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Endometriosis and Estrogen

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Pre and Postmenopausal Women: Progesterone Decreases Aromatase Activity
Hormonal profiles in women with breast cancer

J Clin Endocrinol Metab. 1998 Dec;83(12):4474-80.
Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol.
Zeitoun K, Takayama K, Sasano H, Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE.
Aberrant aromatase expression in stromal cells of endometriosis gives rise to conversion of circulating androstenedione to estrone in this tissue, whereas aromatase expression is absent in the eutopic endometrium. In this study, we initially demonstrated by Northern blotting transcripts of the reductive 17beta-hydroxysteroid dehydrogenase (17betaHSD) type 1, which catalyzes the conversion of estrone to 17beta-estradiol, in both eutopic endometrium and endometriosis. Thus, it follows that the product of the aromatase reaction, namely estrone, that is weakly estrogenic can be converted to the potent estrogen, 17beta-estradiol, in endometriotic tissues. It was previously demonstrated that progesterone stimulates the inactivation of 17beta-estradiol through conversion to estrone in eutopic endometrial epithelial cells…In conclusion, inactivation of 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which is normally expressed in eutopic endometrium in response to progesterone.

Reproductive Biology and Endocrinology 2011, 9:87
The emerging use of aromatase inhibitors for endometriosis treatment
Warren B Nothnick
Endometriosis is defined as the growth of endometrial tissue outside of the uterine cavity. The disease occurs primarily in women of reproductive age but recurrent endometriosis is also detected in post-menopausal women. Regardless of age, endometriosis is associated with pain and reduces the quality of life for millions of women world-wide. Conventional therapies focus on reducing systemic levels of estrogen which results in cessation of endometriotic implant growth and pain symptoms associated with the disease. However, these treatments are not effective in all women and are not without side effects. Based upon the discovery that endometriotic tissue over-expresses aromatase, an enzyme critical for estrogen production, emphasis has been placed upon the use of aromatase inhibitors for the treatment of endometriosis and its associated symptoms. This article will review the rationale behind the use of aromatase inhibitors in treating endometriosis and summarize those studies which have evaluated the use of aromatase inhibitors in the treatment of endometriosis and its associated symptoms.

Drugs. 2009 May 29;69(8):943-52. doi: 10.2165/00003495-200969080-00001.
Pharmacological treatment of endometriosis: experience with aromatase inhibitors.
Ferrero S, Venturini PL, Ragni N, Camerini G, Remorgida V.
Current treatment of endometriosis is mainly based on surgery and ovarian suppressive agents. In the last 10 years, it has been demonstrated that aromatase P450, a key enzyme for estrogen biosynthesis, may have a pathogenic role in endometriosis because it is aberrantly expressed in endometriotic implants and in eutopic endometrium of women with endometriosis. Therefore, inhibition of aromatase activity may represent a new therapeutic option for endometriosis. Case reports and observational studies have shown that pain symptoms caused by endometriosis quickly improve after administration of aromatase inhibitors. Limited data are available on the long-term course of pain symptoms after completion of treatment with aromatase inhibitors; however, some recent studies suggest that symptoms may recur at short-term follow-up. A range of results are reported on the effects of aromatase inhibitors on endometriotic lesions, with some authors describing improvements and other authors reporting persistence of pelvic lesions at second-look laparoscopy after treatment. No severe adverse effect has been reported during treatment with aromatase inhibitors both in pre- and postmenopausal women. On the basis of the available data, administration of aromatase inhibitors should now be offered only to the small number of women who have severe pain despite previous surgical and hormonal therapies. Further research in the form of randomized controlled trials will be required before recommending the routine use of these agents.

Endocr Relat Cancer. 1999 Jun;6(2):293-301.
Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis.
Bulun SE, Zeitoun K, Takayama K, Noble L, Michael D, Simpson E, Johns A, Putman M, Sasano H.
Estrogen is the most important known factor that stimulates the growth of endometriosis. Estrogen delivery to endometriotic implants was classically viewed to be only via the circulating blood in an endocrine fashion. We recently uncovered an autocrine positive feedback mechanism, which favored the continuous production of estrogen and prostaglandin (PG)E2 in the endometriotic stromal cells. The enzyme, aromatase, is aberrantly expressed in endometriotic stromal cells and catalyzes the conversion of C19 steroids to estrogens, which then stimulate cyclooxygenase-2 to increase the levels of PGE2. PGE2, in turn, is a potent inducer of aromatase activity in endometriotic stromal cells. Aromatase is not expressed in the eutopic endometrium. Aromatase expression in endometriosis and its inhibition in eutopic endometrium are controlled by the competitive binding of a stimulatory transcription factor, steroidogenic factor-1, and an inhibitory factor, chicken ovalbumin upstream promoter-transcription factor to a regulatory element in the aromatase P450 gene promoter. In addition, we find that endometriotic tissue is deficient in 17beta-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrial glandular cells and inactivates estradiol-17beta to estrone. This deficiency is another aberration that favors higher levels of estradiol-17beta in endometriotic tissues in comparison with the eutopic endometrium. The clinical relevance of local aromatase expression in endometriosis was exemplified by the successful treatment of an unusually aggressive form of recurrent endometriosis in a postmenopausal woman using an aromatase inhibitor.

