Saturday, December 27, 2014

What You Don't Know About Estrogen

"What You Don't Know About Estrogen

LE Magazine October 2004
What You Don't Know About Estrogen
There are many misconceptions about what estrogen really is and how it works in the body. This widespread confusion exists in the minds of the lay public as well as the medical community. The result is poor choices being made about what women should be doing to maintain youthful hormone balance while also protecting against cancer.
This article uncovers the basic facts about estrogen that are so often overlooked by doctors today. It then reveals dietary modifications that women should consider if they are taking an estrogen drug. The science underlying this article is extremely complex. In order to make this information comprehensible to the lay reader, we have made a special effort to translate these new findings about estrogen metabolism into a version that most people will understand.
Nevertheless, some people may have difficulty understanding a few technical areas of this article. This information is so critically important, however, that we urge you to re-read paragraphs you do not understand in order to gain a full grasp of these crucial anticancer concepts.
The word estrogen strikes fear into the hearts of many. Women equate it with breast cancer, scientists equate it with “endocrine disruptors,” and doctors equate it with hormone replacement. Are these perceptions accurate?
Estrogen is many things. It includes the body’s natural estrogenic hormones and things that look like the body’s natural hormones. As long as something behaves like an estrogen in the body, it is an estrogen, or is, quite simply, “estrogenic.” The strongest natural estrogen in the human body is estradiol. Premarin® is an example of an unnatural estrogen—unnatural, at least, to the human body. It is made from estrogens excreted in the urine of pregnant horses. Chemical estrogens that behave badly once they are inside the body are known as “endocrine disruptors” for their adverse effects on development. All of these estrogens interact with the body’s innate hormonal system. They do not, however, provoke the same responses.
Photomicrograph of estradiol crystals. Estradiol, the most potent of the natural estrogens, is used in its natural or semisynthetic form to treat menopausal symptoms.
What Makes Estrogen Tick
“Estrogen receptors” are rarely talked about unless a woman is diagnosed with breast cancer (or a man with prostate cancer), but they are critical to how an estrogen behaves. For example, tamoxifen is a “known human carcinogen” due to its estrogenic effects, yet it is marketed as an “estrogen blocker” because of its estrogen-blocking effects. It has beneficial effects on bone, but negative effects on the circulatory system.1,2 It blocks estrogen-driven breast cancer growth temporarily, yet later becomes estrogenic in the same tissue, promoting new breast cancer. How can one “estrogen” do all these things?
The answer is, partly, estrogen receptors, which are proteins in the body that react to estrogen. Estrogen is like fuel, and estrogen receptors are like machines. When fuel meets machine, things happen.
Unfortunately, what happens depends on which area of the body is in question. The receptors of different parts of the body are different. In other words, although all the machinery runs on some type of estrogen, not all the machinery does the same thing. Estrogen does different things in different parts of the body. It does one thing in the brain and another in the breast. It might surprise you to learn, for example, that the pituitary gland is second after the uterus as the most estrogen-responsive area of the body.3 So it is not accurate to think of estrogen as the thing that makes breast cancer cells grow.
Just a few years ago, researchers believed that there were two types of estrogen receptors: alpha and beta. That made things fairly simple. Estrogen hits receptor alpha and Y happens. Research focused mostly on the strong estrogen—estradiol—and it seemed that progress could be made in understanding how estrogen affects at least breast tissue, though strange things continued to happen, such as the estrogen “blocker” tamoxifen causing the growth of tamoxifen-dependent cancers. With the discovery of a much larger picture, those days are over and a lot of research is now out the window. As a researcher at Columbia recently lamented, “where will it end?”4 There is more to it than anyone ever imagined.
