LPD in PCO a great hindrance to conception

 

Luteal phase deficiency is a consequence of the corpus luteum inability to produce and preserve adequate levels  of progesterone. This is clinically manifested by short menstrual cycles  and infertility. Abnormal follicular  development  defects in neo angiogenesis  or inadequate steroidogenesis in the lutein cells of the CL have been implicated in CL dysfunction and LPD.

LPD  and polycystic ovary syndrome  aer independent disorders sharing common pathophysiological   profiles. Factors   such as hyperinsulinemia. AMH excess and defects  in angiogenesis   of CL are  at the origin of both LPD  and PCOS  . In PCOS ovulatory   cycles infertility could result  from dysfunctional CL. The aim of this  presentation   was to investigate common mechanisms of infertility  in CL dysfunction and PCOS.

Luteal phase defect an ovulatory dysfunction is defined as a defect of the corpus   luteum to produce   and secret adequate amounts of progesterone during the luteal phase  of 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 chronic anovulation or oligomenorrhea  clinical or biochemical hyperandrogenism and polycystic  ovarian morphology. The pathogenesis   of PCOS 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  1) short menstrual cycles or without  any significant 2) 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 to secretory resulting in defective implantation of the blastocyst and deficient embryonic development.

LPD in Polycystic ovary syndrome

As previously mentioned PCOS is one of the most  common female endocrine disorders. It is a complex syndrome of unclear etiopathogenesis chararcterized  by heterogeneity in phenotypic manifestations although the pathogenesis of PCOS remains unclear  the syndrome appears to involve  environmental and genetic components  Oligo anovulation  in PCOS in likely to be  the cause of infertility . Nevertheless the role of the CL quality  is not well investigated.

Common factors in LPD  and PCOS

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 directly acts on the ovaries where it  stimulates production and secretion of androgens from the theca cells. Acting   indirectly it inhibits  the synthesis of steroid hormone binding globulin  in the liver leading to elevated free androgen levels. Insulin has also been shown  to alter the synthesisand pulsatile pattern  of LH  and FSH  secretion  and therefore  hinders ovulation

In women with PCOS 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 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 and secrete progesterone in presence of hyperinsulinemia This could result from insulin receptor  down regulation or abnormal insulin mediated  glucose metabolism in PCO granulosa cells due to intracellular pathways defect.

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 primordial follicles  and seems to  inhibit  the recruitment of follicles  from the resting pool to 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. It has been   shown to inhibit in culture the proliferation  and the progesterone production of human  granulosa derived lutein  cells  and also reduced the expression of LH  receptors  as well as 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 investigations are required to support this.