Luteal support which agent to choose??

Ovulation induction by CC/Letrozole / IUI with gonadotrophins:-How many members believe  that Vaginal   micronized progesterone is significantly more     effective than oral dihydroprogesterone  SAS Luteal support  in creating   inphase secretory    endometrium.

What are the agents that may be used for luteal support in cases of CC / Letrozole /IUI cycles- i.e. nonART cycles?  Ans:-Therapy for LPD : 1) hCG supplementation 2)  Progesterone supplementation 3)   GnRHa

A)     hCG   as Luteal support : can we use hCG??  :- hCG  supplementation

Advantage  of  hCG          : hCG   stimulates theca cells to produce  more progesterone. It also   increases other steroids form corpus luteum   and ovary   which are helpful   for maintenance of pregnancy. Dose schedule of hCG ??  It is administered   in the dosage of 2000 i.u. on days  postovulatory days   3, 7,  10 c. Or it may be pushed as 5000iu on day 5 & another5000iu    day -9  post ovulatory . . Before the availability of dydrogesterone (Duphaston) & micronized progesterone ( say susten, Naturogest)   hCG   only was used  for luteal phase support and surprisingly  few   studies have shown that it has slightly better results than progesterone e.g. susten VT vaginal Tablets / Dydrogesterone. . Many believe that  hCG    is an good option      for luteal support especially when ovulation   induction drugs are used in non IVF  cycles. Additionally hCG increases placental protein  14 and  relaxin that  helps in implantation . It can be used safely even in IVF   cycles especially in poor responders. Presently it is not used in IVF  for the fear   of ovarian hyperstimulation  syndrome . But   now since  antagonist  can be used   to  suppress  LH   surge and agonist  can be used  for ovulation   trigger  hCG in these  patients can be   used in the dose of   1500 i.u.  every fourth  day as  a luteal  phase support. This means   hCG still has place for luteal   support   in modern medicine as an agent of Luteal support.

Where are the   Disadvantage of hCG as Luteal support in  NonART cycles?? :

1.hCG  should   not be given when E2  is  more than 2500 picopgm /ml  in IUI cycles    and 4000 pcgm /ml  in IVF  cycles  because  of development of OHSS.

2.When    there are    more follicles  suppl of hCG  will increases E2 preferentially   and may   change E2- P which may   decrease   implantation but  this is  only theoretical assumption.

a. Secretory endometrial transformation and receptivity depends solely on duration of exposure to adequate progesterone   concentration provided that sufficient oestrogen   priming has already occurred during follicular  phase .  Progesterone suppl and not hCG supplementation causes local vasodilatation   for better   perfusionà so more implantation rate by progesterone therapy .

b.                        Progesterone in luteal phase cause quiescence of uterine muscles by inducing   nitric oxide   synthesis in deciduas.

c. Uterine    relaxing property of progesterone   prevents   expulsion of the embryo   during and after    embryo   transfer.

Different progesterones: Progesterone vaginal  tablet came in India sometime in the year 2000

1.Luteal support by Synthetic   progesterones: These are medroxy   progesterone acetate and Dihydrogesterone .but none of the two  are   commonly used as luteal  support. Vaginal   micronized progesterone is significantly more     effective than oral dihydroprogesterone in creating   inphase secretory    endometrium.

2  Natural    progesterones

1.Oral

2.Intramuscular

3.Vaginal  routes

1.                        Oral  progesterone

a. It    causes  drowsiness,  flushing  and nausea, It  has selective and hypnotic  effect

b.                        It causes  fluid retention

c. Efficacy changes with food, particle size in te product used and its vehicle.

d.                        Serum   concentration is higher due to first liver pass effect   and its metabolic.

e.                        It   is ineffective in inducing an inphase   secretory    endometrium .

f.   It has lower  pregnancy rate.

2.                        Intramuscular  progesterone

a. It gives   high serum concentrations, adequate endometrial   secretory features and satisfactory   pregnancy rates.

b.                       Daily injections are uncomfortable   and very painful and may result in inferior secretory    endometrial   histology.

c. It can    cause   inflammation at injection  site leading to   redness  pain and even    sterile abscess at injection site.

d.                        Rarely   it may also   cause acute  eosinophilic pneumonia.

e.It is    not preferred in favour of vaginal   progesterone.

3.                        Vaginal    progesterone

4.A stable plasma   concentration and consistent   tissue levels. Are achieved .

5.First uterine pass effect  with targeted  delivery into endometrium

6.Minimal   side effects

Vaginal   progesterone   application is now   most accepted route. Progesterone    because of its first pass effect reaches in high    concentration to uterus. So inspite of low   serum levels   endometrial     secretory    transformation is adequate. It gives   high implantation rate  and low    early pregnancy loss. Progesterone    absorption  changes with the followings like a) oestrinization  of vaginal mucosa b) Manufacturing  process    like  1)  tablets  2)   suppositories , 3)     cream , 4) oil-based  solution   or 5)  gel. But   better steady state serum progesterone concentrations are achieved with vaginal   formulations.