The Plot Thickens
It has now been discovered that there is an entire new class of estrogen receptors called estrogen-receptor-related receptors. These receptors do not respond to the body’s natural estrogen.5,6 They are instead activated by xenoestrogens (estrogens from the outside, or from the environment).7 Pesticides and tamoxifen are two examples of xenoestrogens that activate estrogen-receptor-related receptors.8,9 The extraordinary thing about these receptors is that they represent a whole new class of estrogen machinery, previously unknown. Not only can these receptors do everything the estrogen receptors that respond to “natural” estrogen can do, but they also have a major impact on how an estrogen—any kind of estrogen—behaves.6 The discovery of this new class receptors will enable researchers to understand, for the first time, how environmental estrogens (“endocrine disruptors”) interfere with the body’s normal metabolism, and to better define the use of natural estrogen.
Estradiol Stops Cancer Cell Growth
How can this “strong” hormone—estradiol—stop hormonally responsive cancer cells from multiplying? The answer to that question first appeared in the Journal of the National Cancer Institute,10 and has been known since at least 1977.11 The cancer cells that estradiol stopped from growing had been treated with tamoxifen. Tamoxifen works two to five years after breast cancer treatment to block estrogen and prevent cancer recurrence, and then usually does the opposite.12-14 When it starts doing the opposite of what it is supposed to do, so does estradiol. How can this puzzle be solved?
In 2001, researchers reported for the first time that tamoxifen breakdown products interact with one of the newly discovered estrogen-receptor-related receptors, and keeps it from activating certain genes normally activated by estrogen.8,15 This opened a whole new vista for understanding how tamoxifen and other synthetic estrogens work. Important clues have already been found.
Estrogen Cofactors Discovered
In addition to interacting with estrogen-receptor-related receptors, tamoxifen and other xeno-estrogens interact with yet another new discovery.
In the laboratory, researchers can get estrogen, by itself, to activate estrogen receptors. In other words, in a laboratory setting, any estrogen fuel will activate the estrogen machinery and set things in motion. In real life, this does not happen. In real life, estrogen is only one of many factors that coordinate as a group to activate estrogen receptors.
The body makes proteins known as “coactivators” and “corepressors.” These proteins attach themselves to estrogen and other hormones such as thyroid, creating big, complex “globs.” It is these globs—not estrogen alone—that activate or suppress what was previously attributed to estrogen alone. In other words, studies showing what an estrogen does in the laboratory may have little to do with what actually occurs in the human body; in real life, other proteins run the show. This is bold new territory for hormone research.
Here is an example of just how important these coactivator and corepressor proteins are in determining how estrogen behaves. Corepressor SSN6 blocks estrogen’s effects in cells. In other words, the SSN6 protein shuts the machinery down. The estrogen fuel can be available (estrogen could be floating all around), but the machinery will not start as long as corepressor SSN6 is working. It neutralizes the effects of estrogen. If something interferes with this protein, however, instead of dampening the effects of estrogen, it enhances them. In addition, estrogen blockers turn into estrogen enhancers.16 Sound familiar? The importance of coactivators and corepressors cannot be overstated. They interact with both estrogen receptors and the newly discovered estrogen-receptor-related receptors. As you will soon read, there may be natural ways for women to regulate these “coactivators” in a manner that reduces breast cancer risk.
Estrogen Imposters
The three principal types of estrogen manufactured by the human body are estradiol (17 beta-estradiol), estriol, and estrone. Estradiol is the most feared because it is the strongest and is associated with the growth of cancer cells. Estrone is a metabolite of estradiol, and is less potent. Estriol is another metabolite, but is considered so mild mannered that it is recommended as a safe hormone replacement.17-19 In addition, the human body contains 11 other estradiol metabolites that hardly anyone ever mentions.
