Recurrent pregnancy loss lpd
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Recurrent Pregnancy Loss-LPD. Dr. USHA REDDY MRCOG. ?. Why LPD. Abortion & Infertility Profound personal tragedy a formidable challenge to physician.

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Recurrent pregnancy loss lpd

Recurrent Pregnancy Loss-LPD

Dr. USHA REDDY MRCOG


Why lpd

?

Why LPD


Recurrent pregnancy loss lpd

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


Recurrent pregnancy loss lpd

Human Reproduction Woefully inefficient 15 % of ova exposed to sperm fail to divide 15% fail to implant & 41% of implanted pregnancy are lost41% implanted pregnancy are lost of which 2/3 after Hcg secretion and 1/3 even beforeThus finally only 30% → Viable Preganancy


Recurrent pregnancy loss lpd

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


Recurrent pregnancy loss lpd

Spontaneous Abortion

Incidence

16% of all clinically recognised pregnancies

but

55% after 3 consecutive Spontaneous Abortions

(in patients with Habitual/Recurrent Abortion)

Vlaandeeren W 1987


Proposed 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

Proposed causes of RSA

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


Recurrent pregnancy loss lpd

Pregnancy & Immunomodulation


Recurrent pregnancy loss lpd

Endocrine

-

Immuno

Interaction

Duphaston modulates the mother

‘s-to-

be

immune

response

from

Rejection

Protection

to


Recurrent pregnancy loss lpd

Spontaneous Recurrent Abortion

Causes

Explainable 50-60%

Genetic

Infectious

Endocrine

Autoimmune - SLE, Anticardiolipin Antibodies

Unexplained 40-50%

Allogenic Immune Response to Paternal Antigens

R Raghupathy 1999


Recurrent pregnancy loss lpd

Formation of the Zygote


Recurrent pregnancy loss lpd

In Pregnancy…...

FETUS

Mother

Father

Own

Foreign

Antigens

Mother’s Body

Foreign

Antigens

Mother’s Body


Recurrent pregnancy loss lpd

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


Recurrent pregnancy loss lpd

What follows is…….

Foreign

Antigens

T & B cells

T helper 1 cell response

T helper 2 cell response

Antibodies

Response to Fetus is same as that to any Foreign Antigen


Recurrent pregnancy loss lpd

Immune Reaction During Pregnancy

Fetus with

Paternal

Antigens

T helper 1 cell response

T helper 2 cell response

Protection of

the Fetus

Abortion of

the Fetus


Recurrent pregnancy loss lpd

Pregnancy protective

Immunomodulation starts...

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

30-36h

day 3-4

2 cells

4 cells

8 cells

Morula

day 5-6

Blastocyst


Recurrent pregnancy loss lpd

Four cell stage of Embryo

Start of feto-maternal crosstalk...


Recurrent pregnancy loss lpd

From days 15-16 ...

maternal blood circulates...

within the intervillous space


Recurrent pregnancy loss lpd

How does T helper 1 response cause Abortion?

Fetus

T helper 1 cell response

NK LAK cells

Release harmful

cytokines

Symmetric Antibodiesby B cells

Bind with Antigen

TNF ά

IFNγ

IL2

IL12

IL18

Activation of Complement

Phagocytic & Cytotoxic reactions

Inflammation

Abortion of Fetus


Recurrent pregnancy loss lpd

Let us look at each of these reactions in

detail now…………..


Recurrent pregnancy loss lpd

Cytokines …...

Fetus

T helper 1 cell response activated

Tumor Necrosis Factor ά

Interferon γ

Interleukin 2

Interleukin 12

Interleukin 18

Harmful

cytokines

Inflammation

Abortion of Fetus


Recurrent pregnancy loss lpd

Symmetric Antibodies…...

Symmetricity b/w binding surfaces..

