Different consensus statements of PCO -Over last three decades.

Let us another consensus on PCO . We are aware that there were many conferences and consensus in the decades of ninties and thereafter .There have been many changes in the definition and criteria of PCOS

A)      Definition No 1:-NIH In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a person has PCOS if they have all of the following: oligoovulation signs of androgen excess (clinical or biochemical)

Exclusion of other disorders that can result in menstrual irregularity and hyperandrogenism

A)      Rotterdam In 2003:In 2003 a consensus workshop sponsored by ESHRE/ASRM in Rotterdam, the Netherlands, in 2003 focused on diagnostic criteria indicated PCOS to be present if any 2 out of 3 criteria are met, in the absence of other entities that might cause these findings

Oligoovulation and/or anovulation excess androgen activity,::Polycystic ovaries (by gynecologic ultrasound):: The Rotterdam definition is wider, including many more women, the most notable ones being women without androgen excess. Critics say that findings obtained from the study of women with androgen excess cannot necessarily be extrapolated to women without androgen excess.^\ .Rotterdam diagnostic criteria –originally required as we all know two of Oligo or anovulation, Clinical and / or biochemical signs of   hyperandrogenism. Rotterdam In 2003  .. In 2003 a consensus workshop sponsored by ESHRE/ASRM in Rotterdam indicated PCOS to be present if any 2 out of 3 criteria are met, in the absence of other entities that might cause these findings.

    Androgen Excess PCOS Society, In 2006, the Androgen Excess PCOS Society suggested a tightening of the diagnostic criteria to all of the following: excess androgen activity, oligoovulation/anovulation and/or polycystic ovaries exclusion of other entities that would cause excess androgen activity) . Thessaloniki, Greece, in 2007 dealt with infertility management in PCOS, the second in NIH In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a person has PCOS if they have all of the following:^[56]

oligoovulation

signs of androgen excess (clinical or biochemical)

exclusion of other disorders that can result in menstrual irregularity and hyperandrogenism

oligoovulation and/or anovulation

excess androgen activity

polycystic ovaries (by gynecologic ultrasound)

The Rotterdam definition is wider, including many more women, the most notable ones being women without androgen excess. Critics say that findings obtained from the study of women with androgen excess cannot necessarily be extrapolated to women without androgen excess. Androgen Excess PCOS Society

In 2006, the Androgen Excess PCOS Society suggested a tightening of the diagnostic criteria to all of the following:^[17]

excess androgen activity

oligoovulation/anovulation and/or polycystic ovaries

exclusion of other entities that would cause excess androgen activity

Standard assessment :--

 Rotterdam, the Netherlands, in 2003 focused on diagnostic criteria

for PCOS); 3) Thessaloniki, Greece, in 2007

dealt with infertility management in PCOS . Assessment of Cardiovascular Risk and Prevention of Cardiovascular Disease in Women with the Polycystic Ovary Syndrome: A Consensus Statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. Only studies comparing PCOS with control patients were included. All electronic databases were searched; reviews included individual studies/databases, systematic reviews, abstracts, and expert data. Articles were excluded if other hyperandrogenic disorders were not excluded, PCOS diagnosis was unclear, controls were not described, or methodology precluded evaluation. Inclusion/exclusion criteria were confirmed by at least two reviewers and arbitrated by a third.

Consensus Process: Systematic reviews of CVD risk factors were compiled and submitted for approval to the AE-PCOS Society Board.

Conclusions: Women with PCOS with obesity, cigarette smoking, dyslipidemia, hypertension, impaired glucose tolerance, and subclinical vascular disease are at risk, whereas those with metabolic syndrome and/or type 2 diabetes mellitus are at high risk for CVD. Body mass index, waist circumference, serum lipid/glucose, and blood pressure determinations are recommended for all women with PCOS, as is oral glucose tolerance testing in those with obesity, advanced age, personal history of gestational diabetes, or family history of type 2 diabetes mellitus. Mood disorder assessment is suggested in all PCOS patients. Lifestyle management is recommended for primary CVD prevention, targeting low-density and non-high-density lipoprotein cholesterol and adding insulin-sensitizing and other drugs if dyslipidemia or other risk factors persist.