Premarin® and Prempro™ are drugs made of 17 beta-estradiol and more than a dozen estrogen metabolites from horses.20 These manmade drugs should not be confused with any estrogen manufactured by the human body, with other estrogen drugs, or with estrogen in general. The data from studies of women taking these drugs cannot, and should not, be extrapolated to other hormone replacement drugs or therapy. This is an important point: Premarin® is not estrogen, but instead is an estrogen—one of many estrogens. Different estrogens produce different effects. The manufacturer of Premarin® and Prempro™ has argued that its horse estrogens have unique effects in humans, and undoubtedly they do.
Dozens of studies demonstrate important differences between the effects of Premarin® on the human body and the effects of other estrogen products. Transdermal estradiol, for example, may decrease triglycerides and LDL oxidation, whereas Premarin® may do the opposite.21 Premarin® may increase C-reactive protein (a negative for the heart) while transdermal estradiol may not.22 Changing from Premarin® to transdermal estradiol may reduce triglycerides significantly.23 Estrogen patches may reduce blood pressure, whereas oral estrogen may not.24 These and dozens of other studies show different effects depending on which estrogen drug is being evaluated. Not only are there differences between Premarin®/Prempro™ and other drugs, but there are differences between other drugs as well.
Neutralizing Estrogen: The Asian Advantage
Japanese women have been reported to have higher levels of estradiol in their blood than Americans, yet they have a much lower risk of breast cancer.25,26 Why? Researchers believe it has more to do with environmental factors than genetics. When Japanese and other Asians adopt a Western lifestyle, risk increases.27,28 The Asian diet may contain things that modulate the response to estrogen, and strong evidence indicates that how the body handles estrogen is far more important than how much estrogen it handles. Research indicates significant differences between Japanese and Western women in their number of estrogen receptors and in their response to xenoestrogens.29-31 These differences suggest the involvement of the newly discovered estrogen coregulators. Dietary factors can activate or deactivate these factors, which means that every woman can regulate her own estrogen, to a certain extent.
Researchers have extensively investigated three aspects of the Asian advantage: soy, vegetables, and green tea. Each is associated with a dramatically lower risk of breast cancer.
Drinking 36 ounces of soy milk a day can reduce levels of estradiol by 20-27% within weeks.32,33 Soy contains isoflavones that neutralize “strong” estrogens, converting them to estrogen metabolites that protect against breast cancer.34 When mice implanted with human breast tumors were given soy concentrate and green tea, tumor size was reduced by 72%.35 Estrogen receptor alpha was also reduced, an indication that the combination of soy and green tea was working at the genetic level, probably with estrogen cofactors. Forty milligrams of isoflavones a day significantly decreased “strong” estrogen levels in women, according to a study from the H. Lee Moffitt Cancer Center in Tampa, FL.36 These are only a few of the many studies demonstrating the beneficial effects of soy.
In another experiment that shows the hormonal benefits of soy on the effects of chemical estrogens, when female monkeys were given birth control pills, their cortisol shot up, and their DHEA and testosterone plummeted. When they were given Premarin®, the same thing happened. When the monkeys were given soy protein with isoflavones, however, their hormones normalized.37
Several years ago, there was concern about genistein, an isoflavone in soy, when research showed that it activated estrogen-related genes. Some people took this to mean they should avoid consuming soy, which would be unfortunate given the overwhelmingly positive data about soy’s benefits to humans. Genistein has been called the “good estrogen” for its beneficial effects against estrogen-responsive breast cancer.38 It subsequently emerged that most of the negative research on genistein was generated by one researcher, under conditions that would not exist in real life (such as extremely high levels of genistein put into cancer cells that were deprived of all other estrogen).

