How CL function is adversely affected in PCOS women due to its(PCO) persistent
hyperinsulinaemic effect: :-- In ovulatory PCOS granulosa cells from polycystic ovaries
demonstrate a decreased ability to
produce and secrete progesterone
in presence of hyperinsulinemia .
This could result from insulin mediated
abnormal / altered intracellular glucose pathway defect.
Infertility in PCO could be a resultant effect from dysfunctional
C
L. The common mechanisms of infertility in PCO is CL dysfunction. –Definition:-
Luteal phase deficiency is a consequence
of the corpus luteum inability to
produce and sustain an adequate
levels of progesterone. How to diagnose LPD??
This is clinically 1) manifested by
short menstrual cycles and 2) infertility .
Why LPD’ :What is the
Etiology of PCO associated LPD ?? :-1) Abnormal
follicular development, 2) defects
in neo angiogenesis or 3) inadequate steroidogenesis in the lutein cells of the CL have been implicated in CL dysfunction and LPD. LPD
and polycystic ovary syndrome are
independent disorders but sharing common pathophysiological profiles in the sense of hyperinsulinaemia as the primary defect. .
Factors such as 1) hyperinsulinemia 2) AMH excess and 3) defects in angiogenesis of CL are at the
origin of both PCO & LPD.
LPD and PCOS. Luteal phase defect an ovulatory dysfunction
is defined as a defect of the
corpus luteum to produce and secrete adequate amounts
of progesterone during the
luteal phase of the menstrual cycle .
it includes the defect of the CL to preserve
high levels of progesterone during the
second half of the menstrual cycle as well as the defect
of the endometrium to respond to
the circulating progesterone levels.
Polycystic ovary syndrome is a
heterogeneous disorder of unknown
etiology which
affects 6-10% of women of
reproductive age. The diagnostic
criteria for PCOS include two of the
three following A) chronic
anovulation or oligomenorrhea B) clinical or
biochemical hyperandrogenism and C) polycystic ovarian morphology . The
pathogenesis of PCO is not
clarified as yet LPD and PCOS are
independent disorders but they share
common pathophysiological profiles . Although
the literature on this matter is
limited it would be interesting
to investigate in what extent LPD is involved in subfertility observed in women
with PCOS .
Etiology and
pathogenesis of corpus luteum deficiency
Clinically , LPD may
present with short menstrual cycles or
without any significant change in
menstrual cycle length despite prolonged follicular phases and shortened progesterone
deficient luteal phases .
LPD is a clinical expression of CL deficiency caused by various pathophysiological mechanisms including abnormal follicular development
and secretory dysfunction of CL.
Both mechanisms lead to the inadequate transformation of the endometrium lead to the inadequate transformation of the endometrium to secretory resulting
in defective implantation of the
blastocyst and deficient
embryonic development.
Polycystic ovary syndrome
As previously mentioned PCOS is one of the most common
female endocrine disorders. It is a complex
syndrome of unclear etiogy pathogenesis characterized by heterogenecity
in phenotypic manifestations .Although the pathogenesis of PCOS remains unclear the syndrome appears to
involve environmental and genetic
components . Oligo anovulation
in PCOS is likely to be cause of
infertility . Nevertheless the role of the CL quality is not well investigated.
Common factors in LPD and PCOS
Defect 1:-Hyperinsulinemia in LPD association with PCOS
Hyperinsulinemia seems to have a key role in the pathogenesis of PCOS. Insulin induces
androgen production in multiple ways , it a) directly acts on the
ovaries where it stimulates
production ans secretion of androgens from the thecae cells b) acting indirectly it inhibits the synthesis
of steroid hormone binding
globulin in the liver ,
leading to elevated free androgen levels Insulin also been shown to c)
alter the synthesis and pulsatile
pattern of LH and FSH secretion and
therefore hinders ovulation.
