Exogenous Progesterone is preg protective

1-10-19

How  relevant is   Progesterone in early  pregnancy ?? If we decide to Supplement progesterone at all should we start in luteal  phase or after UPT becomes positive ? If so which kind of progesterone? Dydrogesterone or MNP(micronized progesterone) . If MNP then by which route??

Ans;-Progesterone modulates the endometrial structure and function which is essential for successful human    reproduction. Supplementation of exogenous progesterone has a significant role in  luteal phase support and has a wide clinical    use from natural ovulatory cycles   to assisted reproductive technologies . Even   regulatory   authorities such as   medicines and  health care products regulatory  agency recommend

Part 1: can progesterone  avert RPL ?? If so how??     Use of progesterone in RPL , How rational?? Ans:- Age & risk  miscarriage:-   There   is  a strong   recurrence risk of miscarriage   with an age  adjusted  ratio . Many studies have noticed that the rate of spont miscarriage is much more in elderly women. In younger age group    the overall risk of miscarriage  is found to be 10%     and  such prevalence rose rapidly to 30 %  after 30 yrs to and reach  53%  in women   aged > 45 yrs.  

Background Risk of RPL :-Recurrent   pregnancy loss is an important   reproductive health issue  which affects around 2% -5% of couples . RPL is defined as 3 consecutive   pregnancy losses prior to 20 weeks from the last menstrual period. Reports  have shown   that among  patients  without  a history of a live birth after 2 pregnancy  losses  the risk of miscarriage  in subsequent pregnancies  is 30%  compared   with 33%  after 3 losses. Hence treatment is  directed towards the treatable causes of RPL  .

RPL & routine Prog therapy !!! Does  routine  application  of Vaginal application of micronized progesterone  prevents RPL?? Use of progesterone has been indicated  to decrease   the miscarriage  rate in women  who have experienced at least 3 losses previously .. What do we mean by  “The PROMISE trial    in 2015 “ pertaining to relevance of MNP(micronized Progesterone?? “ The said PROMISE Trial   showed that daily vaginal   progesterone  in first trimester   do not  increase   ongoing pregnancy    or live birth  rates in women   with unexplained  RM. But a recent study    conducted to determine the effect   of administration of progesterone in the    luteal phase of   the cycle demonstrated reduced risk  of miscarriage  in women    with history of unexplained recurrent  miscarriage. 

Part II: Pharmacology of vaginal progesterone ?? --What are the advantages of   Vaginal   application  of progesterone  Ans. -Vaginal   application  of progesterone            results in a rapid and semi selective effect on the uterus  which occurs due to local   counter current  transfer  from the vaginal vein blood     to the uterine arterial blood  . This   leads to an induction of greater concentrations in arterial blood to the uterus or urethra than in other arteries. The transfer  is based on the blood flow and may also involve  lymph vessels.

What are the effects of vaginal Progesterone at cellar level ?? Ans:-Actions of natural micronized progesterone such as  1) immune  modulatory   properties related to positive   regulation of  progesterone  induced blocking factor  , 2) Natural killer   cells and   3) protein coding gene modulation supports  endometrial implantation.

Part III .: Should we supplement at luteal phase?? Serum progesterone & prediction of continuation of pregancy??  Can we predict possibility implantation or continuation of early pregancy with late luteal progesterone level, say day 23/day 24 ? What is the optimum Progesterone at this stage of stimulated / unstimaulted cycle?? Ans:-1)  levels of  < 5  ng/ml   were observed   to be associated   with a spontaneous   miscarriage   in 86% of cases  compared  with   only   8% provided  serum Progesterone  is  20-25  ng/ ml . By and large in normal cycles  the level of progesterone is around     of >14 ng/ ml in the mid luteal  phase  for maintaining pregnancy .

Role of luteal  phase  defect  and progesterone deficiency in RPL :-The luteal phase    is the time period that   begins with ovulation and ends with conception  or onset of menstrual cycle  2 weeks later. During   this luteal phase progesterone secreted by corpus luteum plays an essential role in endometrial transformation and maintenance of early pregnancy.

 The role of Progesterone at endometrium  at  the  level  of  & in the process of  very important implantation process ??? :-- Progesterone is a well established mediator essential for successful implantation   of a fertilized ovum and maintenance   of pregnancy. Inadequate   progesterone secretion during the luteal phase   may be responsible for causing   miscarriage   during the early   weeks of pregnancy . Serum progesterone   levels of  < 5  ng/ml   were observed   to be associated   with a spontaneous   miscarriage   in 86% of cases  compared  with   only 8%  at levels   of 20-25  ng/ ml . Sub threshold progesterone during   luteal phase adversely  affects the normal    embryo implantation   and results  in subfertility  , infertility and loss of pregnancy. The  proposed pathophysiologic  mechanisms for progesterone   deficiency    and luteal phase   defect  are divided into three  categories   with  the corpus luteum as the primary  functional unit.

