evidence based practical tips for luteal phase support by dr shashwat jani

Evidence Based Practical Tips

For

Luteal Phase Support

Dr. Shashwat Jani.M. S. ( Obs – Gyn )

Diploma in Advance Laparoscopy.

Consultant Assistant Professor,

Smt. N.H.L. Municipal Medical College.

Sheth V. S. General Hospital , Ahmedabad.

Mobile : 99099 44160.

E-mail : [email protected]

What is E.B.M. ...???

Evidence Based Medicine…?

Experience Based Medicine…?

Eminence Based Medicine....?

Mob : 9909944160 Dr. Shashwat Jani 2

Sources

Cochrane library .

Royal College of Obstetricians &Gynecologists (RCOG) Guidelines.

American Society of Reproductive Medicine (ASRM)

( April, 2015 )

European Society of Human Reproduction & Endocrinology

( ESHRE )

National Institute of Health & Care Excellence. ( NICE )

Journal of Evidence Based Obstetrics & Gynecology.

National Guideline Clearinghouse . ( U.S. Govt. ).

Royal Austr. & NZ College of Obst. & Gynec .( RANZCOG )

PubMed.Mob : 9909944160 4Dr. Shashwat Jani

Once Upon a Time….

ƒ In 1949, the premature onset of menses was recognized as indicative of a luteal phase deficiency of progesterone production, which was shown to be correctable by exogenous progesterone administration (Jones, 1979). ƒ

The prevalence of a luteal phase defect in natural cycles in normo-ovulatory patients with primary or secondary infertility was demonstrated to be about 8.1%

(Rosenberg et al., 1980)

Mob : 9909944160 5Dr. Shashwat Jani

Maintenance of

pregnancy Corpus luteum Progesterone

– After ovulation ~ during the early first trimester ~ until placental function established

– Removal of the corpus luteum spontaneous pregnancy loss

Ovarian progesterone production implantation & early pregnancy support.


Luteal phase deficiency (LPD)

Endogenous progesterone is NOT sufficient to

– Maintain a functional secretory endometrium

– Allow normal embryo implantation and growth

– 1st described in 1949.


Who requires

Luteal Phase Support ? Confirmed cases of luteal phase defect Unexplained infertility Advanced reproductive age ART techniques – IUI / IVF / ICSI Hyper- prolactinaemia All down regulated cycles Recurrent pregnancy loss PCOS Women with strenous exercises and

underweight Who require Luteal support .


Luteal Phase Deficiency (LPD)

Purportedly been associated with:

1. Infertility

2. 1st trimester pregnancy loss

3. Short cycles

4. Premenstrual spotting

5. Anorexia

6. Starvation

7. Eating disorders

8. Excessive exercise

9. Stress

10. Obesity & PCOS

11. Endometriosis

12. Aging

13. Inadequately treated 21-hydroxylase deficiency

14. Thyroid dysfunction & hyperprolactinemia

15. Ovulation stimulation alone

16. Ovulation induction with or without GnRH agonists

17. ART


Luteal Phase Deficiency (LPD)

Has been shown to occur:

During the postpartum period

With significant weight loss or exercise

In random cycles of normally menstruating women.


Are There Diagnostic

Criteria For

Inadequate Luteal Function ???


Diagnostic tests are influenced by and based on the following

Physiologic observations:

1. Normal luteal phase length is relatively fixed at 12 – 14 days.

2. Progesterone levels peak in nonpregnancycycles 6–8 days after ovulation.

3. Progesterone is secreted in pulses.

12

4. The endometrial response is a reflection of the follicular phase estrogen and the luteal-phase estrogen and progesterone.

5. Once implantation occurs, progesterone secretion by the corpus luteum depends on rising hCG levels.

6. Failure of hCG levels to increase directly causes corpus luteum failure and a decline in progesterone levels.


Methods proposed for diagnosing LPD

Basal body temperature (BBT) charting:

Inaccuracy, inconvenience, should be discouraged

Serum progesterone levels

Endometrial biopsy

TVS

Ovulation & adequate luteal length:

Urinary LH surge detection & Monitoring of luteallength


Sonographic Criteria :

Rupture of follicle < 17 mm

Poorly formed or ill defined dominant follicle

Luteinised unruptured follicle ( LUF )

Lutein cyst formation

Absence of corpus luteum

Lack of endometrial echogenicity on 7th postovulatory day .


Endometrial Biopsy

Abnormalities of endometrial maturation:• Inadequate ovarian hormone secretion

• Intrinsic endometrial abnormality

• ‘‘Gold standard’’ to diagnose luteal inadequacy.

However, prospective, blinded, randomized clinical trials (RCTs) suggest that the endometrial biopsy is an imprecise tool for differentiating fertile women from women with LPD (infertility).

16

April 2015

In summary, currently there is no reproducible, pathophysiologically relevant, and clinically practical standard to diagnose LPD and distinguish fertile from infertile women.

The roles of BBT, urinary LH detection kits, lutealprogesterone levels, endometrial biopsy, and other diagnostic studies have not been established, and performance of these tests cannot be recommended.


