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The dialectic role of progesterone
Maturitas 62 (2009) 326–329
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Review
The dialectic role of progesterone Johannes C. Huber ∗ , Johannes Ott Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
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Article history: Received 1 August 2008 Received in revised form 10 December 2008 Accepted 15 December 2008 Keywords: Progesterone receptor Progesterone metabolites Breast cancer Hormone replacement therapy
a b s t r a c t Progesterone is known to be metabolized into various metabolites exerting various effects, predominantly into 5␣-pregnanes and 4-pregnenes. Studies on uterine tissues showed numerous progesteroneconverting enzymes such as 5␣-reductase (5␣R), 5-reductase, 3␣-, 3-, 20␣-, and 20-hydroxysteroid oxidoreductases and others. The main progesterone-metabolizing enzymes in human breast tissues are 5␣R, 3␣-HSO 3-HSO, and 20␣-HSO. Tumor genesis in the breast has been shown to be enhanced by high 5␣R activity and suppression of 3␣-HSO and 20␣-HSO. A major determinant of 5␣R, the breast’s gate-keeping enzyme activity is the genetic variation in the enzyme’s gene. Two polymorphisms within the steroid 5␣R type 2 gene, Ala > Thr at codon 49 and Val > Leu at codon 89 have been reported to strongly affect the enzyme’s activity, even in regard to breast cancer risk. As steroid hormones are known to be converted into many other steroids occupying different receptors and thereby exerting various different effects, progesterone receptors are important factors when mediating the hormone’s effects. The progesterone receptor (PR) gene is transcribed from one gene by two alternative promoters and translated into PR-B, a potent transcriptional activator, and PR-A, the shorter isoform, necessary to oppose the effects of PR-B. In addition, endocrine reactions are modulated by epigenetics. The expression of progesterone receptors has been shown to be up- and downregulated by various epigenetic mechanisms. Many factors must be also taken into account in hormonal (replacement) therapy. Thus natural steroids should not be disparaged as treatment options for gender-specific diseases. An update on endocrinological knowledge and experience is rather mandatory for gynaecologists. © 2009 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Progesterone metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic variation in progesterone metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The dialectic in progesterone receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epigenetics in progesterone receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Steroid biogenesis is connected to the evolution of the atmosphere. The evolution of oxygen led to the association of this single atom to the former aliphatic compound squalene in position 3. According to biophysical principles, steroids were born.
∗ Corresponding author. Tel.: +431 40400 2816; fax: +431 40400 2817. E-mail address: [email protected] (J.C. Huber). 0378-5122/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2008.12.009
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Until now, adding and removing of oxygen or a hydroxyl group remain important principles in metabolism and generation of new steroids. Hydroxylation of the estradiol-molecule in different positions leads to generation of hormones with various biological effects: for example, 2-hydroxy-estrogen exerts angiostasis and has a low affinity to estrogen-receptor alpha (ER-␣), whereas 4hydroxyestradiol has a high ER-␣ affinity and strong angiogenetic and mitotic power, also generating the dangerous depurinated DNA adducts. As this metabolic switch is needed for nidation and implantation and thus contributes to reproductive processes, endocrine related tissues in the female organism developed into
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highly vascularized organs in order to guarantee these early events of reproduction [1]. Testosterone, produced in the ovarian theca cells, can also be converted into different androgenic metabolites with different functions in the female breast as well as in the brain [1]. 2. Progesterone metabolites As estradiol and testosterone are transformed into various metabolites exerting various effects, progesterone can also be converted into other progesteronic steroids. Progesterone is predominantly converted along two biochemical highways—(i) 5␣-pregnanes and (ii) 4-pregnenes. 5␣-pregnanes are known to enhance the mitotic rate in breast cells and are locally overrepresented in breast cancer. But why is progesterone metabolized via 5␣-reductase (5␣R) into such a steroid exerting a strong mitotic and antiapoptotic effect? Again, it’s all about reproduction: 5␣-pregnanes have a strong tocolytic effect. Thus 5␣R activity increases during pregnancy, whereas it declines during the postpartum period. Studies on uterine tissues from rats [2,3], guinea pigs [4,5], goats [6], and humans [7–11], as well as human placentae [12] showed numerous progesterone-converting enzymes as summarized by Wiebe in 2006 [13]. Similarly, incubations with ovarian tissues (especially granulosa cells) from rats [14–19], chickens [20,21], and humans [22] as well as incubations with testicular cells or homogenates from trouts [23], frogs [24], mouses [25], rats [26–30], rabbits [31], and humans [32,33] revealed various progesterone-converting enzymes. The group of progesteronemetabolizing enzymes includes 5␣R, 5-reductase (5R), 3␣-, 3-, 20␣-, and 20-hydroxysteroid oxidoreductases (3␣-HSO, 3-HSO, 20␣-HSO, 20-HSO, respectively), 6␣()-, 11-, 16-, 17-, and 21hydroxylase, and C17–20-lyase. These enzymes are encoded by their responsible genes, which exhibit a high genetic variability, associated with a high differentiation in enzyme activity and velocity, expressing an individual enzyme pattern in a given patient. A physiologically important enzyme with oncolcogical aspects in the breast is 5␣R converting progesterone into 5␣-pregnane3,20-dione. The reaction of 5␣R is irreversible. However, the further steps of metabolization are reversible: 5␣-pregnane-3,20-dione is converted into 3- and 20-hydroxy pregnanes by the action of 3␣HSO, 3-HSO, and 20␣-HSO, respectively. The second metabolic highway of progesterone in the breast is covered by the actions of 3␣-HSO and 20␣-HSO catalyzing the generation of 4-pregnen-3␣-ol-20-one (3␣HP) and 4-pregnen20␣-ol-3-one (20␣HP). In contrast to 5␣-pregnanes, expression of 4-pregnenes leads to increases in apoptosis and decreases in mitosis [13]. Thus, the main progesterone-metabolizing enzymes in human breast tissues are 5␣R, 3␣-HSO 3-HSO, and 20␣-HSO. Investigations and documentation of the individual enzyme activity might become important, maybe allowing an individual risk assessment for endocrine related cancers in the future. As in vitro studies suggest, tumor genesis in the breast may also be enhanced by high 5␣R activity and suppression of 3␣-HSO and 20␣-HSO. However, the gate-keeping enzyme in the breast is 5␣R; its activity depends on several endocrine and paracrine circumstances: for example, prolactin acts as a paracrine/autocrine mutagenic agent in breast cells and inhibits 20␣-HSO expression in corpora lutea [34]. Different cytokines such as interleukin-4, -6, or -13 regulate activity and expression of 3-HSO [35,36]. In addition, estrogen stimulates 5␣R activity as demonstrated in the uterus [37]. Cellular milieu such as temperature, pH, cofactors such as ions, phospholipids, and other molecules also modulate the enzyme’s activity and expression.