Progesterone  vaginal   effervescent  tablets:

This is   a new delivery    system of progesterone. This  kind of tablet  disintegrates and this  occurs in 7-10   minutes after vaginal insertion. . It increases absorption. Twice a   day dosage can   achieve   higher concentration of progesterone and reach   steady state within 24-32   hours and maintain   mean concentration above 10  ng/ml . Here the absorption occurs by passive diffusion as well as  para cellular    transport which   results  in greater    concentration and prolonged   blood levels.  Disintegration cause release of CO2 that opens up tight junctions of the cells   ans so paracervical   absorption is increased. Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens, and is the major progestogen in the body.

Advantage  of effervescent tablet :

-       Greater  bioavailability

-       Effective      systemic absorption

-       Avoids   hepatic first pass  metabolism

-       Higher   concentration    in endometrium

-       Lower   doses are required

-       Less  fluctuation in serum  levels

-       Healthy  vaginal  environment because  of acidic  pH.

-       As   efficient as other   vaginal   progesterones

-       Less irritation   and discharges. 

Progesterone gel :

It  contains   90 mg of progesterone  . it  contains micronized progesterone in emulsion system   which also contains water soluble polymer. Polycarbophil  having mucin like actions. It  is  as effective as vaginal  tables. Its   dosage schedule is once a day so acceptance  is very   good. Only  disadvantage of this  preparation is its high    cost .

Progesterone   combinations :

1.P +  E2: No  role except in long protocol in ART  where it  may improve   implantation .

2.P+  Ascorbic acid : NO  role

3.P+ Prednisolone : NO  role

4.P+ Aspirin : No role

5.Prednisolone and aspirin might have    role in recurrent  IVF   failures.

D. GnRh Agonist  as luteal support (inj Decapeptyl -0.01 mg) :

1. GnRh agonist  increases  LH  secretion from pituitary

2. It   acts directly on endometrium   through locally expressed GnRh receptors

3. Agonist   increases    serum hCG, E2 and progesterone levels   in luteal phase   of agonist   and antagonist cycles .But   adverse   effects on oocyte    and embryo needs   evaluation by   larger   studies. Why luteal support in IVF ? Ans:=-Luteal  support  is mandatory  in all IVF  cycles. Many believe that     that granulosa cells  are removed  during   ovum pick up is disproved . In  all IVF  cycles GnRh  Agonist   suppresses  LH and FSH  and causes luteal phase defect in almost all  cases in long    protocol. Prolonged   suppression of LH results in lack of support to corpus   luteum.

hCG   for ovulation    trigger   suppresses LH in stimulated   IVF cycles . This is   not the case in  unstimulated  cycles.

Antagonist  cycles  can reduce   luteal   phase   length  and may compromise    pregancy rate. Therefore   luteal   support is mandatory. . In  all IVF  cycles supraphysiological    levels of steroids secreted by large number of corpus lutea during early secretory phase   , This cause  luteal phase    defect by suppressing LH by  negative   feedback   mechanism. Corpus   luteum   requires constant  LH   stimulation  for performing   physiological   functions   and withdrawal of LH  causes  luteolysis.

Onset   of luteal   support. In   IVF  cycles:

There is   no difference in results when luteal support  is started on the  day of hCG  on the day of ovum retrieval  or on the day of embryo   transfer. The onset  of luteal    phase support  should not be later than day 3 after   ovum   retrieval.

Duration  of luteal support :

Prospective randomised controlled  trial by Nyboe et  al   indicated  that prolongation   of progesterone  supplementation   in early pregnancy   had no influence  on  miscarriage rate. Theoretically we can   stop progesterone   support  once hcg is positive  , but most of the IVF  specialists continue  till 10-12  weeks of pregnancy .

Carry   home Message:

1.Doppler   study of corpus luteum can suspect LPD.

2.hCG is very good  for luteal   support but because   of fear of OHSS , it is  not used in ART practice .

3.                        Natural  micronized  progesterone   is the drug of choice   today for LPD and early pregnancy loss.

4.Vaginal route is preferred over all  other routes.

5.                        Effervescent   vaginal   tablets   have higher   absorption  and so lower   doses are  required.

6.Vaginal   gel and vaginal tablets  are equally effective.

Luteal support is required  for all agonist  as well as  antagonist  cycles.  Stimulation of ovulation  will increase  cohort of granulosa cells which will be   leutinised to give progesterone. So   inadequate luteal function is because of inadequate   follicular   activity.   High  E2   with high   progesterone gives  the best  pregnancy  rates. Clomiphene   letrozole or gonadotropins   can be used  for ovulation   induction .

7.Progesterone is also a crucial metabolic intermediate in the production of other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.

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9.Specification:

10.                 

Items	Result
Appearance	White powder
Content	99%min
Moisture	<1.0%
Heavy Metals	<0.0005%

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12.                Packaging details:

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Packaging details:	25kg/drum with double plastic bags inside; packed in a cardboard drum or fiber HDPE drum.
Storage:	Stored in a clean, cool, dry area; keep away from moisture and strong, direct light/heat
Shelf Life:	5 years if sealed and store away from direct sun light.