The conclusions of these meetings were subsequently For instance  International evidence    based guideline was released on July 19, 2018  for the assessment    and management of PCOS addressing  psychological metabolic  and reproductive features   of PCOS. :-Polycystic ovary  syndrome  is a significant public health issue affecting reproductive metabolic and psychological  health   of women PCOS is one of the most common endocrinopathy  in reproductive aged  women with  prevalence of  8%-15%   . Women  with PCOS  present with  diverse   features including reproductive    metabolic   and   psychological  features

Diagnosis   of PCOS   remain controversial and assessment   and management are inconsistent . Previous    guidelines locked  rigorous evidence   based processes did not  engage consumer and   international multidisciplinary     perspectives or were   outdated. In this context  international evidence    based guideline was released on July 19, 2018  for the assessment    and management of PCOS addressing  psychological metabolic  and reproductive features   of PCOS,. In total 37  societies and organizations covering  71  countries  engaged in the process.

Abnormal genes & recurrent miscarriage -a malady

8) Telomeres are the caps on either sends  of chromosomes.  In males with increasing age telomere damage is common.AS such if at the time of conception the age of father is > 40 yrs some gengtic diosrders , autism & behaviour disorders can ensue. But such  telomeric  deletions may also yield to  recurrent  pregnancy loss.

 As we have  mentioned earlier   the amount of genetic  material  content in the embryo is crucial  DNA k imbalance  can be present  in mosaic  or nonmosaic   pattern and some are worse than others  . In general   terms loss of chromosomal   material produces   more important effects   on the growth   of the conceptus than an excess of  material  autosomal monosomies  and trisomies normally   lead to an abortion due to self   destruction of the embryo   Few full trisomies    and many partial   chromosomal   aneuploidies are  associated   with survival of    the fetus  Nevertheless  these babies   carry    a phenotype of   widespread dysmorphogenesis and malformation of internal  organs and limb.

9) Unbalanced Gestations in Carriers of Structural Chromosome  Rearrangements

In this   part of the chapter we will focus on the partial   imbalances   that can lead to abortion  especially those that are carried  by the parents    and can be   the cause of RPL   approximately 2-4%  of RPL are  associated with parental balanced  structural chromosome rearrangements commonly balanced   reciprocal translocations or Robertsonian translocation . A translocation   is a chromosome  abnormality caused by the breakage and rearrangement  of two non homologues   chromosomes. When this structural rearrangement   ends up    with a cell containing the right amount of genetic   material . It is    called balanced   reciprocal   translocation   other  structural     abnormalities   such as chromosomal   inversions,   insertions are associated    with RPL . In the end    we can face a healthy     couple with a    history  of RPL    and discover by   performing  a karyotype   test that one of them is the  carrier    of a balanced  translocation inversion insertion   or deletion This patient could produce    unbalanced   gametes  resulting  in   abnormal    embryos with terminal chromosome    duplications  and deletion   leading     to an abortion  also   embryos   with  full aneuploidies In these cases for further pregnancies  preimplantation genetic   testing can be performed after IVF, with   Trophoectodrm  biopsy at blastocyst stage to   test  the chromosome  conte4nt of the embryos   before replacing    them back to the uterus   with this approach   the risk of a further miscarriage    and unbalanced offspring decrease   to a percentage   similar   to that  of general   population

4) Male  Carriers of Chromosome Y Micro deletions

Micro deletions of the chromosome Y long arm are the most frequent molecular   genetics of severe   male infertility , mainly   by presence of   severe oligozoospermia and non obstructive azoospermia  Nowadays   these genetic    alterations could be screened   as routine   which is important since  they are present  in approximately in 9% of the oligo azoospermia males.

At the molecular   level   Y chromosome  micro deletions affect at least three regions known   as azoospermia factor    these  three regions  are essential   for a   successful spermatogenesis. Different   micro deletions have deleterious  effects  in different  aspects   of male fertility . It is of note though   the AFZ cv 2/64   deletions since men carrying   them produce    a higher percentage   of nullisomy for the sex    chromosome   and NY   disomy  . Once  these findings wee published  a link between male   carriers of Y  chromosome    deletions and RPL   was suggested  . In fact Dewan et al in 2006  observed that in couples  with RPL  a significant percentage   of the  males   had chromosome Y  micro deletions . Another   study   carried out by Agarwal et al in 2015   stated that in couples suffering  RPL  32.5% of males  were carriers of chromosome Y  micro deletions  and after excluding  the female  factor  in 13. 5%   of the cases. Interestingly the most  frequent   micro deletion was the AZFc The incidence of    chromosome Y   micro deletion   is different in different  population    since is linked  to chromosome  Y  haplogroups  . In fact venkatesh et al   did not  detect   any micro deletion  in a population of RPL  in New Delhi.