Defect 2:-In women with PCOS there is
constant increase GnRH
pulsatility is increased favoring the LH over FSH production and secretion which is a common
feature in women with syndrome Pulsatile GnRH secretory pattern is deranged in both LPD and PCOS. In women with LPD previous
studies have shown that GnRH pulse frequency is normal or increased in the
follicular phase and suppressed during the luteal phase. In contrast to PCOS in which there is a constant increase of GnRH
pulsatility .
Furthermore it has
been shown that in ovulatory women with
polycystic ovaries there is a Defect 3 :-defect in luteal phase progesterone excretion . As a
result these women have lower levels of progesterone in the early luteal
phase which may be implicated in their infertility Hyperinsulinemia and insulin
resistance may be in part
responsible for LPD in PCOS women .
Granulosa cells from polycystic ovaries demonstrate
a decreased ability to produce ad secrete progesterone in presence of hyperinsulinemia. Defect 4 :-This could result from insulin
mediated glucose metabolism in PCO granulosa cells due to
intracellular pathways defect. Defect 5 :-Hyperinsulinemia may
also cause LPD via its direct effects on the pituitary gland . Plasma concentrations of LH
and insulin have been
demonstrated to be positively
correlated during the luteal phase.
Anti Mullerian hormone in LPD and PCOS
AMH is a member of the
transforming growth factor B superfamily and is a protein produced by fetal
Sertoli cells in order to promote the Mullerian duct regression during testicular
differentiation in the male fetus
. In the ovaries AMH is expressed by the granulosa cells of primodial
follicles and seems to inhibit the recruitment of follicles from the resting pool to the growing phase . It is
well established that serum AMH levels
are higher in women with
PCOS compared to healthy controls. AMH
can negatively affect the function of granulose lutein cells.
AMH has been shown to
1) inhibit in culture the proliferation and the
progesterone production of
human granulosa derived lutein cells and also
2) AMH also reduced the
expression of LH receptors as well as
3) reduces the activity of aromatase in cultured human granulosa derived
lutein cells. Therefore increased
levels of AMH in PCOS can be
responsible for CL dysfunction
and LPD although further
investigation are required to support this.
How abnormal IS angionegenesis in LPD and PCOS
Angiogenesis is crucial
for the formation and function of CL as the newly formed blood vessels provide the CL with
nutrients and low density
lipoproteins required for steroidogenesis . Under this perspective alterations in concentrations
and / or expression patterns of
angiogenic factors may lead to luteal function.
Decreased VEGF
levels is the chief cause in PCO induced LPD:_
In fact inhibition of
vascular endothelial growth factor
during the luteal phase leads to impaired angiogenesis in the CL and has been associated
with reduced progesterone production and secretion. Therefore decreased VEGF levels can
eventually lead to LPD. But further studies are required to support this .
In contrast VEGF levels are increased in PCOS ans also temporally
and spatially different in
compared to normal controls. A recent animal study suggests a novel auto / paracrine action of
cytokines specifically tumor necrosis
factor alpha (TNF-α) on the up
regulation of VEGF for angiogenesis
stimulation in equine early CL.
Possibly this is a
result of increased sensitivity of lutein granulosa cells of polycystic ovaries to insulin which leads to increased VEGF production in compared to normal ovaries .
Although controversy exists it is
possible that impaired angiogenesis may be a cause of LPD in PCOS . The other angiogenic factors such
as angiopoietins , epidermal growth factors, insulin like
growth factors fibroblast growth
factor 1 and 2 also participate
in luteal angiogenesis but it is
not known whether these factors are involved in the pathogenesis of LPD.
Treatment of LPD
should target to normalize menstrual
abnormalities and improve pregnancy rates. As
LPD is a multifactorial
disorder individualized
approach of the patient is necessary
. Administration of progesterone
or human chorionic gonadotropin
is the most common treatment of LPD. Ovulation can be induced by clomiphene citrate
and / or gonadotropin.
No comments:
Post a Comment