Monday, August 4, 2014

Estrogen produced by endometriotic lesions

We have seen before the importance of the role of estrogen receptor alpha in activating endometriosis lesions (see: Here we look at estrogen being produced by the lesions themselves:

"Conclusion: Endometriotic lesions have higher production of 17 -estradiol than the eutopic endometrium of patients and controls. This is mostly the result of impaired metabolism....

“It has long been viewed that estrogens are delivered to the ectopic (i.e. outside the uterine cavity) lesions in an endocrine fashion through the circulation, however, there are strong indications that the endometriotic lesions may be a source of estrogens itself. The biosynthesis and bioavailability of estrogens depends on the balance between the production of active estrogens and their inactivation. This balance is determined by the activity of a large variety of enzymes involved in the conversion of androgens to estrogens, oxidative metabolism, the conjugation of estrogens and the conversion of conjugated estrogens into non-conjugated steroid hormones. Most of these processes are present in the human endometrium and some of them appear to be aberrantly regulated in the ectopic endometrium of patients.

“Aromatase is responsible for the conversion of androstenedione to estrone and of testosterone to 17_-estradiol. Although some reports indicated that this enzyme is present in normal endometrium with highest expression during the proliferative phase endometrium (4), other studies showed no aromatase expression in the endometrium of healthy women (5–7). Nobel and co-workers (5) were the first to demonstrate that aromatase mRNA and activity levels are increased in pelvic endometriotic implants, and this has been confirmed by others (8 –10)…. The findings in this study demonstrate the capacity of the endometriotic tissues to produce higher levels of 17-estradiol than the eutopic endometrium. Our findings also indicate that this is more likely the result of a reduction in 17-estradiol inactivation, rather than an increase in 17-estradiol synthesis. We were not able to detect aromatase activity in the tissue. Aromatase activity is in general low in the endometrium and endometriotic tissue (11) and our system is not sensitive enough to detect such low levels. Purohit (11) found activities in the range of 0.1 to 1000 fmol/20 h/g wet weight, whereas the detection limit of our system is around 5 pmol estrone/mg protein/ 24 h. Also Kyama and co-workers (32) recently found low expression of the aromatase at the mRNA level in the endometrium. However, they also found high aromatase mRNA expression in the peritoneum. This suggests a possible explanation to those cases in which the use of aromatase inhibitors efficiently treated endometriosis or its symptoms (12, 13) and poses also the question whether the peritoneum itself, rather than the endometrium implanted at ectopic locations may be the major site of androgens into estrogens conversion….

“In conclusion, we have shown convincingly for the first time that the endometriotic lesions are capable of creating a hyperestrogenic environment. This is corroborated by the enhanced expression levels of TFF1 mRNA in the endometriotic tissues, and is a result of increased reduction of estrone into 17_-estradiol and decreased oxidation of 17_-estradiol into estrone, rather than changes in the activities of aromatase or STS.”

(Note for the next study you read below: Aromatase is an enzyme that helps convert testosterone to estrogen, namely estradiol. "Aromatase is located in estrogen-producing cells in the adrenal glands, ovaries, placenta, testicles, adipose (fat) tissue, and brain."

"The mechanism by which endometriosis is able to produce its own estrogen is via the expression of the enzyme aromatase. This enzyme, not expressed in normal endometrium, is stimulated by prostaglandin E2 (PGE2); the resulting estrogen production then stimulates PGE2, further enhancing estrogen." from Modern Management of Endometriosis; edited by Christopher Sutton, G. David Adamson, Kevin D. Jones; CRC Press, Nov 29, 2005

"Aromatase activity is absent in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis, which gives rise to strikingly high levels of aromatase activity in this tissue. Both aromatase expression and activity are stimulated by PGE2. This results in local production of estrogen, which induces PGE2 formation and establishes a positive feedback cycle. Another abnormality in endometriosis, that is, deficient 17β-HSD type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE2 in endometriosis."