The human body manufactures estrogen as a necessary component in many processes; estrogen is always in the body, even in postmenopausal women. Copper, too, is always in the body and is another example of something that can distort the way genistein behaves in a test tube.39 Researchers at the University of California, Davis, recently did the same test tube study on genistein and produced the same negative results. They then put genistein in a test tube with the cancer cells and environmental estrogens. The result showed that genistein suppressed cancer cell growth.40 These studies on pure genistein, however, do not accurately reflect what occurs in a complex environment such as the human body.
Fortunately, the safety of soy isoflavones (including genistein) for human consumption has been confirmed by experiments with monkeys, the experimental model closest to humans.41 Monkeys treated for three years with soy or soy minus its isoflavones exhibited no abnormal cell growth; in fact, the result was just the opposite. The researchers concluded, “These findings suggest that high dietary levels of soy isoflavones do not stimulate breast or uterine proliferation in postmenopausal monkeys and may contribute to an estrogen profile associated with reduced breast cancer risk.” In addition, a new study clarifying the estrogenic effects of genistein on the uterus found that genistein may enhance cell growth for a few days, but then the effect stops. This is a new finding, and the results are different from those for estrogen drugs that perpetuate growth indefinitely.42 With any luck, issues surrounding how genistein behaves will be soon resolved.
It is important to remember that genistein also blocks the growth of estrogen-receptor-negative breast cancer cells. By incorporating soy and isoflavones in her diet, a woman can potentially stop breast cancer before it develops.43 The one caveat is that genistein may interfere with tamoxifen, and thus should not be taken by itself with that drug.44
One of the most exciting new findings is that genistein keeps amyloid from killing brain cells (without any negative effects on uterine cells), and has been suggested as an alternative to synthetic estrogens for the prevention ofAlzheimer’s disease.45 Studies of the popular estrogen drugs Premarin® and Prempro™ show that they may actually increase the risk of dementia.46
Everybody knows that vegetables are good for you, and they are especially good for women who want to avoid breast cancer. Vegetables enable the body to rid itself of excess estrogens. Meat eaters have about 50% more estradiol and estrone in their blood than do vegetarians.47 Women who eat the most vegetables, beans such as lentils, and fiber reduce their risk of breast cancer risk by 50%.48 As you will read next, compounds found in vegetables favorably affect the way estrogen behaves in the body.
Other Ways To Tame Estrogen
The way estrogen is metabolized is critical to how it behaves. Fortunately, we can do more than cross our fingers and hope for the best. Certain compounds found in plants turn harmful estrogen into a more beneficial version. Chief among them is indole-3-carbinol (I3C), a phytochemical found in cruciferous vegetables such as broccoli. In China, where the risk of breast and prostate cancers is minuscule, consumption of cruciferous vegetables is more than three times that of the US.49
I3C helps convert “strong” estrogens into benign or even helpful estrogens such as 2-hydroxyestrone.50,51 It also acts very much like tamoxifen in blocking undesirable estrogenic effects in breast cancer cells, and its antiestrogen effects are enhanced with genistein.52
When digested, I3C is converted to other substances, including diindolylmethane (DIM). Some earlier research suggested that I3C’s beneficial effects were due to DIM. New research shows this is not the case, and that there are important differences in the effects of I3C and DIM on the metabolism of estrogen. Researchers recently stated, “This finding [of I3C’s effects] is inconsistent with the claim that DIM is the biologically active metabolite of I3C with regard to its antiestrogenicity.” DIM does not increase beneficial 2-hydroxylation of estrogen (at least in rats), but it does lower harmful 4- and 6-hydroxylations.53 By contrast, I3C, which partially converts to DIM during digestion, affects all three in a positive way. Moreover, DIM does not have the anti-estrogen effects of I3C.54
Another potential supplement for breast cancer prevention that has drawn a lot of interest is melatonin. Melatonin is associated with sleep because it builds up during the night, but it may ultimately end up being more associated with estrogen than with sleep. Studies show that melatonin plays a major role in how estrogen behaves. In estrogen-receptor-positive breast cancer cells, melatonin can bring cell growth to a halt.55 Research indicates that melatonin controls estrogen, and vice versa.55-57 In studies of rodents, melatonin shows great promise with regard to its ability to prevent breast cancer when given continuously, before and after exposure to a carcinogen, and when given to mice with the HER2/neu genetic alteration.58,59 Researchers have been unsuccessful in correlating blood levels of melatonin with breast cancer.60 This reflects melatonin’s complexity as a hormone that, like estrogen, comes in various forms and has several receptors. Without a doubt, melatonin plays a major role in breast cancer through its effects on estrogen and other cancer-related phenomena.
As an antioxidant, melatonin is not only powerful but also unique. Unlike vitamin E, which essentially has no further effects after it scavenges a radical, when melatonin gets a radical, it creates a new melatonin antioxidant; that is, it self-perpetuates. It also cooperates with other antioxidants like vitamins C and E.61 Antioxidants are very important in preventing cancer, and it has been reported that free radicals can activate or deactivate genes that are involved in breast cancer.62
In addition, melatonin may suppress cortisol, which is a stress-related hormone.63,64 It is interesting to note that the overwhelming majority of breast cancer patients say stress caused their disease.65 In a study of older women, 2 mg of melatonin per day reduced estradiol levels, enhanced sleep, and improved levels of DHEA.66 Melatonin is very potent, and as little as 0.3 mg per day may be enough to produce beneficial effects.
Breast cancer is a serious concern for most women. Understanding that there are different types of estrogen, that different estrogens have different effects, and that women can, to a certain degree, control their own estrogen (through dietary modification and supplement use) will help women make informed choices about estrogen exposure and reduce their risk of breast cancer. Recent discoveries about estrogen receptors and how they interact may finally unlock the mysteries of how estrogens work, and provide the basis for nontoxic treatment and effective prevention."