Nevertheless taking  in account  the population  that we are  working  with  this novel data    suggests   that micro deletions in chromosome Y   could be the cause  of RPL  so the study    of these   chromosomal   abnormalities   could be offered to couples with idiopathic abortion .

11) De novo  Duplications / Deletions from Couples with Normal  Karyotype “What is that ?Sporadic early  pregnancy loss    occurs  in   10-15%  clinically recognized  gestations. As  we have  mentioned   earlier  must of the cases of miscarriages are    due to full chromosomal   trisomies  or monosomies. Nevertheless  in some cases   the  cause of these   abortions could be submicroscopic  chromosomal changes like    duplications and / or   deletions  . The problems is that these structural  abnormalities  could  appear    de novo. This    mens that even though   parents   have a perfectly normal karyotype the embryos could carry   a dup/ del. In these cases the recurrence  risk would be  similar   to general    population  With   the introduction  by pre implantations genetic  testing  for aneuploidies for aneuploidy   screening   also in couples  with normal    karyotype  small dup /del   have been  indentified   in per implantation   embryos  also/ The introduction  of more accurate  techniques like array comparative genomic hybridization and Next   Generation seque3ncing enable the clinicians   the possibility  of  detecting   these small changes in the embryo  before    transfer   in IVF   couples

genetic disorders and Rec abortions.

4) Thrombophilic  Gene   Defects

The    genetic  single defects  in  the group   of inherited  Thrombophilia especially    maternal which have  been associated  with a fetal loss have been  widely reported    but not   without contradiction. Hereditary thrombophilliais  a condition that affects the amount   of a proteins’s  function in the coagulation    system and increases the risk of  thrombosis   . Thrombophilia have been identified as one of the  major cause   of RPL  after  chromosomal abnormalities especially  in the first  half of pregnancy.

Among  the genetic  single defects  mutations  in factor  V Leiden seems to be the most prevalent  and its   relationship   with women   experiencing repeated miscarriages   have been reported by several   studies. But   also RPL   has been   linked to prothrombin gene   mutation protein C and protein S   deficiency  anti thrombin lll  deficiency    and methyitetrahydrofolate reductase mutation  have been reported   by several studies  and meta  analysis . However    nowadays  the association  of some of these gene    mutations and polymorphisms with RPL  is  still open to discussion as some  prospective studies  failed  to support this correlation . Thus   a universal screening   for  inherited   thrombophillia  can be checked  by  analyzing     antiphospholipid syndrome     activated     protein c  resistance serum   fasting homocystine protein  C   protein s  anti thrombin  III prothrombin G 20201A gene mutation and   factor V Leiden in RPL   patients In relation  to the treatment   of anticoagulant agent for the   prevention  of miscarriage in women   with  a history   of at least two  unexplained  miscarriages with or  without inherited   thrombophilia.  However    the analysis  of  most studies  of the past has not been  able to  demonstrate the   beneficial effect of this treatment  and the current guidance   still does not recommend it although it has been suggested   that up to 40%   of American     specialists would  screen in  opposition   of the current   guideline.

 6)   Gentic defect causing Familial Recurrent   Hydatidiform Moles 

Familial recurrent hydatidiform mole is an autosomal recessive condition in which women experience RPL  pre dominantly  classical complete hydatidiform   mole . A   hydatidiform mole is an abnormal    pregnancy characterized    by hydroid placental villi trophoblastic hyperplasia  and poor fetal   development Mutations in two genes   are currently known  to be associated   with FRHM    NLRO7  and KHDC3L being   responsible   for approximately   75%   and 5%    of cases respectively  Both NLRO7  and KHDC3L in normal   pregnancy     and the mechanisms    by which    mutations in these genes   give  rise to complete   hydatidiform mole  remains     controversial   . Although   little is known   about    the  function of KHDC3L   data is emerging   to suggest   that  like other members of NLRP family     of proteins    NLRP7 is  involved in innate immunity leading to the hypothesis that abnormal    immune responses in early   pregnancy underline molar   development in these    conceptions   . In   consonance   with this another group   published    a study in which a tag for SNPs   and haplotype  analysis was used  to investigate  the association   between polymorphisms of NLRP2   and NLRP7   and ididopathic recurrent   miscarriage. They    found that a   tag SNP  of NLRP7  was significantly     associated with  idiopathic    RPL in a recessive  model   while a tag SNP  of NLRP2   showed  marginal  significance codominant  model.