Expert Opin Emerg Drugs. 2004 May;9(1):167-77.
Emerging drugs for endometriosis.
Fedele L, Berlanda N.
Medical treatment of endometriosis relies on drugs that suppress ovarian steroids and induce an hypoestrogenic state that causes atrophy of ectopic endometrium. Gonadotrophin-releasing hormone (GnRH) analogues, danazol, progestogens and oestrogen-progestin combinations have all proven effective in relieving pain and reducing the extent of endometriotic implants. However, symptoms often recur after discontinuation of therapy and hypoestrogenism-related side effects limit the long-term use of most medications. Furthermore, these therapies are of limited value in patients with a desire to become pregnant because they inhibit ovulation. An important target for current research is to identify effective therapies that can be safely administered in the long term. GnRH analogues with add-back therapy, progestogens and continuous oral contraceptive are options available for a medium or long-term systemic treatment. Mifepristone, an antiprogestogen, may constitute an alternative if encouraging preliminary data on its effectiveness and tolerability are confirmed. A very appealing area of interest is the possibility of treating endometriosis without suppressing ovarian function. Aromatase inhibitors might have such characteristics as they have been shown to inhibit oestrogen production selectively in endometriotic lesions, without affecting ovarian function; the clinical role of these drugs in the treatment of endometriosis is under evaluation. Levonorgestrel medicated intrauterine device has proven effective in relieving dysmenorrhoea associated with endometriosis, as well as pain associated with rectovaginal endometriosis. Although a systemic absorption is present determining side effects, this approach is promising in the long-term management of this condition. A fundamental objective of research in endometriosis treatment is to develop new therapeutic approaches based on the findings from experimental studies on the aetiopathogenesis of the disease; current research is focusing on anti-inflammatory drugs and modulators of the immune system. TNF-binding protein-1 and IL-12 have proved effective in reducing endometriotic lesions in animal models, while pentoxifylline and INF-alpha 2b have shown encouraging results in clinical studies. This area may be of paramount importance in the near future in order to develop a therapy that could prevent or eradicate endometriosis rather than merely relieving the symptoms.

Fertil Steril. 1999 Dec;72(6):961-9.
Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target.
Zeitoun KM, Bulun SE.
OBJECTIVE:
To provide a clinically useful model illustrating the molecular aberrations affecting estrogen biosynthesis and metabolism in endometriosis and to discuss the therapeutic role of aromatase inhibitors.
DESIGN:
Literature review.
RESULT(S):
Several molecular aberrations were found in endometriotic lesions (in contrast to eutopic endometrium) that favor increased local concentrations of E2. Endometriotic stromal cells aberrantly express aromatase, which converts C19, steroids to estrogens. Aromatase activity in these cells is stimulated by prostaglandin (PG)E2. Estrogen stimulates cyclooxygenase-2, giving rise to increased PGE2 formation. Thus, this positive feedback loop produces increasing quantities of E2 and PGE2 in endometriosis. The lack of aromatase expression in eutopic endometrium is maintained by binding of an inhibitory transcription factor, COUP-TF, to the aromatase promoter. In endometriosis, however, an aberrantly expressed factor, SF-1, displaces COUP-TF to bind to this same promoter and activates aromatase expression and thus local estrogen biosynthesis. Additionally, endometriotic glandular cells are deficient in 17beta-hydroxysteroid dehydrogenase type 2, which converts E2 to estrone in the eutopic endometrium in response to P. Deficiency of this enzyme in endometriosis impairs the inactivation of E2 and may be a consequence of insensitivity to P.
CONCLUSION(S):
Molecular aberrations that increase local E2 concentrations may be important in the etiology of endometriosis. These molecules may be targeted to develop novel therapeutic strategies. The clinical relevance of aromatase expression in endometriosis was shown recently by the successful treatment of an unusually aggressive case of postmenopausal endometriosis with use of an aromatase inhibitor.

