Benefits of vaginal progesterone

Prevalence and causes of recurrent  pregnancy  loss

Recurrent  pregnancy loss is an  important reproductive health  which   affects around 2%  -5%  of couples  RPL is defined as 3  consecutive pregnancy  losses prior  to 20 weeks  from the last menstrual  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   . Use of progesterone  has been  indicated to decrease the miscarriage rate in   women   who  have experienced  at least  3 losses  previously.

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.

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   that 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 function unit. 

Importance of progesterone in early pregnancy

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 form natural  ovulatory cycles  to assisted   reproductive technologies  .Even  regulatory  authorities  such as  Medicines and Healthcare Products Regulatory  Agency   recommended serum  progesterone   levels  of > 14   ng/ ml  in the mid  luteal phase for   maintaining  pregnancy.

Role of vaginal progesterone  for in phase secretory changes  of the endometrium

In regular    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    tot eh > 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  exogenous  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.

I am manufacturing vaginal progesterone in brand name of “PAL”—I am now at Mt. Everest for promotion of brand of “PAL”-please prescribe  PAL brand of progesterone but not to males please .  “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.

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 .

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 the   uterine arterial blood   . This leads to an induction of greater   concentration 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.

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 achieves  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    va 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 effector 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 summarised .

Researchers  determined if exposure  to progesterone alone  was  sufficient  to increase  the production of the

Immune modulatory  protein PIBF  . They  also determined   what method of  progesterone delivery  or form of progesterone   best  stimulated  PIBF   secretion. They evaluated the serum  samples fro 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.

A marked increase in serum PIBF    was observed with progesterone alone without  exposure  to the fetal  allogeneic 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 allogeneic 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 of   favours  pregnancy  maintenance.

Vaginal  NMP improves utero placental blood   flow

 A study   was conducted to compare the  influence of vaginal  micronized progesterone and oral  Dydrogesterone   supplementation for 6 weeks on uteroplacental   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   treatment . 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  d oxygen  and nutrient  supply   to the embryo.

Peri conceptional  progesterone early during the luteal   phase in women   with   history   of RPL 

The PROMISE   trial  in 2015   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.

At  the start of the luteal phase  patients  were administrated 400 mg vaginal progesterone   pessaries or placebo   twice   daily and  were continued after a positive   pregnancy test till 28 weeks  gestation.

Finding  revealed

 A  significantly  lower miscarriage  rate in the vaginal   progesterone   group

A significant   improvement  in rate of  pregnancy   continuation   beyond 20 weeks in the vaginal  progesterone group .

A   significant improvement   in the live   birth  rate in the vaginal   progesterone   group  in comparison  to placebo   group .

There was  no statistical changes  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  INPy  in the vaginal   progesterone   group   as compared     to the  placebo  through   1^st    , 2^nd  and 3^rd    trimester. The immune  modulatory  effect in   the vaginal   progesterone  group   as compared   to the control  is outlined  .

This was the  first study   the 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 immune modulatory action of progesterone    associated with lower   miscarriage   rates and higher  live birth  rates.

Peri conceptional vaginal NMP  administrated 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.

Summary 

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 uteroplacental   circulation   luteal phase defects  and immunomodulatory  actions.

Application  of micronized progesterone   in the vaginal  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 k plasma  values.

Use of luteal     start   micronized  progesterone is associated with improved pregnancy   success in women   with     a history  of unexplained RPL.

Peri conceptional  vaginal   NMP  is effective in reducing   the risk    of  miscarriage in women  with unexplained  RPL  when   administrated during  the luteal  phase of the cycle. It may also lower the risk of PTB and   higher   liver birth  owing  to its   immune modulatory actions.