 7) A Other single  Gene Defects related to RPL : But problem how & where to diagnose such single genetic defect??

The genetic variant    rs2305957   has been   related with  recurrent   miscarriage in a recent   study. The common maternal genetic   variant rs2305957 encompassing   the PLK4 gene has been  reported  to contribute    mitotic  origin aneuploidy  risk during human       early   embryo development  aneuploidy  by disrupting centrosome duplication and   mitotic progression during postzygotic cell   divisions. The   study analyzed a total of 2,015    infertile Chinese women who underwent in vitro fertilization and genotyping of  rs2305957   was perforemed  by  means of high resolution melting  analysis. The  authors found that infertile women    carrying the  high risk genotype of rs2305957    formed   fewer morphologic good   quality   Blastocysts and demonstrated  that maternal genetic  variant rs2305957   is a risk factor   for early recurrent  miscarriage.

 7) A meiotic  gene SYCP3 has also been   associated  with  RPL  sycp3 is a well known gene  that encodes   a protein    that plays a critical role in the synsptomemal    complex for  the interaction of homologous chromosomes In a study   published  in 2008   authors   found  in two out of  26  women with RPL  of unknown cause    independent  heterozygous  muclotide alterations in SYCP3 gene   which were   not found in control fertile   patients. The  authors reported that the mutant  proteins interacted with their wild type homolog in vitro and inhibited    the normal formation of SYCP3   protein   fiber. These    data suggest that these mutations are prone to generate an aberrant synaptonemal complex  and   may contribute   to  abnormal   chromosomal behavior    that could lead to recurrent   miscarriages. According    to this a subsequent   case control   study identified a higher genotype frequency   of SYCP3T657C   polymprohism in women with RPL   However  the significant    difference between  allelic and genotype    frequencies   between  groups were not clinically  useful in diagnosing the etiology    of that individual recurrent losses. Therefore    although this   polymorphism    can be considered as a genetic  factor   for pregnancy loss in human   further    functional studies  are required   to support  this .

This  CYP genes   encode a family of proteins that are expressed in placenta   during the first trimester   and some of the members    are related to hormonal    metabolism  and  detoxification systems. A gene polymorphism    of the member   CYP17  has been associated with risks of RPL  by several studies. CYP17   gene encodes the cytochrome P450c17a   enzyme  which  mediates both  steroid 17a   hydroxylase and  17,20   lyase  activities and functions at key steps  in the    genesis   of human sex steroid hormones Scientists    in 2003  reported that a variant of CYP17  may   predispose to an increased risk  of RPL with   a gene dosage  effect. In addition   other genetic   variants of this family polymorphisms of cytochrome P450    17   743542   CYPIAI   rs 1048943   and C?YP2D6   rs 3892097   seem to relate an abnormal    placental function  to the risk of recurrent   miscarriage   as suggested by the findings of a very   recent  meta analysis.

Although    several polymorphisms    and genetic variants   associated  with RPL  have been  reported so far additional  research  is still required  to   identify   not only  new genetic   variants but also  select  those   that remain   controversial   to eventually  be introduced as genetic  markers into the clinical routine.

Correlation of genetic material of the embryo and correlation with recurrent abortio

,

Correlation of genetic material of the embryo and correlation with recurrent abortion:

:How normal are the genetic quantum in blastocyst or  embryo?? The possibility of continuation of preg depends chiefly on that . Ans:-abnormal gentic content is the  chief cause of recurrent pregancy loss . If genetic content of embryo is abnormal in arrangement or less in quantum then abortion is bound to follow and such an happening is difficult to  diagnose. By contrast if the embryo   contains is correct sequence and quantum of genetic material then hopefully preg will continue and there won’t be any miscarriage. Around 50%    of RPL    cases remain unexplained. Classically recurrent abortion is defined as three or more consecutive    pregnancy   losses. Although    according to the last   document published by the practice committee of the American    Society  for Reproductive Medicine   in 2013, recurrent  pregnancy  loss   is a disease distinct form infertility defined by two or  more failed pregnancies . The current incidence of   all couples    at reproductive age who suffers recurrent   miscarriages   is   approximately    1-3% and  despite    many efforts by the scientific   community around 50%    of RPL    cases  remains  unexplained .