for more information see

Location of endo and pain felt

I am trying to decipher old notes about the location of endo or associated affected sites (i.e. muscles like the obturator and piriformis) and where the pain can be felt. Please correct and add! (And don't get me started on if it's the lesion itself or its effect on nerve growth, angiogenesis, prostaglandins, cytokines, etc etc!!)
So far I have:    
Obturator internus- hip pain

Levator ani- rectal pain

Uterosacral ligaments- low back and SI joint (hard to differentiate from US endo vs adeno), down legs, painful sex

Round ligament- groin or lateral lower quadrant

Side wall of pelvis- pain or cramps radiating down the leg

Posterior cul de sac- low back, pain with/after sex, GI symptoms, pain with defecation (esp. during menstruation),  sits on the piriformis muscle and can cause spasms and sciatic type pain

Recto-vaginal septum- low back

Bladder- functional urinary tract symptoms

Hip issues and pelvic obliquities (like pelvis torsion where the hips are not level) can cause piriformis spasm

"The most common physical finding is discomfort during the pelvic examination, particularly with stretching of the uterosacral ligaments and palpation of the posterior cul-de-sac. There may be some induration or nodularity of the uterosacral ligaments and in severe cases there may be a very firm palpable mass in the posterior vaginal fornix."

“What is most interesting is that right-left orientation of the pelvis does not exist in some patients. That is to say, palpation of a lesion of endometriosis on the left side of the pelvis may produce pain that the patient perceives as being on the right side of the abdomen, and the opposite is also true.”


Pelvic Congestion Syndrome

"Which Options Are Best for Pelvic Congestion Syndrome?     
Which Options Are Best for Pelvic Congestion Syndrome?
Which Options Are Best for Pelvic Congestion Syndrome?
Pelvic congestion syndrome (PCS) is a poorly understood and often overlooked etiology of chronic pelvic pain. Millions of women worldwide may develop chronic pelvic pain at some time in their life, and the occurrence may be as high as 39.1%.1
Chronic pelvic pain can be debilitating and accounts for 10% to 15% of all gynecologic visits.1 Managing this complex condition can be a challenge for the primary-care provider. When clinical and ultrasound examinations are normal, further diagnostic imaging can helpful to obtain the diagnosis. Once identified, PCS can be treated successfully with embolization therapy. 


PCS is associated with dilated pelvic varices with reduced venous clearance, most often as a result of retrograde flow in an incompetent ovarian vein. The condition is seen more often in multiparous premenopausal women. A relationship between PCS and endogenous estrogen levels is suggested, as estrogen is known to weaken the vein walls.1
The venous congestion stretches the inner surface of the ovarian vein, distorting both the endothelial and smooth-muscle cells. It is postulated that kinking of the ovarian vein leads to venous stasis, flow reversal, and subsequent varicosities.2 PCS can also be caused by external compression, such as that seen in nutcracker syndrome (compression of the left renal vein between the aorta and superior mesenteric artery) and May-Thurner syndrome (compression of the left iliac vein beneath the iliac artery). 

Clinical Presentation

PCS is not easy to diagnose. Women typically complain of a dull, throbbing and achy pain in the vulvar region. This pain often worsens during or after intercourse or just before the onset of menses and/or increases throughout their day. Typically, women with PCS will not be symptomatic in the morning but will become so with prolonged standing or sitting.
The typical PCS patient may or may not have vulvar varicosities but often has varicose veins with the left leg presenting greater than the right. The varicosities usually extend along the medial aspect of the medial to posterior upper thigh and along the buttocks. 

Making the diagnosis more challenging is the vast array of the associated symptoms, including cyclic pain (with menstrual periods), dyspareunia, bladder irritability, GI symptoms and low back pain. Hemorrhoids and/or varicose veins of the perineum, buttocks or lower extremities may also be noted.1 Ovarian point tenderness on examination with a history of postcoital ache is said to be 94% sensitive and 77% specific for PCS.3
PCS is often diagnosed in women younger than age 45 years who have had more than one pregnancy. The ovarian veins increase in size during each pregnancy and do not return to normal in women with PCS. PCS is rarely diagnosed in nulliparous women." 

Please see for more.

Thursday, December 25, 2014

Addback therapy shows no difference in 24 month follow up

When you sit down to talk with your doctor about treatment for endometriosis or adenomyosis or what have you, keep this in mind if they mention Lupron, Zoladex, or any of the GNRH medications:

"Gonadotrophin-releasing hormone analogues for endometriosis: bone mineral density.



