulation     is used to    describe the B)  bright pattern seen  during  the mid luteal  phase.

LFT in pregancy

LFT in pregancy : In normal   pregnancy    serum AST   and ALT  levels   are slightly  lower compared  to non pregnant   normal values   whereas serum  alkaline  phosphate levels   almost double. Viral    hepatitis is one of the commonest liver disease  incidental   to pregnancy   . Hepatitis A and E are transmitted by fecooral route whereas B,D and G are transmitted parentally. Hepatitis A  virus   infection recovers    completely  without any residual    disease., the  clinical   course   of most of the  viral hepatitis  is unaffected by   pregnancy    except  Hepatitis  E and  disseminated   herpes   simplex  hepatitis.

Viral    hepatitis  during  pregnancy is not an indication  for termination   of pregnancy   or  cesarean section.

Breastfeeding   is not contraindicated in viral   hepatitis. 

Newborns  of mothers with hepatitis A virus   infection in 3^rd trimester    should be given passive    immunoprophylaxis  at birth. 

Hepatitis E virus   infection in pregnancy may manifest as  severe   illness  with frequent    fulminant hepatitis.  There  is increased risk of  miscarriage    preterm   labor and stillbirth.  There is  high risk of  maternal  fetal and neonatal     morbidity   and mortality    with Hepatitis    E virus  infection   in pregnancy     There  is 90%   risk of vertical  transmission  from hepatitis B infected  mother to   her fetus  if she is HBeAg positive   at the time of delivery . Prevention   of neonatal infection in babies of Hepatitis B infected   mothers   is with active and passive  immunoprophylaxis  within  12 hrs  of birth.

In mothers    with hepatitis c virus   infection risk    factors  for vertical transmission  are high levels    of hepatitis  C RNA   in maternal blood. HIV   co infection , increased    interval between   membrane  rupture    and delivery  . Risk of transmission to the fetus    can be minimized by  avoiding   fetal scalp    monitoring  and prolonged   labor     after    rupture  of  membrane. Non   cirrhotic partal hypertension is associated with lower  maternal mortality rates   during   episodes of variceal hemorrhage compared to cirrhotic   portal  hypertension .

In pregnant    patients with   known large  esophageal    varices elective   cesarean  is  recommended . The second    stage   of labor should  be cut short   with forceps    in other   women with portal  hypertension.

Pregnant    patients   with chronic  liver disease are    at high risk of postpartum  hemorrhage   due to associated  coagulopathy    and thrombocytopenia. 

Recommended mode of  delivery    is vaginal   in most of the cases  of liver   disease   except those   with large   esophageal  varices.

Pregnancy    should    preferably be postponed for 2 years   after  liver transplantation for better   prognosis.

Pregnant    patients who   have   undergone  liver  transplantation   previously should  be advised  to continue taking  immunosuppressive    drugs  as there  is risk   of acute  graft  rejection.                         

What is the warning recommendations of “FDA pregnancy “-- categorization in pregancy

The FDA assigned   pregnancy  categories    as used in the Drug  Formulator are as  follows :

Category  A :Adequate and well controlled studies have failed  to demonstrate a risk to the fetus  in the first  trimester of pregnancy  

Category B :-Animal    reproduction studies  have failed to demonstrate a risk to the fetus  and there are no   adequate    and well controlled   studies  in pregnant  women.

Category C :- Animal   reproduction studies  have  shown an adverse  effect  on the fetus  and there   are no adequate   and well    controlled  studies  in humans, but   potential  benefits  may  warrant  use of  the   drug in pregnant   women despite   potential  risks.

Category D :-There  is positive    evidence  of human  fetal   risk  based  on adverse   reaction   data from investigational   or marketing  experience   or studies  in humans, but  potential  benefits  may warrant use of the drug in pregnant  women despite    potential risks. 