\

RPL & tets mentioned by Dr The  most   frequent   cause of recurrent miscarriage is an

 What is partial aneuploidy?? Abnormal embryonic karyotype. Or deletion or mutation of even  one gene may yield to the  development   of an unsuccessful pregnancy. So  it is crucial that the amount of genetic material  that the embryo   contains is correct  . Any imbalances  in the DNA   content can   lead to implantation failure   miscarriage   or in the worst scenario  to a live birth   with serious health problems. Such imbalances can involve   loss or gain of a whole chromosome   which is known   as partial  aneuploidy . Besides   the study  of chromosome   also known as partial aneuploidy   Besides    the study of chromosome aneuploidies   there are  other genetic factors significantly   less studied such as  single  gene defects   whose relationship   with RPL   constitutes an   emerging  area of research . There are   several major   groups   of single  gen defects and polymorphisms   that have been  associated    with pregnancy    loss including   musculoskeletal gene   disorders    genes involved in inflammatory processes thrombophillia related    genes and also   polymorphisms  of genes and mutations   in specific     enzymes or proteins that may   confer  susceptibility to RPL .

   Few points on Single gene disorders   related to recurrent   pregnancy   loss

A)           Musculoskeletal  Gene   Defects: mutation/ deletion” :Some  autosomal   dominant   disorders   such as  myotonic  dystrophy   thanatophoric dysplasia  and type  ll  osteogenesis imperfect  are among the single gene   musculoskeletal  disorders that have been most frequently   associated with RPL. Some   of these  disorders belong  to a group   called   trinucleotide  repeat  diseases in which   the mutation   is caused  by the  repetition in a  variable    number   of a trinucleotide sequence    when the number  of these repeats   exceeds  a specific   threshold in the DNA   segment this is  more prone   to errors during   mitosis.

B)           Genetic mutation/ deletion of Immunologic and  inflammatory Gene  Defects:-Immunological mechanisms are responsible among other factors of successful    reproduction so studies   of single  gene   defects    involved  in immune  regulation and RPL   have been    extensively    investigated in recent    years The gene     encoding   the human leukocyte G antigen is a component that  plays  an essential   role in the alloimmune recognition process  at the maternal fetal interface. The presence  of a  null allele for the most common HLA-G    isoform  as well as   distinct polymorphisms in the HLA-G   promoter region    have been associated  with  recurrent   miscarriage  suggesting   that a functional protein   is necessary   for reproduction .

3) Mutations /Deleletions of angiogenesis  and vasoconstriction  related gene  :-Yes it is possible such an defect in embryo may cause RPL.  The processes of angiogenesis and an adequate blood supply are critical of angiogenesis     and an adequate   blood supply  are critical   for several  steps     in early human pregnancy   . So it is not   surprising that there are also some studies  reporting   the association    between   angiogenesis  and vasoconstriction  related gene   and RPL . A recent meta  analysis of available endothelial growth factor    p53   and eNOS    polymorphisms and idiopathic  RPL

Rubella diagnosis in pregancy-Is congenital Rubella syndrome is a preventable malady.

1-10-19

Serologic Testing for Rubella and CRS (Cong RubellaSndrome)- Low Prevalence Setting.

IgM and IgG Detection

Although rubella was officially declared to be eliminated from the United States in 2004, ongoing rubella activity in many other countries can result in sporadic U.S. cases or outbreaks. Detection of specific IgM antibodies in a serum sample collected within the first few days after rash onset can provide presumptive evidence of a current or recent rubella virus infection.

The optimum time-point for collection of serum is five days after the onset of symptoms (fever and rash) when >90% of cases will be IgM positive.

On the day of rash onset only about 50% of cases are IgM positive. Therefore, if serum collected less than five days after onset is negative, a second sample would be necessary to confirm/rule out rubella. The anti-rubella IgG status is determined for every serum received at CDC for rubella testing to aid in case classification.

 The interpretation of rubella laboratory results must always take into account relevant clinical and epidemiological data.

IgG Avidity Detection

Since no assay is 100% specific, serologic testing of non-rubella cases using any assay will occasionally produce false positive IgM results. In countries such as the United States where endemic circulation of rubella has been eliminated, most suspected cases are not rubella.

 Rash and fever illnesses are more likely due to a number of other rash–causing illnesses such as parvovirus B19, enteroviruses such as coxsackie viruses and echoviruses, or human herpesvirus–6 (roseola).\The presence of rheumatoid factor can also result in a false positive IgM.

What is meant by IgM positivity ? IgM reactivity It is important to distinguish IgM reactivity caused by primary infection from that caused by IgM persistence or cross-reactivity with other antigens, especially in pregnant women. The measurement of rubella IgG antibody avidity can be used to distinguish between recent infection and remote rubella infection.