Gonadotrophin-releasing hormone analogues (GnRHas) are generally well tolerated, and are effective in relieving the symptoms of endometriosis (Prentice 2003). Unfortunately the low oestrogen state that they induce is associated with adverse effects including an acceleration in bone mineral density (BMD) loss.


To determine the effect of treatment with gonadotrophin-releasing hormone analogues (GnRHas) on the bone mineral density of women with endometriosis, compared to placebo, no treatment, or other treatments for endometriosis, including GnRHas with add-back therapy.


We searched the Cochrane Menstrual Disorders and Subfertility Group's specialised register of controlled trials (23rd October 2002) and the Cochrane Central Register of Controlled Trials (Cochrane Library, issue 4, 2002). We also carried out electronic searches of MEDLINE (1966 - March Week 2 2003) and EMBASE (1980 - March Week 2 2003). We also searched the reference lists of articles and contacted researchers in the field.


Prospective, randomised controlled studies of the use of GnRHas for the treatment of women with endometriosis were considered, where bone density measurements were an end point. The control arm of the studies was either placebo, no treatment, another medical therapy for endometriosis, or GnRHas with add-back therapy.


Two reviewers (JF and MS) independently assessed trial quality and extracted data. Study authors were contacted for additional information.


Thirty studies involving 2,391 women were included, however only 15, involving 910 women, could be included in the meta-analysis. The meta-analysis showed that danazol and progesterone + oestrogen add-back are protective of BMD at the lumbar spine both during treatment and for up to six and twelve months after treatment, respectively. Between the groups receiving GnRHa and the groups receiving danazol/gestrinone, there was a significant difference in percentage change of BMD after six months of treatment, the GnRH analogue producing a reduction in BMD from baseline and danazol producing an increase in BMD (SMD -3.43, 95 % CI -3.91 to -2.95). Progesterone only add-back is not protective; after six months of treatment absolute value BMD measurements of the lumbar spine did not differ significantly from the group receiving GnRH analogues (SMD 0.15, 95 % CI -0.21 to 0.52). In the comparison of GnRHa versus GnRHa + HRT add-back, that is oestrogen + progesterone or oestrogen only, there was a significantly bigger BMD loss in the GnRHa only group (SMD -0.49, 95 % CI -0.77 to -0.21). These numbers reflect the absolute value measurements at the lumbar spine after six months of treatment. Due to the small number of studies in the comparison we are unable to conclude whether calcium-regulating agents are protective. No difference was found between low and high dose add-back regimes but again only one study was identified for this comparison. Only one study comparing GnRH analogues with placebo was identified, but the study gave no data. No studies comparing GnRH with the oral contraceptive pill (OCP) or progestagens were identified.


Both danazol and progesterone + oestrogen add-back have been shown to be protective of BMD, while on treatment and up to six and 12 months later, respectively. However, by 24 months of follow-up there was no difference in BMD in those women who had HRT add-back. Studies of danazol versus GnRHa did not report long-term follow-up. The significant side effects associated with danazol limit its use."

The companies recommend no more than 2 6-month treatments in a lifetime. If your doctor recommends putting you on them for longer and says that add-back therapy will offset the negative effects, then keep in mind this study.


Saturday, December 13, 2014

The Complex Role of Estrogens in Inflammation

The Complex Role of Estrogens in Inflammation

"There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox.
This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17β-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor α and β depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens.
This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems."

"Estrogens influence systemic response systems by reducing the cytokine-stimulated ACTH and cortisol release, by increasing substance P signaling and sensitization to painful stimuli (increase of neurogenic inflammation), and by increasing signaling through proinflammatory α-adrenergic pathways (Fig. 4). These estrogen effects can partly explain the sexual dimorphism in chronic inflammatory diseases."

