Transcript Luteal Phase Defect ( LPD )

Recurrent Pregnancy Loss-LPD
Dr. USHA REDDY MRCOG
WHY 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
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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 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
*
*
*
*
*
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%
Genetic
Infectious
Endocrine
Autoimmune - SLE, Anticardiolipin Antibodies
Unexplained 40-50%
Allogenic Immune Response to Paternal Antigens
R Raghupathy 1999
Formation of the Zygote
In Pregnancy…...
FETUS
Mother’s Body
Mother’s Body
Mother
Father
Own
Foreign
Antigens
Foreign
Antigens
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…….
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
Immune Reaction During Pregnancy
Fetus with
Paternal
Antigens
T helper 1 cell response
Abortion of
the Fetus
T helper 2 cell response
Protection of
the Fetus
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
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?
Fetus
T helper 1 cell
response
Release harmful
cytokines
NK
Symmetric Antibodies by B cells
Bind with Antigen
TNF ά
IFNγ
IL2
IL12
IL18
Activation of Complement
Phagocytic &
Cytotoxic reactions
Inflammation
Abortion of Fetus
LAK cells
Let us look at each of these reactions in
detail now…………..
Cytokines …...
Fetus
T helper 1 cell response activated
Harmful
cytokines
Tumor Necrosis Factor ά
Interferon γ
Interleukin 2
Interleukin 12
Interleukin 18
Inflammation
Abortion of Fetus
Symmetric Antibodies…...
Paternal
Antigen
Maternal
Antibody
Symmetricity b/w binding surfaces..
Exact alignement b/w binding surfaces
Lock-n-Key pattern
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 …...
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
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?
3 positive responses
NK Activity
T helper 2 cell
response
Asymmetric Antibodies
Protective
cytokines
IL 3
IL 4
IL 5
IL 6
IL 10
IL 13
No binding with
Antigen
No activation of
Complement
Cascade
Protection of Fetus
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
Embryo Protective Immunomodulation in
Successful Pregnancy
PIBF
NK Activity
T helper cell 2 response
Asymmetric Antibodies
Protective
cytokines
IL 3
IL 4
IL 5
IL 6
IL 10
IL 13
No binding with
Antigen
No activation of
Complement
Cascade
Protection of Fetus
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
duphaston
Progesterone (P)
Receptor
Activation
PIBF
Embryo Protective Immunomodulation
Protection of Fetus
Treatment of LPD
Treatment of LPD can be by any of the following :

Progesterone

Non luteolytic progestogen

hCG
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.
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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
Parameters
Dydrogesterone Nonrethisterone MPA Clinical advantages of
Dydrogesterone
Androgenic
activity
-
+
+
No side effects like acne,
hirsutism, voice changes
Impairment of
carbohydrate
metabolism
Impairment of
lipid metaboilsm
Virlization of
foetus
Anabolic effects
-
+
+
Safe in diabetics and in
post menopausal women
-
+
+
Decreases risk of CVD
-
+
+
-
+
+
Thermogenic effect
-
+
+
No adverse effects on
female foetus
No weight gian /
increased BP
No masking of the BBT
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.

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
1997, Fourth edition, 739-40 )

Reproductive Endocrinology,
There is a risk of ovarian hyperstimulation syndrome
( OHSS )associated with hCG use.
…contd.
Micronised progesterone…NATURAL?

The term natural progesterone ( as used to describe
micronised progesterone ) is misleading.
Diosgenin ( plant source - Dioscorea villosa )
Synthetic Steps
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 )
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.
CH3
CH3
COCH3
CH3
CH3
H
H
O
O
O
progesterone

COCH3
dydrogesterone
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 )
Dydrogesterone’s different metabolism...
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The metabolites of dydrogesterone retain 4,6- diene-3one
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

The metabolites of progesterone do not retain 4 - ene - 3one 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

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

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

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

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.