Endometriosis and infertility IL17 production leads to failed implantation and miscarriage Surgery, immune therapy and dietary supplements can help minimize IL-17 production

Posted By Braverman IVF & Reproductive Immunology || 24-Feb-2016

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T-lymphocyte response to fetal antigens is a key component of the maternal immunological tolerance towards the semi-allogenic fetus during pregnancy.

Dysregulated responses of the maternal immune system to the conceptus have been involved in immunological rejection resulting in infertility and recurrent pregnancy loss (RPL).
The role of cells producing IL-17 in pregnancy related complications is now emerging.

Interleukin-17 (IL-17) is a group of inflammatory cytokines that are involved in your protection against fungal and bacterial infections (1). When produced in excess, it induces chronic inflammation associated with many inflammatory and autoimmune diseases including psoriasis, rheumatoid arthritis (RA), multiple sclerosis (MS) or Crohn’s disease (CD).

IL-17A is the most abundant member of the IL-17 family and is mostly produced by a subset of CD4+Tcells, namely Th17 cells, contributing to the inflammatory response.

Th17 cell differentiation is linked to the differentiation of Treg cells (an important cell with unique property of generating tolerance in the maternal immune system for the embryo/fetus) where there is a conversion from Treg cells to Th17 cells during the inflammation process (2) and a shift away therefore from tolerance for the embryo/fetus.

IL-17 is also produced by a subset of CD8+ cells, known as Tc17 cells. Natural killer (NK) and natural killer T cells (NKT) have also been described as source of IL-17 production (3).

  1. Pleiotropic effects of IL-17A on women fertility

a-Oocyte quality

During the oocyte (egg) maturation, the follicular fluid composition is critical to support the egg development. It directly reflects the potential for a follicle to mature and give rise to a fertilizable egg.
Inflammation and oxidative stress impact the follicular microenvironment that might result in poor oocyte quality thus disrupting a woman’s reproductive potential.
A recent study, screening follicular fluid and blood serum of infertile patients showed that the level of IL-17A was higher in the follicular fluid and in the serum of endometriosis and polycystic ovary syndrome (PCOS) women than the control group (4). In addition, a strong correlation was found between the IL-17A levels and the number of meiosis I (MI) oocytes which are immature eggs, not suitable for fertilization. By inducing oxidative stress, IL-17A could have deleterious effects on oocyte quality (5-6).

With inflammation potentially inducing oocyte mitochondrial dysfunction and often associated with higher rate of aneuploid embryos (for more information, read our blog ("Correctible Reoccurring Aneuploid Conversion Syndrome (CRACS) 79% had a successful pregnancy with BRI A Review of 155 cases​”), IL-17A could play an important role in damaging egg quality and could be a key player in the Correctible Recurrent Aneuploid Conversion Syndrome (CRACS).

b- Miscarriages

The suggestion that Th17 cells may have a detrimental role in pregnancy maintenance comes from the transplant field where acute kidney rejection was characterized by elevated levels of IL-17 (7). Several studies showed increased number in Th17 cells in the peripheral blood in RPL patients which is inversely proportional to Treg cells levels (8-10). Interestingly, IL-23 concentration, a cytokine that induces the production of Th-17 cells, was found to be highly expressed in RPL patients when compared to normal pregnancies (8). In the same way, IL-6 and IL-1b, two cytokines playing a role in Th17 cell differentiation, were reported to be higher in RPL patients when compared to healthy controls (11).

Altogether, these data strongly suggest that IL-17 could be a major contributor in rejecting conceptus antigens and therefore may be harmful to the maintenance of pregnancy.

c- Pregnancy complications

  • Pre-eclampsia (PE):

Pre-eclampsia is affecting up to 7% of pregnancies in the United States. Characterized by hypertension and proteinuria during pregnancy, PE is associated with an immune imbalance where pro-inflammatory CD4+T cells are increased while Treg cells expression is repressed. This disorder is characterized by inflammation with an increased secretion of pro-inflammatory cytokines and oxidative stress that injures the placenta leading to placental ischemia during pregnancy.

In the peripheral blood, Th17 cells have been found in higher number in PE when compared to healthy pregnancies (12). Higher than normal levels of circulating Th17 were observed in pre-eclamptic women compared to women with normal pregnancy (13).

In the latter study, they also showed a correlation between Th17 cells and IL-2- and IFN-g-producing T-cells, suggesting a strong Th17 and Th1 involvement in PE development during pregnancy.

Most importantly, in a rat model, blocking IL-17 actions through its soluble receptor (IL-17Rc) could reverse PE symptoms by lowering Th17 production, oxidative stress, autoantibodies secretion and hypertension (13). In a same way, increased levels of Treg cells could have similar effects on reversing the symptoms in a rat model of pre-eclampsia (14).

  • Pre-term Labor:

Preterm births are a leading cause of neonatal mortality and morbidity worldwide. Preterm labor has been strongly linked to inflammation. Pro-inflammatory cytokine production can trigger uterine activation thus leading to preterm labor.

Being a key cytokine involved in the inflammation process, IL-17 was suggested to play a role in preterm labor.