J Clin Endocrinol Metab. 1997 Feb;82(2):600-6.
Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells.
Noble LS, Takayama K, Zeitoun KM, Putman JM, Johns DA, Hinshelwood MM, Agarwal VR, Zhao Y, Carr BR, Bulun SE.
C19 steroids are converted to estrogens by aromatase P450 (P450arom). Aromatase expression in humans is regulated by use of tissue-specific promoters in the placenta (promoter I.1), adipose tissue (promoters I.4, I.3, and II), and gonads (promoter II). The use of each promoter gives rise to a population of P450arom messenger ribonucleic acid (mRNA) species with a unique untranslated 5′-terminus. Aromatase is not expressed in the endometrium of disease-free women. We demonstrated, however, the presence of P450arom mRNA in pelvic endometriotic implants and eutopic endometrial curettings of women with endometriosis. In the current report, aromatase activity and P450arom gene expression were investigated in cultured stromal cells derived from eutopic endometrium and ovarian endometriomas of women with pelvic endometriosis. We also investigated the hormonal regulation of aromatase expression and alternative promoter use in these cells. The effects of interleukin-1 beta (IL-1 beta), IL-2, IL-6, IL-11, oncostatin M, IL-15, tumor necrosis factor-alpha, PGE2, estradiol, R5020, dexamethasone, and dibutyryl cAMP (Bt2cAMP) on aromatase activity in endometriosis-derived stromal cells were assessed. We chose treatments with PGs and ILs because of the inflammatory nature of endometriosis. PGE2 stimulated aromatase activity in endometriosis-derived stromal cells by 19- to 44-fold (37-221 pmol/mg protein-4 h), whereas Bt2cAMP induction was 26- to 60-fold the baseline level. No stimulation was observed by estradiol or R5020 or by IL-1 beta, IL-2, IL-6, IL-11, IL-15, or TNF alpha in the presence or absence of glucocorticoids. A modest induction of aromatase activity (2-fold) was observed in dexamethasone- plus oncostatin M-treated cells. These changes in aromatase activity were accompanied by comparable changes in the levels of P450arom mRNA levels, determined by a quantitative reverse transcription-PCR method. Promoter-specific 5′-ends of P450arom transcripts in total RNA from endometriosis-derived stromal cells treated with PGE2 and Bt2cAMP were amplified employing a novel modified rapid amplification of cDNA5′-ends/Southern hybridization method using exon-specific oligonucleotide probes. The majority of P450arom transcripts in these cells contained the gonadal-type promoter II-specific sequences, whereas very few transcripts contained adipose-type promoter I.3- and I.4-specific sequences. PGE2 appears to be the most potent known stimulator of aromatase in endometriosis. Aromatase expression in PGE2-stimulated stromal cells of endometriosis is regulated primarily by the classically located promoter II, which, in turn, is regulated by cAMP. As PGE2 is known to increase intracellular cAMP levels, estrogen biosynthesis in endometriosis may be primarily regulated by PGE2 that is locally produced. Consequent local estrogen production may promote the growth of endometriotic implants.

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Endometrial Cancer & Estrogen:

Br J Obstet Gynaecol. 1993 Dec;100(12):1115-9.
Plasma oestrogens in postmenopausal women with endometrial cancer.
Nyholm HC, Nielsen AL, Lyndrup J, Dreisler A, Hagen C, Haug E.
OBJECTIVE:
To study plasma levels of estrogens and androgens, sex hormone-binding globulin (SHBG) and follicle stimulating hormone (FSH) in postmenopausal patients with endometrial cancer.
DESIGN:
Patients and controls were matched for age, body mass index, parity and years since menopause.
SETTING:
Department of Obstetrics and Gynaecology, Hvidovre Hospital, Denmark.
SUBJECTS:
Fifty postmenopausal patients with endometrial cancer and 54 matching controls.
MEASUREMENTS:
Plasma levels of SHBG, FSH, oestrone, oestradiol, oestrone-sulphate, dehydro-epiandrosterone sulphate, testosterone, and androstenedione were measured by radio-immunoassays. Free fractions of oestradiol and testosterone were calculated according to levels of SHBG and albumin.
RESULTS:
The levels of oestradiol, free oestradiol, and oestrone were elevated (P < 0.001) in patients compared with controls (oestradiol: 51 (45-59) vs 37 (34-41) pmol/l; free oestradiol: 0.69 (0.59-0.80) vs 0.48 (0.42-0.54) pmol/l; oestrone: 180 (159-204) vs 119 (107-133) pmol/l (mean values (95% CI) in patients vs controls)). Furthermore, an increased oestrone:androstenedione ratio (0.095 vs 0.072, P < 0.01) was found in patients. SHBG correlated negatively (P < 0.001) with body mass, while the free fractions of oestradiol and testosterone correlated positively (P < 0.01) with body mass, in both patients and controls. Multiple regression analysis showed that the differences in oestrogen levels between the two groups persisted when controlling for the effect of body mass, age, years since menopause, parity, and levels of SHBG and FSH.
CONCLUSION:
Patients with endometrial cancer exhibit increased plasma levels of oestradiol and oestrone. Speculatively, these oestrogens may result from an increased oestrone conversion from androstenedione, an increased ovarian and adrenal secretion of androstenedione, or alternative oestrogen production routes. The present findings support the hypothetical role for oestrogens in the aetiology of endometrial cancer.

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