RPL and role of progesterone

 

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  .

 

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 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.

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 from natural ovulatory cycles   to assisted reproductive technologies . Even   regulatory   authorities such as   medicines and  Health care products regulatory  agency recommend.

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 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 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.

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(micronzed 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.

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.

 

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 .