"In conclusion, immune stimuli (foreign antigens or autoantigens) and respective immune responses, the cell types involved (not only immune cells), the target organ, the reproductive status in a woman and timing of E2 administration in relation to the disease process, concentration of estrogens (dual effects), expression of ERα and ERβ (and their isoforms) depending on the microenvironment and the cell type, and intracellular metabolism of estrogens all play important roles in inflammatory diseases. In addition, systemic supersystems such as the HPA axis, the sensory nervous system, and the SNS can be influenced by estrogens to establish a proinflammatory milieu.
This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned influencing factors. This review also explains that a uniform concept for the action of estrogens cannot be found for all known chronic inflammatory diseases (Figs. 3 and 5). Nevertheless, for strictly B cell-dependent diseases such as those shown in Fig. 5, the female to male preponderance can be explained by the propagating effects of estrogens (but possibly also of progesterone). The smaller the influence of B cells and the bigger the weight of T cells and other cells, the less evident is the sex dimorphism in chronic inflammatory diseases (Fig. 5). In addition, because men never experience high estrogen (or progesterone) levels like women during pregnancy, the apparent gender dimorphism of chronic inflammatory diseases during the reproductive period of women can be explained. In addition, and this was not reported here, higher androgen levels in men most often exert inhibitory effects on many immune phenomena, which is an other important argument for why women with low androgen levels are protected from infectious diseases but more prone to B cell-dependent autoimmunity. Finally, we should not forget that sexual dimorphism of diseases may also depend on factors independent of sex hormones (588)."

Fig. 3. Relation between estrogen levels and inflammatory diseases. Red indicates that estrogens at respective concentrations exert proinflammatory effects, whereas green demonstrates estrogen levels with an antiinflammatory effect. In this summary, RA and MS (upper block) are divided according to the underlying dominant cell type involved. Today, we know that in a fraction of patients B cells play a dominant role, whereas in another group of patients macrophages, dendritic cells, T cells, and other non-B cells are predominant (164 165 166 167 ). In diseases with a B cell predominance, estrogens at all levels stimulate the proinflammatory process, whereas in disease without a strong B cell involvement, estrogens demonstrate a dual role: at low concentrations estrogens stimulate, and at high levels, estrogens inhibit the disease process. A somewhat different picture appears for prostatitis and LPS-induced Kupffer cell-dependent shock where estrogens seem to sensitize the inflammatory response. DC, Dendritic cell; NK cell, natural killer cell.

Role of Estrogen Receptor-β in Endometriosis

Role of Estrogen Receptor-β in Endometriosis

Serdar E. Bulun, M.D., Diana Monsavais, B.S., [...], and Emily J. Su, M.D., M.S.
"Endometriosis-related pain has conventionally been treated with endocrine agents such as synthetic progestins, oral contraceptives, or gonadotropin-releasing hormone analogs.1 These treatments, which interrupt ovulation and ovarian estrogen production, are successful in only half of the patients treated, however.9–11 Treatment with aromatase inhibitors in combination with an ovulation suppressor has successfully been used in cases refractory to these conventional measures of pain management.12 Patients often develop resistance to repeated treatments with the same agent over a period of 6 months to 3 years....
"Endometriotic tissue in ectopic locations, such as the peritoneum or ovary, is fundamentally different from eutopic endometrium within the uterus in terms of the production of cytokines and prostaglandins, estrogen biosynthesis and metabolism, and clinical response to progestins.11,22,23 There are substantial molecular differences with regard to progesterone response between normal endometrium and eutopic and ectopic tissues from women with endometriosis.17,24,25... Circumstantial and laboratory evidence strongly support the notion that estradiol is a key hormone for the growth and persistence of endometriotic tissue as well as inflammation and pain associated with it. Estradiol, which reaches endometriosis by circulation or is produced locally in endometriotic tissue, acts as a steroid hormone to regulate growth of endometriotic tissue. Estradiol enters cells and binds to the ER in estrogen-responsive cells. ER subtypes α and β are proteins with high affinity for estradiol and are encoded by separate genes....
"Despite its sensitivity to estrogen, endometriosis appears to contain a unique complement of steroid hormone receptors compared with that of its normal tissue counterpart, the eutopic endometrium. For example, several investigators reported markedly higher levels of ERβ and lower levels of ERα in human endometriotic tissues and primary stromal cells compared with eutopic endometrial tissues and cells.31,32 The levels of both isoforms of PR, particularly PR-B, are significantly lower in endometriosis compared with eutopic endometrium.6,33 The estradiol-receptor complex acts as a transcription factor that becomes associated with the promoters of estradiol-responsive genes via direct DNA binding or binding to other docking transcription factors at basal promoter regions.34 This interaction brings about ER-specific initiation of gene transcription, which promotes the synthesis of specific mRNAs and proteins.34 PR is one of many estradiol-responsive genes, and estradiol acts in eutopic endometrial tissues and stromal cells to promote endometrial responsiveness to progesterone.35 In contrast, PR mRNA and protein levels are not elevated in biopsied endometriotic tissues exposed to high estradiol levels during late proliferative phase or in endometriotic cells treated with estradiol, indicating that estradiol-induction PR expression in endometriosis is markedly blunted.33