Antibody avidity (the overall strength of binding between the antigen and antibody) increases with time; this is known as maturation of the immune response. As the immune response matures, low avidity antibodies are replaced with high avidity antibodies. These avidity differences can be detected by using protein denaturants such as diethylamine (DEA) in the washing step of an enzyme-linked immunoassay (EIA) for rubella IgG. In acute rubella virus infections, specific, low-avidity IgG lasts for up to three months after appearance of the IgG response. The presence of high avidity antibodies, which develop by about three months after infection, provides evidence of remote infection. The cut-off between low and high avidities has to be established by using standardized sera and a particular EIA kit.

For pregnant women, avidity testing is most useful in early pregnancy to help rule out a rubella infection in the first trimester, when the risk of congenital defects due to rubella is highest. It is not as useful in late pregnancy because avidity will be high by the third trimester if infection occurred in the first trimester. 

Serological testing for congenital rubella syndrome (CRS)

Congenital Rubella Syndrome (CRS), which can occur when a woman is infected with rubella during a pregnancy, consists of a variety of possible birth defects including cataracts, hearing loss, heart defects, developmental disabilities, and low birthweight. CRS was eliminated from the United States in 2004, but cases can still be imported by pregnant women who contract rubella in an endemic country. In rare cases, CRS can occur in the United States when susceptible pregnant women are exposed to imported rubella cases.

CRS cases can be diagnosed in newborns and young infants using detection of rubella IgM. Suspected cases should be tested as close to birth as possible and again at 1 month of age if the initial IgM test is negative. At 3 months of age, approximately 50% of cases would still have detectable rubella IgM in their serum. Additionally, the presence of rubella IgG in an infant after the decline of maternal antibodies (9 months of age) and the absence of vaccination or exposure to rubella will confirm CRS.

GDM & DM newer agents & take home message

The  main advantages  of extenatide and Gliptins  over SUs are Lack of  weight  gain and hypoglycemic episodes. In addition in  experimental  animals long term  exposure  of these agents has led to some degree  of beta cell preservation Bea cell regeneration replication as well as  reduced  apoptosis have been  postulated SUs do not have  this properly Thus SUs  are expected  to be gradually   replaced by these agents particularly   in rich countries . Due to economic limitations only a small fraction of diabetics   can afford these expensive agents thus  time tested SUs will continue to remain once of the mainstay of oral anti diabetic therapy  in our country   for a long time to come. However  it should be noted that while SUs  have with stood the test of time these new agents are in clinical   use for  very short  time. Thus  it s a bit early to write  obituary of SUs and hail incretion mimetics  and DPPs  inhibitors  as great discoveries  and wonder  drugs. Type 3 Antidiabetic drugs:- OAD ( oral antidiabetic drugs)::_Thiazolidinedione

Glitazones work as insulin sensitizers. Like metformin they act only on peripheral tissues mainly  muscle  and fat cells  and increase their sensitivity to insulin. They do not increase  pancreatic insulin   secretion thus when  given alone or in combination with  metformin  they do not cause  hypoglycemia.

Their action is mediated  through activation of Par gamma activated intra nuclear receptors. The cellular site of action is predominantly adipocyte and muscle cells with some  action on hepatocytes Glitazones sensitize tissues  towards insulin and reduce  circulating  free fatty acid levels.

Rosiglitazone and Pioglitazone  were the two glitazones  available in  our country  till recently  In September 2010 the regulatory authorities of Govt  of India  banned rosiglitazone  following its  ban in advanc3ed countries . Both  have identical  mechanism of action and indications water retention leading  increased volume of fluid  in intra vascular  compartment is liable to occur  with both the  compounds. Precipitation  of incipient   cardiac failure has occurred with both the glitazones thus they  are contraindicated in those in cardiac failure or those who have history  of cardiac failure In addition a meta analysis  published in 2007   associated  rosiglitazone with higher   prevalence of myocardial   infarction and sudden cardiac death Pioglitazone  has a favorable  influence on plasma lipids and was  not associated   with increased prevalence of myocardial infarction or sudden   cardiac   deaths  in any of the clinical   trials  or meta analysis. The usual daily   dose of Pioglitazone is 15  to 45 mg in a single dose. Most of  the Indian authorities do not  prescribe  it beyond 30 mg /day  both  the  agents produce weight   gain  which  can be  as much as ten kegs in some patients.  The weight  gain is mainly due to water  retention  with some contributions from adipogenesiis  and weight  regain due to better metabolic  control . In those with  significant  edema or weight gain glitazones need to be  discontinued.

