Recurrent Pregnancy Loss-LPDRecurrent Pregnancy Loss-LPD

Dr. USHA REDDY MRCOGDr. USHA REDDY MRCOG

WHY LPDWHY LPD

??

Abortion & Infertility Profound personal tragedy a formidable challenge to physician.

Human Reproduction Woefully inefficient

15 % of ova exposed to sperm fail to divide

15% fail to implant & 41% of implanted pregnancy are lost

41% implanted pregnancy are lost of which 2/3 after Hcg secretion and 1/3 even before

Thus finally only 30% → Viable Preganancy

Human Reproduction Woefully inefficient

15 % of ova exposed to sperm fail to divide

15% fail to implant & 41% of implanted pregnancy are lost

41% implanted pregnancy are lost of which 2/3 after Hcg secretion and 1/3 even before

Thus finally only 30% → Viable Preganancy

Hormonal bio essays Imaging techniques Newer surgical endoscopic procedure Pharmaceutical treatment

▼

Successful management of this heterogeneous disorder and endowing the blessing of parenthood to many a

despondent couple

Hormonal bio essays Imaging techniques Newer surgical endoscopic procedure Pharmaceutical treatment

▼

Successful management of this heterogeneous disorder and endowing the blessing of parenthood to many a

despondent couple

Spontaneous Abortion

Incidence

16% of all clinically recognised pregnanciesbut

55% after 3 consecutive Spontaneous Abortions (in patients with Habitual/Recurrent Abortion)

Vlaandeeren W 1987

Proposed causes of RSAProposed causes of RSA

Endocrine etiologies - Luteal phase defect - Thyroid dysfunction

- Uncontrolled diabetes mellitus * Immune-based * Uterine anatomic anomalies* Endometrial infections * Antiphospholipid syndrome* Inherited thrombophilias & Alloimmune causes* Parental chromosomal abnormalities

Endocrine etiologies - Luteal phase defect - Thyroid dysfunction

- Uncontrolled diabetes mellitus * Immune-based * Uterine anatomic anomalies* Endometrial infections * Antiphospholipid syndrome* Inherited thrombophilias & Alloimmune causes* Parental chromosomal abnormalities

Lee RM, Silver RM 2000 Recurrent pregnancy loss: summary and clinical ecommendations. Semin Reprod Med 18:433–440

Pregnancy & Immunomodulation

Endocrine -Immuno Interaction

Duphaston modulates the mother ‘s-to- be immune response

from

Rejection to Protection

Spontaneous Recurrent Abortion

Causes

Explainable 50-60%GeneticInfectious EndocrineAutoimmune - SLE, Anticardiolipin Antibodies

Unexplained 40-50%Allogenic Immune Response to Paternal Antigens

R Raghupathy 1999

Formation of the Zygote

In Pregnancy…...

Mother Father

Own ForeignAntigens

Mother’s Body ForeignAntigens

Mother’s Body

FETUS

We all agree that …….

Material from Father………………….

…………. Is Foreign to Mother

Therefore …Mother’s body will recognize it as An Antigen&set up an Immune reaction to Fetus

What follows is…….

Response to Fetus is same as that to any Foreign Antigen

ForeignAntigens

T helper 1 cell response T helper 2 cell response

T & B cells

Antibodies

Immune Reaction During Pregnancy

T helper 1 cell response T helper 2 cell response

Protection of the Fetus

Abortion of the Fetus

Fetus with Paternal Antigens

30-36h day 3-4

day 5-6

Morula

Blastocyst

4 cells8 cells

2 cells

Pregnancy protectiveImmunomodulation starts...

...Pre-embryo‘s journey in the Fallopian Tubes

Four cell stage of Embryo

Start of feto-maternal crosstalk...

From days 15-16 ...

maternal blood circulates...

within the intervillous space

m

f

f

day 22

How does T helper 1 response cause Abortion?

