The causes of endometriosis appear to start while a baby girl is developing in the womb, and finding the disease in pre-pubescent girls supports this idea. We know that abnormal sex hormone levels, an imbalanced immune system and inflammation combine to drive the disease, with the vast majority of cases found in women of childbearing age.
Endometriosis is a complex, chronic inflammatory disease that profoundly affects the fertility, health and quality of life of 5-15% of women of childbearing age. There have been significant advances in understanding the issues that promote its development in recent years, and the three main drivers of the condition are:
- Abnormal sex hormone levels
- Immune system abnormalities
There’s a close relationship between inflammation, immune balance and hormone balance, and environmental and behavioural factors can influence the chances of developing or controlling endometriosis. The environment and our behaviour can alter how genes are “expressed” and the ratio of hormone receptors in cells. The science behind endometriosis is complex, but understanding how the different strands interconnect when seeking to manage and reverse the condition.
The good news is that it’s possible to change the environmental and behavioural aspects of our lives. Being informed of these factors empowers women to take back control of the disease and their fertility.
Abnormal sex hormone levels
Imbalances of three sex hormones are involved in endometriosis:
- Estrogen (which dominates the first phase of the cycle)
- Progesterone (which controls the second phase of the cycle)
- Testosterone which is crucial to both male and female fertility
Endometriosis is fundamentally a disease dominated by elevated estrogen levels, and we explore the relationship between this hormone and the condition in depth. Testosterone is a crucial sex hormone for male and female sexual development in the womb and, in combination with progesterone, balances the inflammatory, growth-stimulating action of estrogens. The biological availability of both these sex hormones is low in endometriosis, which further enables estrogen dominance.
Inflammation and Altered Immune state
Inflammation is a natural part of an altered immune state environment which is part of the body’s response to endometriosis. The combination of processes develops an environment that’s hostile to conception because:
- Many more white blood cells arrive to fight the problem, and they will “eat” sperm they encounter
- Cytokines are hormone-like chemicals released by white blood cells that affect how cells behave, including how likely they are to attach to each other.
The inflammation and altered immune state central to endometriosis reduce implantation rates in all circumstances:
- IVF cycles are half successful for women with endometriosis
- 35-50% of infertile women have endometriosis
- Women with endometriosis are significantly more likely to experience a miscarriage. i
Mild endometriosis is difficult to detect, but it is inflammatory, and it significantly raises the risk of miscarriage by altering: ii
- Follicle development
Mild endometriosis raises miscarriage risk more than other forms of the disease, possibly because the inflammation and altered immune state are particularly active at this time. The unfortunate but significant issue is that they promote estrogen dominance, further disrupting the immune balance and stimulating inflammation.
Theories for Endometriosis
1. “Retrograde menstruation”
This is the original and generally held theory for endometriosis. Parts of the functional layer of the womb lost in menstruation enter the peritoneal cavity via the Fallopian tubes instead of leaving the body via the vagina. This tissue survives, attaches and then grows outside the womb, and the suggestion is that endometriosis is more likely when bigger endometriotic tissues enter the perineal cavity.
- 76-90% of women experience retrograde menstruation iii
- Nowhere near 75% of women develop endometriosis
- Endometriosis is seen in adolescent girls before the onset of their periods and men iv
- Endometriosis is found outside the pelvic cavity
2. “Tissue Injury and Repair” theory
This is the currently favoured theory in which micro-trauma triggers repair. In this case, it involves excessive levels of estrogen due to excessive, localised aromatase enzymes that promote the growth of endometrial tissue.
3. “Autoimmune Dysfunction” theory
This theory suggests that disruptions to normal immune responses drive endometriosis, and the evidence supporting this includes:
- The early stages of endometriosis have more antibody, white blood cell, and cytokine activity than the later stages of endometriosis. ii
- A low immunity to endometrial antigens (IgG and IgA) correlates to higher rates of endometriosis.
- A specific tumour necrosis factor type of cytokine (TNF-α-MMP9-SRC-1 isoform) is linked to the development of endometriosis. i
4. Embryological theories
There are a couple of embryological development theories that revolve around the shared origin of the cells that form the peritoneum and endometrial cells. The theory is that these peritoneal cells somehow “transform” into endometrial cells or didn’t migrate as normal and form the basis of future endometriosis.
The growth of endometriosis
Whatever the initial cause, the cells that become endometriosis have to:
- Attach themselves to organs and structures in the perineum
- Invade the membrane of those structures
- Proliferate to form a lesion (damaged or abnormal collection of cells)
To accomplish this and grow, the cells in an endometriosis lesion need to:
- Avoid being detected as “abnormal” by the immune system and removed by a process called “apoptosis” (programmed cell death)
- Develop a blood and nerve supply that will nourish the lesion
- Instigate inflammation that promotes cell growth (rather than cell removal)
- Generate abnormally high levels of estradiol (E2), a potent estrogen that promotes growth and inflammation
- Reduce the availability of other sex hormones (progesterone and testosterone) that inhibit the effects of estrogen
i Pietro Santulli, et al., Increased rate of spontaneous miscarriages in endometriosis-affected women, Human Reproduction, Volume 31, Issue 5, May 2016, Pages 1014–1023, https://doi.org/10.1093/humrep/dew035
ii Alexandra S Kohl Schwartz, et al., Endometriosis, especially mild disease: a risk factor for miscarriages, Fertility and Sterility, Volume 108, Issue 5, 2017, Pages 806-814.e2,
iii D. T. Y. Liu and A. Hitchcock, “Endometriosis: its association with retrograde menstruation, dysmenorrhoea and tubal pathology,” British Journal of Obstetrics and Gynaecology, vol. 93, no. 8, pp. 859–862, 1986
iv Marsh EE, Laufer MR. Endometriosis in premenarcheal girls who do not have an associated obstructive anomaly. Fertil Steril. 2005;83:758–60.
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