(You can see why doctors would then come to the conclusion that prescribing aromatase inhibitors would help. And for some they may. But these drugs have powerful effects on the whole body, some of which can be quite deleterious and permanent. Remember, estrogen has many helpful attributes that helps the function and protection of your bones, brain, heart, and other organs as well as reproductive organs. And it only works as long as one takes the drug. This is why experts today feel that removing the endometriotic lesions in their entirety is the best long term method of treatment. Rather than using a drug that affects your whole system, removing the actual source of the problem is preferred)
I think that above, in addition to saying that endo produces its own estrogen, is saying that there is an impaired metabolism of estrogen at the endo sites. This puts it well I think:

"Furthermore, two forms of estrogen are altered in women with endometriosis, which is significant because estrogen causes endometriosis tissues to grow.  Estrone is a weak form of estrogen, and estradiol is a much more potent form of estrogen.  Estrone is converted to estradiol and vice versa by two enzymes that work with the help of progesterone.   In a normal endometrium, progesterone is able to increase the conversion of estradiol (strong)  to estrone (weak), thereby keeping the growth effects of estrogen on tissues under control.  In endometriosis, the enzyme which converts estradiol to the weaker form estrone is not at all found in the endometrial tissue.  This causes levels of the stronger estradiol to accumulate.   The enzyme which converts weaker estrone to stronger estradiol, however,  is fully functional. This  results in even higher amounts of more powerful forms of estrogen at the level of the endometrial lesions, causing more and more growth of this tissue outside of the uterus."

"For decades, scientists assumed that the ovary alone produced steroid hormones during pregnancy. In a new study in mice, however, researchers demonstrate that once an embryo attaches to the uterine wall, the uterus itself actually synthesizes the estrogen needed to sustain the pregnancy....The findings may also be helpful to the study of endometriosis, said molecular and integrative physiology professor Milan Bagchi, an author on the study. This disorder involves the growth of endometrial tissue, which is normally shed during menstruation, at sites outside the uterus, such as the peritoneal cavity and ovaries, producing painful lesions. Endometriosis is spurred, in part, by unusually high levels of estrogen secreted from endometrial tissue growing at these extrauterine sites, he said. Except during pregnancy, "a normal cycling uterus does not make estrogen," he said. High estrogen levels block the activity of progesterone and can cause the non-cancerous growth of tissue seen in endometriosis."

Also take a look back on progesterone resistance in endometriosis:

The enzyme aromatase catalyzes the conversion of androstenedione and testosterone to estrone and estradiol. The gene that encodes this enzyme is expressed in several human tissues and cells such as ovarian granulosa cells, placental syncytiotrophoblast, adipose tissue and skin fibroblasts, and the brain.

On the other hand, in postmenopausal women, estrogen formation takes place in extraglandular tissues such as the adipose tissue and skin[16-18] (Fig. 1). In contrast to cAMP regulation of aromatase expression in the ovary, this is controlled primarily by cytokines [interleukin (IL)-6, IL-11, tumor necrosis factor alpha (TNFα)] and glucocorticoids via the alternative use of promoter I.4 in adipose tissue and skin fibroblasts.[15] The major substrate for aromatase in adipose tissue and skin is androstenedione of adrenal origin. In postmenopausal women, ~2% of circulating androstenedione is converted to estrone, which is further converted to estradiol in these peripheral tissues. This may give rise to significant serum levels of estradiol capable of causing endometrial hyperplasia or even carcinoma.

Among estrogen-responsive pelvic disorders, aromatase expression was studied in greatest detail in endometriosis.[6,7,22,23] First, extremely high levels of aromatase mRNA were found in extraovarian endometriotic implants and endometriomas. Second, endometriosis-derived stromal cells in culture incubated with a cAMP analog displayed extraordinarily high levels of aromatase activity comparable to that in placental syncytiotrophoblast.[22] These exciting findings led us to test a battery of growth factors, cytokines, and other substances that might induce aromatase activity via a cAMP-dependent pathway in endometriosis. Prostaglandin E2 (PGE2) was found to be the most potent known inducer of aromatase activity in endometriotic stromal cells.... In fact, this PGE2 effect was found to be mediated via the cAMP-inducing EP2 receptor subtype (our unpublished observations). Moreover, estrogen was reported to increase PGE2 formation by stimulating cyclooxygenase type 2 (COX-2) enzyme in endometrial stromal cells in culture.[24] Thus, a positive feedback loop for continuous local production of estrogen and prostaglandins (PGs) is established, favoring the proliferative and inflammatory characteristics of endometriosis (Fig. 2). Additionally, aromatase mRNA was also detected in the eutopic endometrial samples of women with moderate to severe endometriosis (but not in those of disease-free women) albeit in much smaller quantities compared with endometriotic implants.[6] This may be suggestive of a genetic defect in women with endometriosis, which is manifested by this subtle finding in the eutopic endometrium."

^^^^A vicious cycle of estrogen stimulating endo, endo with aromatase capabilities, and prostaglandins being produced in this process and then turning around and causing aromatase activity continues. Thus the endo grows and inflammation flourishes.