TNF άIFNγIL2IL12IL18

Release harmful cytokines

T helper 1 cell response

Phagocytic & Cytotoxic reactions

Bind with Antigen

NK LAK cells

Fetus

Inflammation

Symmetric Antibodies by B cells

Abortion of Fetus

Activation of Complement

Let us look at each of these reactions in

detail now…………..

Cytokines …...

Tumor Necrosis Factor άInterferon γInterleukin 2Interleukin 12Interleukin 18

Harmful cytokines

T helper 1 cell response activated

Fetus

Inflammation

Abortion of Fetus

Symmetric Antibodies…...

Paternal Antigen

Maternal Antibody

Symmetricity b/w binding surfaces..

Lock-n-Key pattern

Exact alignement b/w binding surfaces

Antigen-Antibody binding

Activation of Complement Cascade

Abortion of the Fetus

Binding of Antigen & Antibody

The Complement Cascade

Destruction of Cell by Complement

LAK cells …...

Tumor Necrosis Factor άInterleukin 2

Harmful cytokines

T helper 1 cell response activated

Fetus

Natural Killer cells

Abortion of Fetus

Lymphokine Activated Killer cells

Having shown the immune response in Abortion

Let us see what happens in a successful

Pregnancy

In successful Pregnancy Embryo protective Immunomodulation

takes place

Embryo Protective Immunomodulation -What is it?

IL 3IL 4IL 5IL 6IL 10IL 13

Protective cytokines

3 positive responses

T helper 2 cell response

No activation of ComplementCascade

NK Activity

Asymmetric Antibodies

Protection of Fetus

No binding with Antigen

Embryo Protective Immunomodulation - How is this brought about ?

Progesterone Induced Blocking Factor (PIBF)

Normal Pregnancy

Progesterone (P) Receptor Activation

Protection of Fetus

Embryo Protective Immunomodulation

Embryo Protective Immunomodulation in Successful Pregnancy

IL 3IL 4IL 5IL 6IL 10IL 13

Protective cytokines

PIBF

T helper cell 2 response

No activation of ComplementCascade

NK Activity

Asymmetric Antibodies

Protection of Fetus

No binding with Antigen

Unfortunately …..As we have seen ….

In up to 50 % of women with Recurrent Abortion,

Embryo-protective Immunomodulation does not take place

In these women with Recurrent Abortion duphaston is the key to

Embryo survival

Let us see…..How duphaston ensures Embryo

protective Immunomodulation

Embryo Protective Immunomodulation - Role of duphaston

PIBF

Progesterone (P) Receptor Activation

Protection of Fetus

Embryo Protective Immunomodulation

duphaston

Treatment of LPDTreatment of LPD

Treatment of LPD can be by any of the following :

Progesterone

Non luteolytic progestogen

hCG

Treatment of LPD can be by any of the following :

Progesterone

Non luteolytic progestogen

hCG

Recent Indian DataRecent Indian DataReport of the study undertaken by Dr. Sonia Malik, MD, Sr. Consultant, Obstet & Gynaecology, Infertility & IVF, New Delhi in the year 1998-1999, publihed in Obs & Gynae Today, August 2000 : 497-501

Aim - To study the effect of duphaston (dydrogesterone) on the endometrium in case of luteal phase insufficiency.

Patients and Methods - 25 patients undergoing infertility investigations were identified as having luteal phase insufficiency according to the following criteria -.

Report of the study undertaken by Dr. Sonia Malik, MD, Sr. Consultant, Obstet & Gynaecology, Infertility & IVF, New Delhi in the year 1998-1999, publihed in Obs & Gynae Today, August 2000 : 497-501

Aim - To study the effect of duphaston (dydrogesterone) on the endometrium in case of luteal phase insufficiency.

Patients and Methods - 25 patients undergoing infertility investigations were identified as having luteal phase insufficiency according to the following criteria -.

an endometrial biopsy on day 21 showing a lag of 3 days or more.

A serum progesterone concentration of < 10 ng/ml. An ultrasound scan showing either poor endometrium or

corpus luteum.

…contd.

an endometrial biopsy on day 21 showing a lag of 3 days or more.