Category X :_Studies  in animals   or humans    have demonstrated fetal   abnormalities   and / or  there is  positive   evidence of human fetal  risk based on adverse  reaction   data from investigational   or marketing   experience   and the risks  involved  in the use of  the drug in pregnant   women clearly     out weight   potential   benefits.

Salient points on few commonly / uncommonly used drugs in pregancy: Drug 7 :-Urosodeoxycholic Acid – FDA pregnancy   category B.Uses  and safety – Low risk    use in ICP -Drug 1:-Trientine FDA   pregnancy category C , Uses  and safety – Limited   data potential toxicity . Drug 2=Azathiprine  - FDA pregnancy   category  D – Uses and  safety – Data   suggest low risk . Drug 3= Penicillamine – FDA pregnancy  Drug 4:- Therapy      for Wilson’s  disease  category D- Uses  and safety – Embryopathy    but need to maintain  therapy      for Wilson’s  disease  Drug 5:-Vasopressin – FDA  pregnancy  category X, uses  and  safety – Contraindicated    , Causes   uterine   ischemia Drug 6:- Ribavarin – FDA  pregnancy    category X, Uses   and safety – Contraindicated   as it causes   severe    fetal toxicity   .

Drug 8 : Oetreotide – FDA pregnancy category B, Uses  and safety – Probably   safe limited  data :Drug 9

Prednisolone – FDA pregnancy  category C,  uses  and safety  - Low risk  ,Risk of cleft  palate  and adrenal   insufficiency Drug  10:-Cyclosporine – FDA  pregnancy   category  C, Uses   and safety – Most   safety  data of immunosuppressant Drug 11:-Tacrolimus – FDA  pregnancy  category C – Uses   and safety Probably  safe. Use    as needed , Drug 12;- Mycophenylate –FDA pregnancy  category C . Uses and safety – Not   recommended   . Drug 13:- Limited data on

Sirolimus – FDA  pregnancy  category C – Uses  and   safety – Not   recommended ::Drug 14:: Lamivudine – FDA  pregnancy  category C .  Uses and safety – Low risk .

Drug 15:- Adefovir – FDA  pregnancy    category C . Uses and safety --  Few   data  . Limited toxicity 

Drug 16::Entecavir – FDA pregnancy category  C . Uses  and safety – Few data . Not   recommended

Drug 17 :: Interferone – FDA pregnancy  category C . Uses and safety – Not   recommended.

High Risk HPV DNA : Relevance of cossetting for HC-II , co testing for HR-HPV along with Thin prep or pap tets.

High Risk HPV DNA : Relevance of cossetting for HC-II , co testing for HR-HPV along with Thin prep or pap tests.

 Most HPV test gives results for 14 genotypes. By getting report of HPV 18 positive it means that HR-HPV test has been done.      

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·          Screening protocols should be read before letting labs recommend everything, Pap smear before 30 is good enough, and HPV is transient and should not be taken into account, if Pap smear is normal, repeat test after three years. If abnormal than you have d...

·         As, Dr Pal, I agree with you regarding assurance to the patient 

·         Should we insist on HPV serotype tests (Hybrid II Capture test) along with scheduled wet smear as is done 5 yarely. Relevance of Screening & adding HPV tests in addition to LBC??:- In most economically- sufficient countries initial dual screening is a common practice even in normal looking cervix (i.e. routine screening). It cost additional Rs. 2500/- only for HPV tests. In fact, if my relative is asked to undergo thin prep, I will advocate her to add HPV test as well. This will guide me about compulsion of subsequent screening.

·          The other reasons Why Co-testing (Pap & HPV-DNA) is desirable & relevant: The issue of life style modification if HPV test is also +ve: -- Testing for Pap (preferably- by Liquid Based Cytology (Pap- LBC) and concurrently HR –HPV(High Risk HPV)  test is very accurate and informs / warns about scheduling further subsequent screening. If HPV –DNA is +ve then, I have a feeling that I shall discourage the women concerned not to use OCP. Is that right? Opinion of Forum members please? I shall also counsel her on giving up smoking and if HPV +ve should be closely followed up for malig .changes.