Maternal

Antibody

Paternal

Antigen

Exact alignement b/w binding surfaces

Lock-n-Key pattern

Antigen-Antibody binding

Activation of Complement Cascade

Abortion of the Fetus


Recurrent pregnancy loss lpd

Binding of Antigen & Antibody


Recurrent pregnancy loss lpd

The Complement Cascade


Recurrent pregnancy loss lpd

Destruction of Cell by Complement


Recurrent pregnancy loss lpd

LAK cells …...

Fetus

T helper 1 cell response activated

Harmful

cytokines

Tumor Necrosis Factor ά

Interleukin 2

Natural Killer cells

Lymphokine Activated Killer cells

Abortion of Fetus


Recurrent pregnancy loss lpd

Having shown the immune response in Abortion

Let us see what happens in a successful Pregnancy


Recurrent pregnancy loss lpd

In successful Pregnancy Embryo protective Immunomodulation takes place


Recurrent pregnancy loss lpd

Embryo Protective Immunomodulation

-What is it?

3 positive responses

NK Activity

T helper 2 cell response

Asymmetric Antibodies

Protective

cytokines

No binding with Antigen

IL 3

IL 4

IL 5

IL 6

IL 10

IL 13

No activation of

Complement

Cascade

Protection of Fetus


Recurrent pregnancy loss lpd

Embryo Protective Immunomodulation - How is this brought about ?

Normal

Pregnancy

Progesterone (P) Receptor

Activation

Progesterone Induced Blocking Factor (PIBF)

Embryo Protective Immunomodulation

Protection of Fetus


Recurrent pregnancy loss lpd

Embryo Protective Immunomodulation in Successful Pregnancy

PIBF

NK Activity

T helper cell 2 response

Asymmetric Antibodies

Protective

cytokines

No binding with Antigen

IL 3

IL 4

IL 5

IL 6

IL 10

IL 13

No activation of

Complement

Cascade

Protection of Fetus


Recurrent pregnancy loss lpd

Unfortunately …..

As we have seen ….

In up to 50 % of women with Recurrent Abortion,

Embryo-protective Immunomodulation does not take place


Recurrent pregnancy loss lpd

In these women with Recurrent Abortion duphaston is the key to Embryo survival


Recurrent pregnancy loss lpd

Let us see…..

How duphaston ensures Embryo protective Immunomodulation


Recurrent pregnancy loss lpd

Embryo Protective Immunomodulation - Role of duphaston

duphaston

Progesterone (P) Receptor

Activation

PIBF

Embryo Protective Immunomodulation

Protection of Fetus


Treatment of lpd

Treatment of LPD

Treatment of LPD can be by any of the following :

  • Progesterone

  • Non luteolytic progestogen

  • hCG


Recent indian data

Recent Indian Data

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.


Advantages of dydrogesterone over other progestogens

Advantages of Dydrogesterone over other Progestogens

Androgenic -++No side effects like acne,

activityhirsutism, voice changes

Impairment of-++Safe in diabetics and in

carbohydratepost menopausal women

metabolism

Impairment of -++Decreases risk of CVD

lipid metaboilsm

Virlization of -++No adverse effects on

foetus female foetus

Anabolic effects-++No weight gian / increased BP

Thermogenic effect-++No masking of the BBT

ParametersDydrogesteroneNonrethisteroneMPAClinical advantages of Dydrogesterone


Human chorionic gonadotrophin

Human 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.


Recurrent pregnancy loss lpd

  • 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.


Recurrent pregnancy loss lpd

  • 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 )

Synthetic Steps


Recurrent pregnancy loss lpd

DIOSGENIN

the same natural source of

dydrogesterone and micronised progesterone

What is the difference between dydrogesterone and micronised progesterone?


Recurrent pregnancy loss lpd

COCH3

CH3

COCH3

CH3

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

CH3

H

H

O

O

O

dydrogesterone

progesterone


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 )


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; )


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) ).


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 )


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 ;


Conclusion

Conclusion

  • 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.


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