Firing gasoline: Estrogen, macrophages and peritoneal inflammation: the triad to counteract to fight endometriosis

Posted By Braverman IVF & Reproductive Immunology | 10-January-2019

1- Endometriosis, Macrophages and Estrogen

Endometriosis is considered as an inflammatory disease, which suggests a role for the immune system (1, 2). It is thought that a defective immune response makes ectopic implantation possible, because the immune system fails to clear the implants from the peritoneal surface (3).

a-Macrophages and endometriosis

Macrophages represent one of the major leukocyte subsets in the endometrium. They act as primary mediators of tissue remodeling and are involved in the maternal immunotolerance.

  • Increase macrophages number in patients with endometriosis Macrophage number is significantly increased in the peritoneal fluid of women with endometriosis (4), further their number is also increased in the eutopic endometrium (5). Macrophages are essential actors in ENDO development, their depletion in the peritoneal cavity inhibits the initiation and growth of ENDO lesions in mice (6, 7). Ectopic endometrial lesions themselves are enriched with macrophage.
    • Macrophages promote inflammation Peritoneal macrophages from women with endometriosis are highly activated by the master regulator of inflammation Nuclear Factor-B (8) and produce high levels of pro-inflammatory cytokines such as:
  • PGE2 and PGF2α: promoting the survival and growth of endometriosis lesions (9)
  • IL-1 that stimulates fibrinogen formation which causes the adhesions (10).
  • IL-1 activates B cells that produce autoantibodies.
  • IL-1 induces IL-6 and IL-8 production (potent angiogenic, pro inflammatory cytokines).
  • TNF alpha facilitates implants adhesion (11).

    Further, peritoneal macrophages induce oxidative stress as seen by increased activity of nitric oxide synthase (NOS) in patients with endometriosis (12), which dramatically damage oocyte quality (13, 14)

    • Macrophages promote angiogenesis and lesions adhesion Macrophages promote angiogenesis by inducing the factor VEGF developing the growth of blood vessels in the endometriotic lesions (15). 
Blocking VEGF pathway reduced lesion formation in mouse model studies (16).

    • Macrophages phagocytic activity is reduced in patients with endometriosis In vitro, the production of indoleamine 2, 3-dioxygenase-1 (IDO-1) by the ectopic endometriotic tissue induces IL-33 production that in return inhibits macrophages phagocytic abilities.

    • Macrophages directly promotes endometriosis Cocultures of macrophages with endometriotic cells were shown to promote the disease by increasing endometriotic cell proliferation (17, 18)

    b- Estrogen and Endometriosis

    • Estrogen and immunomodulatory activities Patients with endometriosis have higher estradiol levels (19) driving the growth of extrauterine endometriotic implants (20).

    This is due to a dysregulation of the aromatase P450 enzyme whose expression is upregulated in patients with endometriosis leading to higher levels of estradiol secreted by the lesions (21).

    Estradiol has proinflammatory and antiapoptotic effects on endometrial cells, even more when ectopically located (22).
    Many studies show that estradiol and its receptors ER regulate inflammatory pathways of innate immune cells, including macrophages (23). Estradiol induces macrophage proliferation by two mechanisms:

  • direct effects through ERα receptors localized on macrophages (24)
  • Indirectly through the production of growth factors by other cells types (25).

    ERα promotes the production of proinflammatory cytokines (such as TNFα) in response to macrophages stimulation (26).

    Retrograde menstruation is a possible cause of endometriosis. This largely accepted theory could be one of the causes of macrophages recruitment in the peritoneal cavity. Menstrual fluids contained debris and blood products with some abnormal stem cells that have an increased implantation and angiogenic capabilities (27).

    The accumulation of aging red blood cells causes an iron overload propitious to macrophage activity as macrophages are involved in recycling the metal (28). Further, estrogen increases cellular iron uptake (29) which amplifies the process.

    The estrogen–macrophage interplay plays a key role in endometriosis development.

    • Estrogen and progesterone resistance Progesterone is a hormone playing a crucial role in decreasing inflammation in the endometrium (30). During the second half of a menstrual cycle, progesterone prevents the estrogen-driven endometrial proliferation, inducing differentiation of the endometrium (decidualization), and recruiting specific immune cells to support the implantation of an embryo. In endometriosis, estrogens are locally overproduced (by the endometriotic lesions), increasing inflammation and leading to a decrease in progesterone receptor expression (through a complex mechanism involving methylation process) thus inhibiting the action of progesterone, a phenomenon known as progesterone resistance (31). This altered progesterone signaling further exacerbate the proinflammatory environment.