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·         Regarding Co-testing opinion defers--This HPV test can be contemplated during routine Pap LBC test or a separate sample taken right after the Pap LBC. Usual Policy in India about HPV tests as on 2015:-

When to do? A) If borderline Pap LBC test result (tests shows unusual cells but not dysplasia).b) during routine screening for ca Cx screening and Pap smear. Women in their twenties do not need an HPV test in addition to the Pap test. HR HPV infection is very common in this age group and it usually goes away.

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Revisiting at Cx - by some serum marker in Virus induced CIN-instead repeated Colposcopy/ Cx biopsy: -a remote possibility?
Once, one of our forum members mentioned in this post that it should be clearly explained that the protection offered by any vaccine (especially regarding Ca Cx) cannot be expected to 100% and vaccination is NOT alternative option for screening. Incidentally, that member is working on identification of cofactors which prevent natural clearance of viruses and modifies viral activity.

Is there any serum Marker which can inform us about the activity of HPV virus which do remain at CX? ---The known cofactors which prevents spontaneous normal clearance of viruses from Cx are smoking, OCP intake? Spermicidal which causes chemical injury to epithelium of Cx-he added. In fact research should be oriented as to why few women fail to clear viruses of their own (like HBV)) and factors which predisposes to persistent cytological insults by the presence of virus. We, gynecologist are observing only the outward expression by carrying out Pap/ Colposcopy. Much research work remain to be done about dynamics of clearance of viruses .As a corollary , may I mention that there are some serum markers in HBsAg Chr. carriers which warns clinicians about the virulence / activity of Viruses. For instance, HbE presence shows activity of HBV in Liver and one can institute therapy at that juncture. But for Ca Cx only serial cellular abnormalities can give a guide to us yes, samples can be sent together. LBC and HPV DNA with the same sample .

 How to screen endocx? Why endocervical scrapings are difficult? Why it escapes screening??  Endocervical epithelium including glandular epithelium is not immune to Ca.  The problem which worries us  is that there is rising trend of endocervical Ca---which is  anatomically  difficult to screen .Many us do not use appropriate brush/ employ standard  ECC (endo cervical curette) along with Pap. This imprecise technique of collecting the sample can yield false negative result. The reason why there is a steady rise of endo Cx ca is unclear but the fact remains it is difficult to diagnose CIN at that site at an early stage not to speak of framing standard Screening protocol aiming at endocervical health. Can any forum member highlight on this aspect of screening-practical tips.

 Globally annual death rate due ca Cx is about 5, 00,000. Screening alone and if appropriate measures are adopted there can be reduction of death rate by 70% not the prevalence rate. Therefore, early diag is a distinct advantage if screening is duly implemented in a community. A 70% reduction is, in my opinion, a great achievement in screening tests.

A text Book (Danforth.10 Th Edition, 2008, lamented that absence of regular screening is associated with 2-6 fold increase in Ca Cx.  The editor also expressed concern about the fact that half of the newly disguised cases of ca Cx at US had never had Pap! To whom to blame? I have no answer.

Relation of HPV with occurrence of Ca Cx: - The same book has admitted that in 99.7% cases of diagnosed Ca Cx there was presence of HPV as documented by PCR. HPV DNA genome have 7,800 to 7,900 base pairs. Of the >100 types of HPV-only 30 subtypes infects anogenital region.HPV 16 & 18 accounts > 67% of all invasive ca Cx.-egulation of tumour suppressor gene. Over expression of the E6 and E7 viral proteins products cause inactivation of naturally occurring tumor suppressor proteins. May invite problem Bottom of Form

Myo inostol : DCI excretion is incresd in PCO : Metformin in PCO when

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The task of killing of Jackal, the task of killing a Tiger  are not of  same skill

 How many gynaecologist can assure a PCO woman in 3^rd decade of Life that  her  future  Quality of life( in PCO women)  in 4^th to  6 th decade of life  will be normal. Let me tell you my dear members that the duty & responsibility of gynaecologits do not end with after achieving one or 2 live births in the florid PCO cases.  Achieving preg is like   killing a jackal but to keep her( your old patient)   healthy upto the decades of eighty with  normolipidaemic normotensive,  average wt , with no endometrial cancer free life with no depression . God QOL(quality of life)  in PCO women as like a challenge with a tiger .