Indications :

1)           In predominantly insulin resistant type 2 diabetic patients Pioglitazone is used as an alternative to metformin particularly if the latter is not tolerated or contra indicated. It can also be combined with metformin when monotherapy with metformin fails to achieve glycemic targets.

2)           In combination with SUs or other insulin secretogogues when latter agents  alone are not sufficient  to control  blood glucose  level.

In triple drug  combination  along with any two from  SU metformin and gliptin group  in  groups when two  drug  therapy  fails to meet  glycemic targets  and the patient  is still some distance  away from end stage  beta cell  failure  . Experienced clinicians can make such a judgment

Uncommon agents: Quick Release  Bromocriptine  Tablets

Conventional  Bromocriptine has been  in clinical  practice  for more  than two decades  for the management  of parkinsonism and Galactorrhoea. Quick release  preparation of Bromocriptine has been introduced  in India  in mid 2010 and in USA in November  2010. It is indicated  in the management   of type 2 diabetes.

In type 2 diabetes dopaminergic tone in hypothalamic area  is reduced . This  is associated  with increased secretion of  noradrenalin in hypothalamic  hypophyseal axis  which in turn leads  to insulin resistance obesity  and hyperglycemia Bromocriptine is dopamine agonist Administration of quick  release version leads to rapid   buildup of its associated  with reduction in insulin  resistance and  improvement  in glycemic status  particularly post  prandial hyperglycemia.

Quick release  bromocriptine has better bio availability  than its  conventional version. It is available  in tablet  form  each tablet contains 0.8 mg of bromocriptine in special quick  release  formulation. The therapeutic   dosage  is 1.6  to 4.8 mg once daily  two hours after  getting  up in morning . preferably  after food. In order to avoid gastro intestinal  side effects treatement  should be started with 0.8 mg and dosage  should  be stepped up at weakly interval.

Quick  release  bromocriptine  is the first and so far only anti  diabetic medication which has successfully undergone  elaborate   pre marketing cardio  vascular safety studies  in USA. After the publication of report    of excess  cardio  vascular  mortality  with  rosiglitazone   in the  New  Engalnd   journal of medicine  in June   2007  Th US FDA has made  these tests  mandatory   for any new  and diabetic  agent  before  its introduction in the market.

Quick release   bromocriptine can be  used as one of the add on agents  particularly  in those  with manifestations of insulin resistance .

Tips from  Dr S K Pal in lieu of a good dinner : It is dinner time for this old man: send your delicious dinner sharp by courier . Clinical  applications of OADs

OADs are indicated in type 2 DM patients  when diet fails to control hyperglycemia. Stressful conditions  such as  severe  infections pregnancy and major  surgery  renal and hepatic  insufficiency are contra indications  to the use  of OADs These  drugs  do not work  in the absence  of insulin hence  should not be  used alone in Type 1 DM.

CRITERIA FOR  CONTORL

 One  should aim at total  freedom form  glycosuria  and steady  near normal blood glucose . Table 2 gives  criteria  for control

Note  : Criteria for control need to be modified as per the individual patient’s  situation

In elderly  people in those  who do not have warning  adrenergic symptoms  and in those with significant cardiovascular  affection with long standing diabetes less stringent criteria should be applied.

During  pregnancy   fasting and 2 hours  post prandial plasma  glucose  values  should be < 100 and 125 mg % respectively . In young  ad recently  diagnosed  diabetic  patients  generally aggressive criteria should be applied. Their  all the three  glycemic values i.e. fasting and post prandial plasma  glucose  values  and HbA1c  should be  at or very   near  lower  limit of the range  mentioned above.

Failure of control

 A common cause  of failure is inadequate   dietary regulations Some diabetes  are under the wrong  impression that since they are taking OAD they are  at liberty to eat anything  . In   addition  to review  of diet in patients   failing to respond  to  OAD a systematic   search for occult  infection   should be made.

It is also  advisable to thoroughly analyze all the medicines  he/ she is taking . In addition to medicines  prescribed by you he/ she  may be taking say for example steroids for asthma  strong  potassium wasting  diuretics like Fursemide  and Diphenythydanatoin  can also interfere with the action of OAD . If a  failure occurs  even after proper  dietary  regulations and maximal  dose of OAD  drugs  from other  groups  should be added and the dosage  gradually  increased  until  optimal  control is  achieved . After  a prolonged use for  several years   OAD  gradually start   losing  their  effect  and  ultimately a stage is reached  in many  patients  where a maximum dosage of combined agents  is also unable  to control  hyperglycemia and  . At this stage OAD should be replaced by insulin.