A serum progesterone concentration of < 10 ng/ml. An ultrasound scan showing either poor endometrium or

corpus luteum.

…contd.

Advantages of Dydrogesterone over other ProgestogensAdvantages of Dydrogesterone over other Progestogens

Parameters Dydrogesterone Nonrethisterone MPA Clinical advantages of Dydrogesterone

Parameters Dydrogesterone Nonrethisterone MPA Clinical advantages of Dydrogesterone

Androgenic - + + No side effects like acne,activity hirsutism, voice changes

Impairment of - + + Safe in diabetics and incarbohydrate post menopausal womenmetabolism

Impairment of - + + Decreases risk of CVDlipid metaboilsm

Virlization of - + + No adverse effects onfoetus female foetus

Anabolic effects - + + No weight gian / increased BP

Thermogenic effect - + + No masking of the BBT

Androgenic - + + No side effects like acne,activity hirsutism, voice changes

Impairment of - + + Safe in diabetics and incarbohydrate post menopausal womenmetabolism

Impairment of - + + Decreases risk of CVDlipid metaboilsm

Virlization of - + + No adverse effects onfoetus female foetus

Anabolic effects - + + No weight gian / increased BP

Thermogenic effect - + + No masking of the BBT

Human Chorionic GonadotrophinHuman Chorionic Gonadotrophin

HCG stimulates cells of the corpus luteum to produce progesterone. In the normal corpus luteum, the luteal cells are adequate in number and have adequate capacity to produce progesterone.

However, malfunctioning corpus luteum has less number of luteal cells. Also, the capacity of each luteal cell to produce progesterone in response to HCG is compromised ( decreased ) in luteal phase defect . Therefore progesterone production via stimulation of malfunctioning corpus luteum by HCG will be less. ( ref. Momoeda et al, Human Reproduction, 1998, July; 13 (7), 1907-11 )

…contd.

HCG stimulates cells of the corpus luteum to produce progesterone. In the normal corpus luteum, the luteal cells are adequate in number and have adequate capacity to produce progesterone.

However, malfunctioning corpus luteum has less number of luteal cells. Also, the capacity of each luteal cell to produce progesterone in response to HCG is compromised ( decreased ) in luteal phase defect . Therefore progesterone production via stimulation of malfunctioning corpus luteum by HCG will be less. ( ref. Momoeda et al, Human Reproduction, 1998, July; 13 (7), 1907-11 )

…contd.

Stimulatory effect of exogenous HCG on progesterone production is minimal on malfunctioning corpus luteum. This suggests that LPD does not benefit from HCG administration.

( ref. Momoeda et al, Human Reproduction, 1998, July; 13 (7), 1907-11 )

…contd.

Stimulatory effect of exogenous HCG on progesterone production is minimal on malfunctioning corpus luteum. This suggests that LPD does not benefit from HCG administration.

( ref. Momoeda et al, Human Reproduction, 1998, July; 13 (7), 1907-11 )

…contd.

Among the characteristics of LPD in women is the

inability of the corpus luteum to respond appropriately

to LH/HCG. This defect may be caused by

inappropriate formation of new LH/HCG receptors. ( Felig P, Endocrinology & Metabolism, 1995, third edition, 994 )

HCG will not correct the luteal phase defect in patients

with inadequate ovarian LH/HCG receptors. ( Mishell’s

Text Book of Infertility, Contraception and Reproductive Endocrinology,

1997, Fourth edition, 739-40 )

There is a risk of ovarian hyperstimulation syndrome

( OHSS )associated with hCG use.…contd.

Among the characteristics of LPD in women is the

inability of the corpus luteum to respond appropriately

to LH/HCG. This defect may be caused by

inappropriate formation of new LH/HCG receptors. ( Felig P, Endocrinology & Metabolism, 1995, third edition, 994 )

HCG will not correct the luteal phase defect in patients

with inadequate ovarian LH/HCG receptors. ( Mishell’s

Text Book of Infertility, Contraception and Reproductive Endocrinology,

1997, Fourth edition, 739-40 )

There is a risk of ovarian hyperstimulation syndrome

( OHSS )associated with hCG use.…contd.