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Part IV:-How to prepare “in phase secretory endometrium” in ART cycles??   ART & Role of vaginal  progesterone for in phase secretory changes  of the endometrium

In ART   hormonal supplements    are necessary for optimizing pregnancy   chances because of the impaired  production of endogenous    progesterone .Evidence  has   shown   that progesterone    administration  is effective at priming the endometrial changes  seen in the menstrual cycle in the absence of endogenous progesterone . Evidence of predecidualization was observed with progesterone supplementation   on the 11^th day of exposure     and was corresponding to the >10^th  day   of the luteal phase   and thus fulfilled the criteria   for being in phase . A study conducted in patients with   premature ovarian failure   after estrogen  endometrial   priming    vaginal micronized  progesterone  200  mg was observed  to be more effective  in creating an in phase secretory endometrium   compared with 10 mg  oral  Dydrogesterone .  Vaginal micronized progesterone was also found  to induce significantly higher  progesterone and  lower luteinizing hormone and follicle   stimulating  hormone serum  concentrations on day 21  of the cycle.

Part V:__ Benefits of using  natural micronized  progesterone

Micronization of  natural  progesterone increases  the half  life of progesterone with the metabolites    exerting indirect  stimulatory   effect on progesterone receptor.

Micronization decreases   particle size  and enhances the dissolution of progesterone with two fold  increase in absorption .

What are te advantages of MNP(micronized Progesterone over)  dydrogesterone??  Ans: Unlike synthetic progestins micronized progesterone does not affect mood does not decrease high density    lipoprotein cholesterol levels  nor adversely affects pregnancy outcomes. Other   actions of natural micronized  progesterone  such as  immune  modulatory   properties related to positive  regulation of  progesterone  induced blocking factor  , Natural killer   cells and   protein coding gene modulation supports  endometrial implantation.

 What about vaginal route of supplementing progesterone? Vaginal application of micronized progesterone

Vaginal   application  of progesterone results in a rapid and semi selective effect on the uterus  which occurs due to local   counter current  transfer  from the vaginal vein blood     to the uterine arterial blood  . This   leads to an induction of greater  concentrations  in arterial blood to the uterus  or urethra than in other arteries. The transfer  is based on the blood flow and may also involve  lymph vessels. Other   actions of natural micronized  progesterone  such as  immune  modulatory   properties related to positive  regulation of  progesterone  induced blocking factor  , Natural killer   cells and   protein coding gene modulation supports  endometrial implantation.

Point VI : Physiology of MNP?? Application of micronized progesterone in the vagina  doubles the concentration in the uterine  arterial blood compared with peripheral  arterial blood . Reports    have demonstrated  10-20   times greater  progesterone   concentration  after vaginal   administration compared with parenteral administration in doses resulting in identical peripheral plasma   values. 

Rapid  absorption  stable plasma   levels low inter  subject  variation and lack of first pass metabolism  with vaginal  progesterone . Following  vaginal administration  micronized progesterone is   absorbed rapidly and achieved stable plasma   levels with much less inter subject     variation  than following  oral administration .

Following    vaginal administration only low plasma  levels  of pregnenolone and 5a  dihydroprogesterone  are detected   due to  the lack of first pass   metabolism vs oral administration.

Vaginal NMP  in immune modulation

Certain   immune factors are required to be inhibited for the fetus  to survive since it is a semi allograft. This is    a selective  process so that it does not have  an impact on the maternal general immune  suppression Cytotoxic   T cells    and natural killer cells are the two main effect or     cells that need to be suppressed . Moreover progesterone  secretion that influences circulating   PIBF may be an important factor  in cellular  immune suppression Progesterone  is also shown to may act in an extra nuclear  manner to suppress T cell   rejection of    the fetal semi  allograft. The pivotal role of progesterone   receptor mediated immune modulation in a  successful  pregnancy  is summarized .

Researchers  determined if exposure to progesterone alone was sufficient to increase the  production of the  immunomodulatory protein PIBF  . They also determined  what method of progesterone delivery  or form of progesterone best stimulated  PIBF   secretion. They   evaluated the serum samples from infertile  patients for both PIBF   and progesterone    at various  times during the follicular phase and the luteal  phase in both natural cycles and cycles involving   embryo  transfer after endogenous   and exogenous progesterone exposure.