"In addition to ERα, ERβ, and PR, the orphan nuclear receptor SF1 is also differentially regulated in endometriosis versus eutopic endometrium (Fig. 2). SF1 is responsible for coordinately activating the full steroidogenic cascade of genes including aromatase. The protein products of this set of steroidogenic genes are capable of converting cholesterol to estradiol locally in endometriotic tissue.36 We recently used real-time polymerase chain reaction (RT-PCR) to compare tissue mRNA levels of these key nuclear receptors in endometriosis and eutopic endometrium (Fig. 2). Ovarian endometriotic tissue SF1 and ERβ mRNA levels were >12,000 times and 142 times higher than in endometrium, respectively. In contrast, ERα, PR, and PR-B levels were remarkably lower in endometriotic tissue (Fig. 2).... ERα mRNA and protein levels are several fold lower in endometriotic tissue and stromal cells compared with endometrial tissue and stromal cells. ERα deficiency in endometriosis may be responsible for the failure of estradiol to induce PR expression, thus contributing to secondary PR deficiency and progesterone resistance in women with this disease. In vivo observations strongly suggest that estradiol induces ERα expression in mouse uterine tissue.39 It is quite likely that estradiol also plays a key role in regulating ERα expression in human endometrial stromal cells. However, strikingly high quantities of estradiol produced via local aromatase activity in addition to high ERβ levels in stromal cells of endometriosis may perturb this regulation and may suppress ERα expression.26,38... 

High estrogen production is a consistently observed endocrine feature of endometriosis. Expression of steroid receptors and other nuclear receptors are strikingly different between endometriotic and eutopic endometrial tissues. Among these nuclear receptors, ERβ expression is maybe >100 times higher in endometriotic tissue than in endometrium. Defective DNA methylation and other accompanying epigenetic mechanisms may be responsible for strikingly high ERβ expression in endometriosis. ERβ suppresses ERα expression and results in strikingly high ERβ-to-ERα ratios in endometriotic cells. We speculate that a strikingly lower ERα-to-ERβ ratio in endometriotic stromal cells may cause a shift from estradiol stimulation to inhibition of PR expression in endometriotic stromal cells under in vivo circumstances (Fig. 3). This proposed mechanism may explain severely deficient PR-B in endometriotic stromal cells, which contributes to progesterone resistance in women with endometriosis. ERβ overexpression in endometriosis possibly has other broad effects important in the pathology of endometriosis. It is likely that ERβ simulates prostaglandin production in endometriotic tissues and cells via inducing COX2 expression."

Increased expression of antimüllerian hormone and its receptor in endometriosis.

Increased expression of antimüllerian hormone and its receptor in endometriosis.



To evaluate antimüllerian hormone (AMH) and AMH receptor II (AMHRII) mRNA and protein expression in endometrium and in ovarian or deep lesions of women with endometriosis.


Prospective study.


University hospitals in Italy and Brazil.


Patients with endometriosis (n = 55) and healthy women (n = 45).


Specimens of endometrium obtained by hysteroscopy from patients with endometriosis and from healthy control subjects; specimens of ovarian endometriosis (n = 29) or of deep endometriosis (n = 26) were collected by laparoscopy. Serum samples were collected in some endometriotic patients (n = 23) and healthy control subjects (n = 20).


AMH and AMHRII mRNA levels were evaluated by quantitative reverse-transcription polymerase chain reaction and protein localization by immunohistochemistry. AMH levels in tissue homogenates and in serum were assessed by ELISA.


Endometrium from women with endometriosis showed higher AMH and AMHRII mRNA levels than control women, with no significant differences between proliferative and secretory phases. Specimens collected from ovarian or deep endometriosis showed the highest AMH and AMHRII mRNA expression. Immunolocalization study confirmed the high AMH and AMHRII protein expression in endometriotic lesions. No difference of serum AMH levels between the groups was found.


The increased AMH and AMHRII mRNA and protein expression in endometrium and in endometriotic lesions suggests a possible involvement of AMH in endometriosis.