By this time we have to come know that PCO is correlated with raised CRP –->metabolic aberrations often seen in PCO women: Why & how? Ans: Vascular inflammatory   process is reflected by the CRP is the most    reliable    circulating marker of chronic low grade   inflammation in PCOS  . -PCOS is a pro inflammatory state    and emerging   data suggest that chronic low grade   inflammation   supports  the development of  metabolic aberration and ovarian dysfunction . CRP is the most    reliable    circulating marker of chronic low grade   inflammation in PCOS  . Recently    CRP   was found to be a direct promoter of the   atherosclerotic   processes and endothelial cell inflammation   leading to athero thrombosis . CRP has a  direct   role in the vascular  inflammatory   process  stimulating  the release   of inflammatory   cytokines  and increasing   endothelial  expression of cellular  adhesion   molecule  which mediate    leukocyte  migration .

Correlation with level of CRP with probality of heart attack??  Ans;-Findings of a study suggest that increased cardiovascular   risk may be seen in 83.3 % of the PCO women with A) CRP > 2.42  mg /1 .But luckily in those women with B)  CRP  values < 1  mg / 1 are  considered C) low  risk  1-3   mg/ 1 are considered  intermediate  risk and  3-10   mg / 1    are considered high   risk for cardiovascular   disease . 

PCO, insulin resistance à Hyperinsulinaemia, abnormal OGTT  :--Till date  the most accurate    method to diagnose insulin   resistance is the OGTT after 75  g glucose challenge even   in adolescent  women. What is the normal value?? Normal values are the following euglycemia :

1) Fasting 70-100  mg/ dL 2) 60 min after   glucose  administration < 180  mg / dL 3)  120 min after glucose administration < 140 mg/ dL

II. But in case of IGTT :--Impaired  glucose   tolerance is defined  when glucose level is > 140  mg/ dL 2 h after glucose load   but < 200 mg /dL 

III. Diabetes   is defined   when glycemia  is > 200 mg/ dL   2 h after   glucose  load

What is the insulin level?? A) Normoinsulinemia : Fasting  < 10 mUI /mL B) 60 min after glucose administration  < 60 mUI/mL c) 120 min after  glucose   administration , =  10 mUI/mL .Of course   the majority  of PCOS   patients   are not diabetic yet but only insulin resistant . Insulin resistance is defined  when insulin value   1 h after OGTT  is  > 60 mUI/ mL  and / or   its level   is not very   close   to the fasting   insulin  value   after 2 h   post glucose administration.

It has  been suggested  that an OGTT    be performed   every   2 years   for those  with normal   glucose tolerance and annually if IFG  or IGT    is present . Glucose screening  recommendation for PCOS  women are  summarized  .

HOMA index : OGTT is not a very comfortable  method  and it is  also expensive  and time consuming for this   reason the need for a simple way of measuring   insulin resistance   has led to the creation  of a large  number   of insulin sensitivity  indices.  The most    used model  is the HOMA     index.

The homeostatic  model for assessment   of insulin resistance    is a simple and noninvasive   method of estimating    insulin   sensitivity  from the steady  glucose   and insulin  concentrations  measured under  fasting  conditions  . it was calculated   using   the following formula .

Examining scientific  literature studies  are very conflicting  to each other   and a  unanimous opinion  on the effectiveness of insulin   sensitizing  drugs  has not yet been  reached. According  to the ASRM committee  of 2008   insulin   sensitizing  agents   should  be considered in patients    with impaired   glucose  tolerance   and PCOS.