Micronised progesterone…NATURAL?Micronised progesterone…NATURAL? The term natural progesterone ( as used to describe micronised

progesterone ) is misleading.

Diosgenin ( plant source - Dioscorea villosa )

Micronised Progesterone Dydrogesterone

Either both are natural or both are synthetic.

( Ref: : Peterson C M, Clinical Obstetrics and Gynecology, 1995, 38 ( 4 ) : 819;

http://www.skinbiology.com/menopause&aging.html; data on file )

The term natural progesterone ( as used to describe micronised

progesterone ) is misleading.

Diosgenin ( plant source - Dioscorea villosa )

Micronised Progesterone Dydrogesterone

Either both are natural or both are synthetic.

( Ref: : Peterson C M, Clinical Obstetrics and Gynecology, 1995, 38 ( 4 ) : 819;

http://www.skinbiology.com/menopause&aging.html; data on file )

Synthetic Steps

DIOSGENIN

the same natural source of

dydrogesterone and micronised progesterone

What is the difference between dydrogesterone and micronised progesterone?

DIOSGENIN

the same natural source of

dydrogesterone and micronised progesterone

What is the difference between dydrogesterone and micronised progesterone?

The difference is in the structure.

This structural difference brings about the difference in the metabolism. (ref. Amsterdam P H et al, European J of Drug Metabolism and Pharmacokinetics, 1980, 5 (3): 173-184 )

The difference is in the structure.

This structural difference brings about the difference in the metabolism. (ref. Amsterdam P H et al, European J of Drug Metabolism and Pharmacokinetics, 1980, 5 (3): 173-184 )

CH3

COCH3

CH3

H

O

progesterone

O

CH3

H

CH3COCH3

O

dydrogesterone

Dydrogesterone’s different metabolism... Dydrogesterone’s different metabolism...

The metabolites of dydrogesterone retain 4,6- diene-3-one structure. The major metabolite of dydrogesterone retains progestational activity. Hence, it is orally effective .

Dydrogesterone has very good oral bioavailability. It brings about 100% conversion to secretory endometrium

( Identical endometrial histological appearance as seen in natural cycles ).

(ref. Amsterdam P H et al, European J of Drug Metabolism and Pharmacokinetics, 1980, 5 (3): 173-184; Malik S, Nagpal S, Obs & Gynae Today, August 2000, V ( 8 ) : 497-501 )

The metabolites of dydrogesterone retain 4,6- diene-3-one structure. The major metabolite of dydrogesterone retains progestational activity. Hence, it is orally effective .

Dydrogesterone has very good oral bioavailability. It brings about 100% conversion to secretory endometrium

( Identical endometrial histological appearance as seen in natural cycles ).

(ref. Amsterdam P H et al, European J of Drug Metabolism and Pharmacokinetics, 1980, 5 (3): 173-184; Malik S, Nagpal S, Obs & Gynae Today, August 2000, V ( 8 ) : 497-501 )

Oral micronised progesterone’s different metabolism

Oral micronised progesterone’s different metabolism

The metabolites of progesterone do not retain 4 - ene - 3-

one structure. Hence, it is not orally effective.

95% of micronised progesterone administered orally was

converted to inactive metabolites due to first pass effect.

Incomplete secretory conversion of endometrium has

been reported with oral micronised progesterone.

(ref. Amsterdam P H et al, European J of Drug Metabolism and

Pharmacokinetics, 1980, 5 (3): 173-184 ; Levine H L, Watson N A, Abstract

presented at the 8th International Congress on the menopause, Sydney,

Australia,November 3-7, 1996; )

The metabolites of progesterone do not retain 4 - ene - 3-

one structure. Hence, it is not orally effective.

95% of micronised progesterone administered orally was

converted to inactive metabolites due to first pass effect.

Incomplete secretory conversion of endometrium has

been reported with oral micronised progesterone.

