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.