In 2010  AE- PCOS  Society   consensus  treatment   emphasized that   metformin  should be  used in women with PCOS   who have  already   started  lifestyle    treatment      and do not   have improvement in IGT   or in those  who have normal   weight  but still having  .

When   administered to insulin resistant patients these drugs    act to increase  target  tissue  responsiveness in order  to reduce   hyperinsulinemia .

In the past   limited   studies    on the use of Diazoxide acarbose and somatostatin  for PCOS women    were conducted  then thiazolidinediones aroused  more interest   while to  date metformin is the most   worldwide studied insulin  sensitizing agent . Moreover   statins  have also been used to improve   lipid profile  in PCOS women .

Metformin

Despite  there is no   universal  consensus  on metformin benefits in PCOS  in this chapter   all the   beneficial  effects of metformin  therapy  in patients   with PCOS are highlighted.

The positive    effects of  metformin have been   demonstrated in nondiabetic women   with PCOS   and they are   associated   with increased   menstrual cyclicity improved   ovulation     and reduction in circulating   androgen levels.

To date   neither   in Europe  nor in the  United  States   metformin   has been   approved for  the treatment   of insulin   resistance  associated  with PCOS  its use should be restricted to those   patients   with IGT   however it is largely  prescribed as an off label drug .

For   off label  use of any  medication it is extremely  important   to fulfill several criteria   for safe  use :

The condition  should  have health  consequences   significant   enough to   warrant     treatment

The   treatment    should have   demonstrated safety and efficacy

The proposed  treatment   should be  superior   to the presently available   alternatives 

 Mechanism   of Action of metformin:-

Metformin   is a second   generation  biguanide  used  as an  oral antihyperglycemic  agent   and it is  approved  by the US  Food   and Drug   Administration   as treatment   for type ll diabetes  mellitus .

It is   considered an insulin   sensitizing  agent because   it lowers   glucose   levels  without   increasing    insulin secretion but   improving   insulin sensitivity 

Metformin causes

 Increased   peripheral  insulin sensitivity by   activating  glucose   transporters   which  allows      passage of glucose into hepatic  and muscle cells  inhibition of hepatic   glucose production

Reduction of circulating free fatty    acid concentration  which  helps    in reducing    gluconeogenesis .

Metformin  activates  the adenosine monophosphate  activated protein kinase pathway    phosphorylaction of threonine in AMPK   is necessary   for  metformin  action resulting   in decreased  glucose   production  and increased  fatty  acid oxidation in hepatocytes  skeletal muscle   cells   and mouse   ovarian tissue.

Furthermore metformin  inhibits  hepatic   gluconeogenesis  through  an AMP   activated protein    kinase   dependent regulation  of the orphan  nuclear    receptor   small heterodimer partner.

Importantly    the actions of metformin are nor  associated with an increase  in insulin secretion and consequently   with hypoglycemia.

Metformin  affects ovarian   function    in a dual  mode.

Alleviation of systemic  insulin   excess acting  upon the ovary   particularly   on steroidogenesis  and follicular    growth 

Direct  ovarian   effect.

Furthermore   metformin acts at the hypothalamic levels  on AMPK   pathway the latter  is essential in the modulation of LH  secretion

During    the last  two decades   some studies   demonstrated  that metformin  inhibits  androstenedione    and testosterone    production form theca  cells through inhibition  of  the steroidogenic    acute regulatory    protein   and 17 a hydroxylase  expression.

 At the  ovarian   level   hyperandrogenic intra follicular    pattern is improved  by a   decrease   in IGF-1   availability  that has an important  role in  controlling  granulosa   cell aromatase   levels.

It has been  shown that  granulosa cells from  women with  PCOS have higher   levels of FSH  receptor    expression  compared with those   from normal   ovaries .