(ref. Amsterdam P H et al, European J of Drug Metabolism and

Pharmacokinetics, 1980, 5 (3): 173-184 ; Levine H L, Watson N A, Abstract

presented at the 8th International Congress on the menopause, Sydney,

Australia,November 3-7, 1996; )

Safety ...Dydrogesterone vs micronised progesterone

Safety ...Dydrogesterone vs micronised progesterone

Unlike oral micronised progesterone, dydrogesterone does not cause hepatotoxicity, natriuresis.

Unlike progesterone, dydrogesterone does not cause impairment of carbohydrate metabolism.( Ref. - AICOG News, December 2000, ; Martin A J, Supplement to Modern Medicine, December , 1986, 31(12) ).

Unlike oral micronised progesterone, dydrogesterone does not cause hepatotoxicity, natriuresis.

Unlike progesterone, dydrogesterone does not cause impairment of carbohydrate metabolism.( Ref. - AICOG News, December 2000, ; Martin A J, Supplement to Modern Medicine, December , 1986, 31(12) ).

Dydrogesterone vs vaginal micronised progesterone

Dydrogesterone vs vaginal micronised progesterone

Vaginal administration of progesterone is complicated by a marked variability within and among patients.

Side effects include vaginal irritation, discharge, monilial vaginitis.

Dydrogesterone being administered by oral route, the above limitations, side effects are not observed.

Vaginal micronised progesterone is found to deter embryo implantation and decrease pregnancy rates. Dydrogesterone maintains implantation site and achieves good pregnancy rates.

( Maxson W S , Clin Exp Obst & Gyn, June 1987, 30(2):470, Wang H S, Soong Y K,

Gynecol Endocrinol, 1996, 10(5): 349-355 )

Vaginal administration of progesterone is complicated by a marked variability within and among patients.

Side effects include vaginal irritation, discharge, monilial vaginitis.

Dydrogesterone being administered by oral route, the above limitations, side effects are not observed.

Vaginal micronised progesterone is found to deter embryo implantation and decrease pregnancy rates. Dydrogesterone maintains implantation site and achieves good pregnancy rates.

( Maxson W S , Clin Exp Obst & Gyn, June 1987, 30(2):470, Wang H S, Soong Y K,

Gynecol Endocrinol, 1996, 10(5): 349-355 )

Efficacy of Dydrogesterone comparable with parenteral progesterone

Efficacy of Dydrogesterone comparable with parenteral progesterone

The implantation rate and pregnancy rate with dydrogesterone was similar to intramuscular progesterone injection in IVF programme.

Pregnancy rate in oocyte donation programme using dydrogesterone is comparable to that reported with natural products.

The activity of dydrogesterone is comparable to that of parenterally administered progesterone.

{ ref. : Jan Domitrz et al Ginekol Pol 1999 Jan 70 (1) : 8-12; Abu Musa, Clin Exp Obst & Gyn, 1998, XXV (3 ) : 84; Gelfand M M et al, Menopause: The J of North American Menopause Society, 1997, 4(1): 11 ;

The implantation rate and pregnancy rate with dydrogesterone was similar to intramuscular progesterone injection in IVF programme.

Pregnancy rate in oocyte donation programme using dydrogesterone is comparable to that reported with natural products.

The activity of dydrogesterone is comparable to that of parenterally administered progesterone.

{ ref. : Jan Domitrz et al Ginekol Pol 1999 Jan 70 (1) : 8-12; Abu Musa, Clin Exp Obst & Gyn, 1998, XXV (3 ) : 84; Gelfand M M et al, Menopause: The J of North American Menopause Society, 1997, 4(1): 11 ;

ConclusionConclusion

Based on the results of various studies and

looking at the various pharmacological

advantages duphaston offers as compared to

other drug therapies, it is concluded that

therapy with duphaston is very effective in

treatment of LPD without any side effects.

Based on the results of various studies and

looking at the various pharmacological

advantages duphaston offers as compared to

other drug therapies, it is concluded that

therapy with duphaston is very effective in

treatment of LPD without any side effects.