 Progesterone promotes the development of a cytokine   microenvironment   which   favours  pregnancy  maintenance.   Exposure   to a high  concentration of progesterone is sufficient  to secrete high   levels of PIBF.     A marked increase in serum PIBF  was observed with progesterone alone without exposure  to the fetal  Allogenic  stimulus . The serum PIBF  levels  for the combined  progesterone  groups      were significantly higher   in the luteal  phase than the follicular  phase controls. Therefore  exposure  of the fetus to an  Allogenic stimulus   is not   needed to cause a marked rise in PIBF. Exposure   to a high  concentration of progesterone is sufficient  to secrete high   levels of PIBF.

Progesterone promotes the development of a cytokine   microenvironment   which   favours  pregnancy  maintenance. The expression of Th2  type cell  responses   and leukemia inhibitory factor is   increased  in the presence   of progesterone ,.Therefore  elevated concentrations of progesterone   promote  an immune environment  that favours  pregnancy   maintenance.

Point VII :- spiral   artery pulsatility and resistance   index and systolic / diastolic ratio  is decreed satisfactorily in MNP group than in   oral Dydrogesterone treatement Group:: Vaginal   NMP  improves utero placental blood flow than oral supplementation.

A study   was conducted in cases of  threatened  abortion to compare the influence of vaginal micronized progesterone  and oral dydrogesterone  supplementation for 6 weeks   on utero placental circulation   in early  pregnancy complicated  by threatened  abortion. Researchers demonstrated that vaginal   progesterone administration resulted   in the decrease      in the spiral   artery pulsatility and resistance   index and systolic / diastolic ratio but not   oral Dydrogesterone treatement . Dydrogesterone   treatment   was only accompanied by the decrease in the uterine artery  systolic / diastolic ratio. Analysis of the spiral artery impedance indices suggests   increased  vascular    resistance   in these  vessels  were partly  normalized  by vaginal   progesterone supplementation which  potentially resulted to improved  oxygen    and nutrient supply to the embryo Peri conceptional  progesterone early during the luteal   phase  in women    with history  of RPL

Any member have ever used 400mg vag prog at luteal phase ??? At the start of the luteal phase   patients  were administered  400 mg vaginal  progesterone  pessaries or placebo  twice   daily and were   continued after a positive   pregnancy  test till 28 weeks of gestation. Measuring   the cytokines  levels  through first second and third trimester:-

Findings   revealed that Observation 1:-A significantly lower  miscarriage rate in the vaginal   progesterone   group  and a  significant    improvement in rate of pregnancy   continuation   beyond  20  weeks  in the vaginal   progesterone group . Observation 2:- A significant improvement   in the liver birth rate in the vaginal   progesterone group   in comparison to placebo  group . Observation 3:-There  was no statistical change  in levels     of cytokines pre conceptionally  between  the 2 groups. However  there was  significant progressive  increase   in IL- 10 and  decline in IL-2 and TNF α in the vaginal   progesterone   group   as compared    to the placebo  through  1^st , 2^nd   and 3^rd  trimester. The   immunomodulatory effect  in the vaginal  progesterone  group  as compared   to the control is outlined  .

This was the first study that correlated   clinical findings   with the laboratory    findings by measuring   the cytokines  levels  through first second and third trimester .Greater  changes in cytokines levels were observed in the progesterone group   as compared    to placebo. This reflected the  immunomodulatory   action of  progesterone associated  with lower  miscarriage   rates and higher live birth rates. Periconceptional vaginal NMP administered  during the luteal    phase effectively reduces  the risk of miscarriage in women with unexplained RPL. It may   also lower   the risk of   PTB   and lead to higher   live birth  owing  to its immunomodulatory actions.

Point VIII: Take home message :

Progesterone   secreted by corpus  luteum  during the luteal phase plays an essential role in  endometrial   transformation   and maintenance of early pregnancy .

Progesterone  supplementation may help to improve  its physiological  levels primarily arising due to some  of the key defects in RPL  including smaller   trophoblast   volume and reduced   trophoblast  growth  defects  in utero placental   circulation luteal   phase defects   and immunomodulatory   actions. Application  of micronized progesterone in the vagina doubles the concentration in the uterine arterial blood compared  with peripheral  arterial blood. Progesterone  concentration after vaginal   administration is 10-20  times greater compared    with parenteral    administration in doses resulting in identical  peripheral  plasma   values. Use  of luteal   start vaginal   micronized progesterone  is associated  with improved  pregnancy  success in women with   a history  of unexplained RPL. 

Peri conception vaginal   NMP  is effective in reducing  the risk of miscarriage  in women   with unexplained   RPL when     administered   during the luteal  phase of the  cycle. It may also lower   the risk of PTB  and higher    live birth   owing to its  immunomodulatory    actions.