Metformin reduces  FSH      without     altering   cAMP  levels.  This involves  blocking  activation    of CRE  on promoter  ii of CYP19   via inhibition of pCREB   and possible    disruption  of the formation of the CREB – CRTC  2  co activator complex.  This is   via an  AMPK  independent    mechanism . 

Dosage  and side  effects

Metformin   is available as 500, 850 and 1,000 mg  tablets with a target   dose of  1,500-2,550 mg / day.

Metformin  has a dose dependent    absorption  in humans   and its   bioavailability  is  limited to 50-60 %   because   the amount    available   may result    from pre  systemic    clearance  or binding to the intestinal wall.

Therapeutic regimens of metformin    administration are not well  standardized   and its dose   should probably be adjusted  according   to the patient’s   BMI   and insulin  resistance .

For example it was  demonstrated   that nonobese  women with PCOS  respond better than obese women to metformin    treatment   at a dosage  of 1,500   mg/ day   for 6 months   Nonobese    women in fact  showed a statistically   significant    decrease   in serum androgen    level   and fasting insulin level and also an  improvement  in menstrual  cyclicity    . Moreover   it is    possible   that women    who did not respond   to metformin   1.5 g dose  per day   might show  clinical   changes   if the dose is increased  to 2 g.

Common   side effects are gastrointestinal   such as   diarrhea nausea vomiting   bloating  abdominal  discomfort flatulence and  unpleasant metallic taste   in the mouth.

Lactic   acidosis   and hypoglycemia are very rare.

To reduce these side  effects. It is recommended to start metformin  with a low   dose  and then   gradually  increase  within a period  of  4-6 weeks.

Why Creatinine estimation on 6 monthly basis while on Met RY?: In cases of IGTT renal function may be impaired. As such if a man or woman is on long term met  therapy  then  before initiation of metformin ,serum creatinine estimation seems prudent  thereafter on   6 monthly basis .

.Metformin  may cause vitamin  B12  malabsorption  and so  every   patient   should be  monitored for signs   and symptoms  of vitamin  B 12     deficiency    numbness paresthesia  macroglossia  behavioral     changes   and pernicious anemia.

Metformin   prescription     should be avoided in women   with renal   insufficiency   congestive heart     failure    sepsis   or hepatic   dysfunction .Therefore   testing  of hepatic  and renal    function is  necessary  in advance   of prescription  and thereafter yearly   testing  is indicated.

However   it has been   demonstrated    that metformin use for up to 6 months  dose not adversely affect renal   or liver   function    in  a large   sample  of  PCOS   women even   those with   mildly  abnormal    baseline    hepatic  parameters .The length  of metformin  treatment  in PCOS  patients   is not   standardized but   data present in literature    showed that   after a  long term   metformin treatment   drug suspension  is related   to a quick   reversion  of its beneficial  effect  on peripheral  insulin sensitivity. The    insulin resistance  is associated  with

Abnormally low levels  of DCI  in urine  plasma   and insulin target  tissues  

Vote for MI  :: NOTA to DCI::How many members believe that “ PCO is often associated with excessive MI  urinary  excretion : . Intracellular MI  deficiency   in  insulin sensitive  tissues  In the contrary more recently    Nestler  proposed that in a woman   with PCOS   an initial   genetic   or environmental    insult  causing  insulin    resistance   leads to  a compensatory   hyperinsulinemia. The latter   induces a defect   that increases  renal   clearance of  DCI   and this  lead to a reduction   in circulating   DCI and its   availability     to tissue. The consequence   is an intracellular   deficiency   of DCI  and of DCI – IPG   a mediator of insulin action .Diminished release  of DCI IPG  in response   to stimulation   by insulin    results  in a further   decrease   in insulin  sensitivity  .  Moreover  defective DCI-  IPG  release  in response    to insulin   could be due to a  qualitative    defect in the insulin signaling mechanism  that  activates  DCI IPG  mediator     release   from the membrane   there may  be a primary     defect  in the union  of the insulin   receptor  B unit to the G protein   or a defect   in  G protein activation   of phospholipase.