    2- How can we help patients with endometriosis in their fertility journey?
    At Braverman Reproductive Immunology, we have put in place a program targeting the triad responsible for endometriosis progression. With the right care, we may improve your chance for a successful and healthy pregnancy.

    a- Reduce peritoneal inflammation by excising endometriotic lesions (ELE) and laser destruction of the peritoneum (PD) by surgery: ELE+PD

    Endometriosis is clearly associated with inflammation as seen by high levels of pro-inflammatory cytokines such as IL-1α, TNFα, IFN-γ in ENDO patients as compared to endometriosis-free individuals.

    The removal of lesions modifies the inflammatory profile inducing a shift toward a less inflammatory environment (32).

    Peritoneal destruction induces a more tolerogenic uterine environment when combined with endometrial lesion excision resulting in a higher successful pregnancy rate in our patients treated with immune therapies. It is now our recommendation that those patients with immunologic and clinical evidence for endometriosis, even if MINIMAL or NO LESIONS are identified, undergo ELE+ PD.

    To learn more on the topic, read our blog.

    b- Immune therapies

    All our patients have to undergo a battery of tests including a complete immune testing to determine the possible causes of infertility and determine which immune therapies they might benefit from. In addition, we do monitor these parameters through the pregnancy, to detect any alterations that could potentially trigger pregnancy complications. This allows us to adjust our treatment in a timely manner and give you the best chance of having a healthy baby.

    c- Dietary supplement with ENDO-Optimize

    The Endo-Optimize supplement is the result of our work and has been developed to be the best solution to counteract oxidative stress induced-DNA damage. It optimizes your egg quality as well as minimizing your symptoms associated with endometriosis. This all in one pill contains many ingredients enhancing mitochondrial activity (a key component in oocyte development), reducing inflammation and oxidative stress thus allowing optimal microenvironment for the oocyte development and maturation.

    For more information, read our blogand learn how every ingredient included in our formulation can positively impact your egg quality. 

    d- Adequate cycle protocol with letrozole and progesterone to overcome the progesterone resistance: better endometrial lining and receptivity • Letrozole
    Elevated levels of estradiol and prostaglandins as well as progesterone resistance may reduce endometrial receptivity in endometriosis patients (33), thus disrupting implantation and contributing to patients’ infertility (34).

    To induce ovulation in endometriosis patient, we are using letrozole, a drug that suppresses estrogen production which in return increases the hormone FSH (follicle stimulating hormone) that will induce follicle growth and egg maturation.

    Unlike clomid (another ovulation induction drug), using letrozole does not alter the endometrial lining and even further improve endometrial receptivity through its effects on integrin protein (35, 36) whose levels have been shown to be reduced in failed IVF (37).

    Indeed, in ovulatory infertile patients, letrozole was shown to induce higher midluteal progesterone levels, leading to normal endometrial development and increase endometrial receptivity (38).

    Interestingly, in women undergoing IVF, clinical pregnancy and delivery rates were significantly higher in women with normal integrin expression (40% and 38% respectively) compared with integrin-negative women (13.7% and 7% respectively). Most importantly, the same study (39) showed that in integrin-negative women treated with letrozole, clinical pregnancy rate (60%) and delivery rate (50%) were significantly higher as compared to untreated, integrin-negative women (14% and 7% respectively).

    • Progestin Progesterone induces secretory changes in endometrial lining that are essential for implantation and maintenance of normal pregnancy (40).
    Indeed, a study showed that the use of progesterone supplementation during the luteal phase improved endometrial receptivity in women undergoing IVF cycle and led to increased rate of clinical pregnancies that was 2 times higher compared to the non-treated group (41). We have seen previously that progesterone resistance, one of the main characteristics of endometriosis, may be caused by inflammation and may “fuel” the proinflammatory condition. During a cycle, we are supplementing our patients suffering from endometriosis with progestin. Progestins (synthetic progesterone) may overcome progesterone resistance by increasing progesterone receptor expression and decreasing proinflammatory cytokines.

    Questions? Call 516.584.8710
    We would be happy to help you take control of your fertility journey and answer any questions you may have.


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