Side effects

Sulphonylureas : A number  of non specific gastrointestinal  symptoms ranging from dyspepsia to diarrhea occur with the sulphonylura in a small number   of patients  . A  variety of skin reactions also  occur . these are  mostly of minor  significance  and resolve  on drug cessation however  an  occasional   severe complication may arise such as exfoliative dermatitis or stevens Johnson syndrome. A cholestatic  type of jaundice is rarely seen as is bone marrow depression . water  retention   giving rise to delusional Hyponatraemia was  first described  with chlorpropamide  but has also  been reported  with other sulphonylureas Hypoglycemia should be regarded  as a consequence  of excessive  dosage rather  than as a side effect  unless due to drug  interaction

What about Biguanides(metformin- My fair lady!!) : Gastro intestinal side effects including  anorexia nausea and diarrhea occur in 10-15% of patients  and being dose dependent these may limit the opportunity  to employ  maximum dosage. Vitamin B12  deficiency  may result  from the effect of biguanides  on the dowel . In contrast  to the sulphonylureas  hypoglycemia  is rare  and usually is only reported with suicidal drug  use. We have already discussed  lactic acidosis.

Glitazones : Weight gain  swelling of feet  due to edema and cardiac  failure  when used  in patients  with left  ventricular  dysfunction are main side effects  Mild   anemia is also  seen This is due to dilution of blood following  increased  blood volume due to water  retention.

Alpha  Glucosidase Inhibitors : Abdominal  distention borbigmy  and diarrhea  are main  side effects.

DPPS inhibitors A variety  of skin  reactions are occasionally reported. These are  mostly of minor significance   and resolve  on drug cessation   however   an occasional   severe  complication  such as  exfoliative dermatitis or Stevens johnson  syndrome  has been reported  in those  on sitagliptin Rare  cases of pancreatitis   in those  on sitagliptin   and incretin  mimetics have  been  reported however   cause  and effect has not been proved As such pancreatitis is more    common in diabetics  as compared to others

Incretin mimetics : main side effects are gastro intestinal  intolerance . These can be  reduced by starting the therapy  with smaller dose and subsequently stepping up Pancreatitis has been reported   in rare  cases.

Bromocriptin: Gastro intestinal intolerance is not uncommon The prevalence   and severity is reduced by starting with lower  dose and stepping up after  one week. Giddiness and postural  hypotension  is seen in some patients . Bromocriptine  should be avoided in those  on other  ergot  agents  antipsychotic  agents  and dopamine antagonists.

Drug  Interactions

These  occur mainly with sulphonylureas Alcohol intolerance occurs in a number   of patients  particularly those on chlorpropamide Many drugs  potentiate hypoglycemic   effects of sulphonylureas. These   include clofibrate Dicumarol  large doses of salcylates  Beta  blockers   NSAIDs  and Biguanides In those  taking biguanides  the risk of lactic acidosis increases if they consume alcohol.

 The  entire work was a joint  effort of ADA EASD  IDF and IFCC .

In order in express average blood glucose  in patient  friendly and meaningful manner a large multi centric multinational work was carried out in 700 persons . 300 each had type 1 and 2 diabetes and 100 were normal controls Originally 11  centers  spread across North America Europe Africa  and Asia  were included . One centre dropped out   due to technical reasons.

 Those  having conditions such as anemia haemoglobinopathies and renal impairment  were  excluded from eh study  A large amount   of data on glycemic control was generated in these people by studying  was generated in these  people by studding them for 4 months  in this period   all were subjected

It is proposed that in future IFCC  will standardize and cal liberate    all the equipment used for estimation  of HbA1c  and also officially release the mathematical formula subsequently the laboratories  will give  report in HbA1c    formal  expressed in %  as currently done in mmol/L  format as well as in ear in mg%  format.

In other words HbA1c   will not be done away  with but will  be  standardized and cal liberated by IFCC method  . In addition eAG  in mg% will be calculated by mathematical  formula and given along with HbA1c  report as an additional value 7%  HbA1c  will be equivalent to 154  mg%  of glucose instead of 150mg% as at present . Hence in future indicators of long  term glycemic control and spot  or point of time  glycemic  control will be expressed in same  units. This move will be very much patient  friendly