If Diagnosis Is Not

Possible,

Is Treatment For

Luteal Inadequacy

Ever Appropriate ???


Treatment Of Potential Luteal

Inadequacy

1st approach: Correction of any underlying

condition …(hypothalamic or thyroid dysfunction, hyperprolactinemia)

2nd approach : Empiric Treatment

(based on limited reliable data)

• Promote endometrial maturation

• Enhance endometrial receptivity

• Support implantation and development of an early pregnancy


What to use for LPS …???

Progesterone,

progesterone + estrogen,

hCG

Ovulation induction with clomiphene or gonadotropins

GnRHa

Prednisolone

Aspirin

Heparin

Ascorbic acid

ImmunoglobulinsMob : 9909944160 20Dr. Shashwat Jani

PROGESTERONE


Action

Improves endometrial receptivity

(Kolibianakis & Devroy, 2002)

Promotes local Vasodilatation and uterine musculature quiescence by inducing nitric oxide synthesis in decidua

(Bulletti & de Ziegler, 2005)

Act as immunologic suppressant blocking Th1 and inducing release of Th2 cytokines


I. M. Progesterone

Effective

Physiological serum levels

Painful (long, thick needles)

Occasional sterile abscess

Occasional allergic reaction (oil vehicle)

Needs to be administered by trained person

Acute eosinophilic pneumonia associated with IM administration of progesterone as luteal phase support after IVF: 3 case report


Vaginal Progesterone

Effective

Convenient (self-administration)

First uterine pass effect / targeted delivery

Might require multiple dosing /day (suppositories)

High uterine concentration of progesterone

Minimizes the potential for adverse systemic effects (Bulletti et al., 1997)


Dosage Micronized Progesterone:

No dose finding studies. Most frequently:

300–600 mg daily, spread over 2-3 dosages

(Tavaniotou et al., 2000; ASRM, 2013 ) Vaginal progesterone pessaries:

no dose finding studies. Most frequently used:

400-800 mg daily, spread over 3-4 doses

(NG et al, 2002, Tay et al, 2005)


Vaginal Gel

8% gel in a dose of 90 mg once daily

No differences when administered twice daily

(Tavaniotou et al, 2000)

Low dose or high dose vaginal progesterone gel

Both are equally effective

(van der Linden et al., 2012)


Which Vaginal

Preparation…???

Gel or Capsules ? Both are equally effective (Daya & Grundy, 2004)

Capsule: solid evidence of effectiveness and convenience (Elenany et al, 2011) more cost effective than gel.

Gel is at least 4 times more expensive than Capsules.

No difference exists regarding CPR between vaginal P gel and all other vaginal preparations for LPS

(MA: Polyzoz et al, 2010)


Oral Progesterone

Ineffective ?

Low bioavailability

High rate of metabolites

(scant endometrial effect)

High rate of side effects (somnolence)


Rectal Progesterone

Resulted in serum concentration during the first 8h twice as high as other forms.

No prospective RCT to compare the rectal administration of progesterone with other administration routes for IVF

(Chakmakijan & Zachariah, 2008)


S/C Progesterone

A new water-soluble progesterone

Implantation rate, PR, LBR and early miscarriage rate for Prolutex were similar to those for Crinone.

The adverse event profiles were similar and Prolutex was safe and well tolerated.

Less painful than IM


Which is better…??? Oral or I.M. progesterone ?

Definitely I.M. progesterone

(Daya & Grundy, 2004)

Oral or vaginal progesterone ?

Definitely vaginal progesterone

(Daya & Grundy, 2004)

I.M. or vaginal progesterone ?

Both are equally effective No difference in CPR (Daya & Grundy, 2004; MA: Zarutiski & Philips, 2009)


Vaginal progesterone increases endometrial tissue levels (Fert.Steril, 2012)


IM progesterone is associated with the highest serum levels (Fert.Steril, 2012)


For Ideal LPS…

IM Progesterone for the Highest Serum levels and Vaginal Progesterone for increasing the Endometrial levels, Until Placental progesterone production adequate, around week 8-10 w of gestation.

(Fert.Steril, 2012)


hCG


hCG “Progesterone and estradiol are hormone

supplementations, whereas hCG is used to stimulate these hormones in the corpora lutea. “

Placental protein 14 (Anthony et al., 1993), integrin άν (Honda et al., 1997) and relaxin (lutelpeptide hormone) concentrations, which has been shown to increase at the time of implantation are higher with hCG support ( Ghosh and Sengupta, 1998).


Limitations

OHSS.

Luteal support with hCG should be avoided: ƒ

- If E2 >2700pg/ml (Buvat et al., 1990) ƒ - If Number of follicles is >10 (Araujo et

al., 1994)


Which is better…???

Progesterone is as effective as hCG for luteal phase support but provides a higher safety with regard to ovarian hyper-stimulation syndrome .