Th17 cell were found to be increased in the chorioamniotic membrane of preterm delivery cases with chorioamnionitis (CAM). Additionally, in amniotic fluid, IL-17 levels were significantly higher in severe CAM (stage III) preterm delivery cases than those in CAM-negative preterm delivery cases or in normal delivery cases. A correlation was also found between IL-17 and IL-8 levels in amniotic fluids of these patients (15) with IL-17 indirectly inducing IL-8 secretion thus leading to inflammation at the feto-maternal interface.

These data strongly support a role of IL-17 in chorioamnionitis causing preterm deliveries.

  1. IL-17 and its role on fertility associated disorders

a- Polycystic ovarian syndrome (PCOS)

PCOS is a common and complex disease affecting women of reproductive age, characterized by hyperandrogenism and chronic anovulation in addition to systemic inflammation.

A study including women with PCOS showed that IL-17A was higher in PCOS women when compared to healthy controls (16). These results were confirmed in another study where IL-17 levels were found to be significantly higher in serum and follicular fluid of PCOS female (4).

b- Endometriosis

Endometriosis is a benign, chronic, inflammatory gynecologic disorder that affects 5–10% of women of reproductive age worldwide and is characterized by the presence of endometrial cells growing outside the endometrium. This disorder could affect fertility in patients at multiple levels:

  • anatomic distortion
  • diminished ovarian reserve
  • alteration of oocyte quality
  • peritoneal inflammation that can disrupt the endometrial receptivity

Many studies strongly suggested that compromised peritoneal fluid with high levels of inflammatory factors and ROS could directly impact oocyte quality by altering mitochondrial function and disrupting the meiosis process but these same changes could also lead to a disruption of the implantation process thus leading to miscarriages (17-19).
Among the pro-inflammatory cytokines, IL-17 seems to have a place of choice, being involved in the pathogenesis of endometriosis.
IL-17 concentration in the peritoneal fluid of women with endometriosis correlated with endometriosis disease severity and infertility of the patients (20).
In a recent study, endometriotic lesions were shown to secrete various amounts of IL-17A, depending on the disease severity, which reflected at a systemic level where women with endometriosis had significantly higher IL-17 levels than healthy controls. Most importantly, serum concentrations of IL-17A drop significantly in patients with endometriosis after surgical removal of endometriotic lesions as soon as two weeks post-surgery (21). Lowering of these levels very likely plays a role in pregnancy success after corrective surgery.

  1. Solutions to minimize IL-17 production

a- Surgery to limit IL-17 production and reduce inflammation

Endometriosis creates a noxious environment in the whole peritoneal cavity with pro-inflammatory cytokines being increased in the serum.

Endometriotic lesions resections by laparoscopy induce a dramatic decrease in IL-17 serum levels as soon as two weeks post-surgery (21).

The benefits of laparoscopy in endometriosis-related infertility cases have been shown in moderate (22) and stage III endometriosis subjects (23) where higher pregnancy rate have been reported post-surgery.

b- Immune therapy to counteract IL-17 production

  • Prednisone:

It is a glucocorticoid that reduces inflammation and suppresses the activity of several types of immune cells including T cells. By binding to its receptor, this glucocorticoid inhibits the action of a transcription factor, namely NFKB, which prevents the production of pro-inflammatory factors such as IL-1b, IL-6 or TNF-α therefore inhibiting IL-17 production (24).

  • IVIG:

IVIG may reduce Th17 differentiation (25) and increase Foxp3 expression therefore promoting Treg cell expression (26-27), while limiting IL17 production.

c- Dietary supplement

  • Probiotics:

Probiotics are live micro-organisms (bacteria and yeast) that can have beneficial effects on your health. There is a wide range of probiotics with diverse effects on the immune system promoting immune tolerance or inducing inflammation.
A particular strain “Lactobacillus gasseri” was shown to suppress IL-17 production in a mice model (28). Another strain, “Lactobacillus Reuteri” seems to have similar effect as seen in a recent study showing that L Reuteri could lower pro-inflammatory cytokines including IL-6, TNF-α and IL-17 in patients with chronic periodontitis (29).
Another strain, namely L. gasseri OLL2809 directly suppressed development of endometriosis via activation of NK cells and reduction of inflammation (30).

  • Endo-Optimizer: our supplement, which are all the supplements we have ordered for years now on in one pill

Endometriosis is characterized by inflammation with dramatic effects on oocyte/ embryo quality and immune changes in the uterine environment that in many cases also leads to implantation failure. Many of these issues are a direct result of IL17 levels. The ingredients we have put in Endo Optimize have been shown to lower these IL17 levels and is one of the likely mechanisms that lead to improvement in endometriosis pregnancy outcomes that we have seen in our patients. (for more information click here).

An accumulation of recent studies pinpoints IL-17 production as a key factor involved in gynecological pathologies, infertility and pregnancy complications. Our work and efforts currently focus on better understanding how IL-17 secretion and IL-17 producing cells expression could impact fertility at these multiple levels.

By detecting any disruption in IL-17 levels and being able to prevent or counteract IL-17 increases through surgery, immune therapies and dietary supplement, we believe we can significantly increase the chances of our patients achieving a successful pregnancy.
Patients with pregnancy issues related to their endometriosis need this meticulous diagnostic and treatment program. Immune therapies to lower IL17 must be correct in choice of medication, dosage and frequency and therefore MUST be prescribed based on detailed immune analysis carried out ONLY by those with thorough understanding of immunology.


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