(Ludwig and Diedrich, 2001)

( RANZCOG 2014 )


E2

No effect of oral estrogens


Transdermal estrogen is beneficial


No effect in antagonist protocol


Low dose Aspirin

M.O.A : Vasodilatation and decreased platelet

aggregation, increased ovarian and endometrial blood flow, ovarian responsiveness, endometrial thickness, decrease uterine contraction at the time of ET

Low-dose aspirin (100 mg/d) doesn’t improve ovarian responsiveness, blood flow, and PR

(Dirckx et al., 2009; Lambers et al., 2009).


Piroxicam

An oral dose 10 mg 1-2 h before ET

significantly improves PR (Moon., 2004)

Doesn’t improve PR (Dal and Borini, 2009)


Indomethacin

100 mg q12h rectally for 3 doses from the night before ET does not improve PR in oocyterecipients

(Bernabue, 2006)

43Dr. Shashwat Jani

Low dose Heparin

5000 IU BD and Aspirin 100 mg/day from the day of ET did not improve PR or IR.

(Stern et al., 2003)


Prednisolone

• 10 mg/d before or after ET does not increase PR

(Ubaldi et al., 2002)


Sildenafil

25 mg qid

vaginally from stimulation D1 to hCG day.

(Sher, 2002;

Paulus,2002)

Not Recommended…. ( ESHRE , 2013 )


Ascorbic Acid

Luteal regression is associated with ascorbate depletion and the generation of reactive oxygen species, which inhibit the action of LH and block steroidogenesis

No value

(Griesinger et al.,2002)


GnRHa in Midluteal phase

• GnRH receptor is expressed in the human preimplantation embryos, endometrium, corpus luteum .

• GnRHa has been shown to stimulate trophoblast production of hCG .

• Increased LBR

(MA: Kyrou et al., 2008)


GnRHa Vs no treatment : GnRHa is beneficial (Glujovsky et al., 2010)

Effective (van der Linden et al., 2012)

Which GnRHa is more beneficial? No differences (Glujovsky et al., 2010)


Cochrane 2012

Single dose of 0.5 mg S/C on 6 th day after ICSI Increases implantation rate, CPR per transfer, increases live birth rate Single dose GnRH agonist.

Addition of GnRH agonist to progesterone improved outcome of live birth, clinical pregnancy and ongoing pregnancy .


Natural Cycle

No treatment for luteal phase insufficiency has been shown to improve pregnancy outcomes in natural, unstimulated cycles.

( ASRM April 2015 )


Ovulation Induction

Improved pre-ovulatory follicular dynamics Should improve corpus luteum function

Use of agents that induce ovulation Improved corpus luteum function & fertility outcomes.

( ASRM APRIL 2015 )


ART

For luteal support in assisted reproductive technologies (ART), exogenous progesterone supplementation is associated with a significantly higher pregnancy rate.

Strongly Recommended ( ASRM , 2015 )


Why in ART Cycles ?

Abnormal luteal function after COS for IVF

Suppression of LH

Continued down-regulation by GnRHa

Removal of granulosa cells at OR

Supra physiological E2/P4 in early luteal phase

hCG injection before OR


When to start..?

From day of OR or ET

Not be later than day 3 after OR


How long …???

Not established firmly

Often continued Unnecessarily till 12 week

Most evidence based studies suggest to continue till 9 weeks gestation


Pregnancy

First trimester progesterone supplementation in IVF may support early pregnancy through 7 weeks by delaying miscarriage but does not improve live birth rates .

First trimester progesterone supplementation in natural cycle pregnancies also does not prevent a miscarriage. (Wahabi et al., 2007)


Recurrent Miscarriage

There is insufficient evidence to evaluate the effect of progesterone supplementation in pregnancy to prevent a miscarriage .

(RCOG- Green Top Guidelines2011)


It was only in 2011 that Cochrane meta analysis suggested that progesterone supplementation has beneficial effects in patients with Recurrent Pregnancy Loss.

It dose, route, frequency & duration does not affect the outcome.

Cochrane 2011 for Recurrent Miscarriages


“ PRO MIS Trial “

PROgesterone in MIScarriage trial

Newer Evidence is coming up as large multicentre study PROMISE is currently on the Way…


Take Home Message

Abnormal luteal function may occur as the result of a medical condition (e.g., elevated prolactin, abnormal thyroid function), and infertile women suspected of having one of these disorders (e.g., irregular menses, galactorrhea) should be evaluated and appropriately treated for identified conditions.


No diagnostic test for luteal phase insufficiency has been proven to be reliable in a clinical setting.

The roles of BBT, urinary LH detection kits, luteal progesterone levels, endometrial biopsy, and other diagnostic studies have not been established, and performance of these tests cannot be recommended.


There is no proven role in adding progesterone or hCG for luteal support once a pregnancy has been established.

Use of supplemental progesterone in a non-ART cycle beyond the time of expected menses (i.e., 2 weeks after ovulation) is Not proven to be beneficial.


No treatment for luteal phase insufficiency has been shown to improve pregnancy outcomes in natural, unstimulated cycles.

Luteal support after ART procedures with progesterone or hCG improves pregnancy outcomes, but hCG increases the risk of OHSS.


evidence based practical tips for luteal phase support by dr shashwat jani

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