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3. Genetic variation in progesterone metabolism A major determinant of 5␣R activity is the genetic variation in the enzyme’s gene. Two polymorphisms within the steroid 5␣R type 2 (SRD5A2) gene, Ala > Thr at codon 49 (A49T) and Val > Leu at codon 89 (V89L) affect the activity of the SRD5A2 enzyme and have been investigated by several study groups. The Ala > Thr Codon 49 polymorphism increases the activity of SRD5A2, whereas the Val > Leu Codon 89 polymorphism decreases the activity of SRD5A2. The A49T polymorphism appears to result in a strongly increased enzymatic activity also in females, but this polymorphism is relatively rare, with the frequency of the Thr allele being <4% [38]. In regard to the V89L polymorphism, the Leu allele appears to be related to lower levels of 5␣-androstane-3,17-diol17-glucuronide, a metabolite of dihydrotestosterone, which is commonly used as an in vivo measure of 5␣R activity [39,40]. The V89L polymorphism is fairly common with the Leu allele frequency in Caucasian control populations being 30% [39–41]. This polymorphism has been examined in relation to breast cancer risk in one study [42], reporting a decreased risk for Japanese women with two Leu alleles. Another study examined this polymorphism in relation to breast cancer prognosis [43] and showed that the Leu allele was associated with lower breast tumor extract concentrations of prostate specific antigen, an earlier onset of breast cancer and a shorter disease-free and overall survival [43]. However, another trial found no evidence for a consistent relationship between the V89L SRD5A2 polymorphism and breast cancer risk. However, the Leu/Leu genotype was associated with larger tumor size, higher frequency of positive lymph nodes, higher TNM stage, and as a result, shorter survival than the Val/Val or Val/Leu genotypes [44]. These conflicting data can be explained by the dialectic role of 5␣R effect in the breast. On the one hand side, progesterone is metabolized in 5␣-pregnane-3,20-dione with tocolytic and anxiolytic effects, but also with stimulated proliferation rates, changed cell-to-cell and cell-to-substrate adhesion and cytoskeletal and adhesion molecules, enhancing growth regulating signals and mitogenic growth signaling pathways. On the other hand side, 5␣R converts testosterone into dihydrotestosterone that is further metabolized by hydroxysteroid-dehydrogenase into androstenedione, which cannot be aromatized to estrogen and thus a decrease in the substrate for aromatase takes place. In regard to the breast, 5␣R exerts a ying-yang mechanism. Metabolization of progesterone into 5␣-pregnane-3,20-dione burdens breast tissue, whereas conversion of testosteron to dihydrotestosterone protects the breast gland. Treatment with dihydrotestosterone not only completely reverses the stimulatory effect of estradiol on breast tumor growth but also decreases total tumor area to 48 ± 10% of its original size. The androgen dihydrotestosterone is thus a potent inhibitor of the stimulatory effect of estradiol on ZR-75-1 human breast carcinoma growth in in vivo athymic mice. Ovariectomized animals supplemented by exogenous estrogen were used in these studies. These data support the hypothesis of a direct inhibitory action of androgens on tumor growth under in vivo conditions [45,46]. Former studies with several human breast cancer cell lines such as ZR-75-1 [47–49], T47-D [48,50], MDA-MB-231 [50,51], MFM-223 [52], and CAMA-1 cells [53] and with DMBA-induced rat mammary tumors [54] have shown that both testosterone and dihydrotestosterone inhibit cell growth more or less to the same extent. However, testosterone is further metabolized into estradiol. 5␣-pregnane-3,20-dione has anaesthetic and analgesic effects via mechanisms involving calcium channels, gamma-aminobutyric
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acid (GABA), chloride complex and endogenous opioid systems [55]. In stress situations, 5␣R activity is upregulated; this may coexplain the oncogenic dimension of human stress on endocrine related cancers. Progesterone metabolites are neurosteroids with rapid physiological effects. There is growing evidence, that these steroids also use cytoplasmatic receptors. The possible location of the receptors for 5␣-pregnane-3,20-dione and 3␣-HP on the cell membrane suggests involvement of nongenomic mechanisms of action via cell signaling pathways. Thus the action of 5␣-pregnane3,20-dione on breast cancer cells may involve modulation of the mitogen-activated protein kinase (MAPK)-signaling pathway, that controls cell proliferation and adhesion and plays a central role in human cancer [13]. 4. The dialectic in progesterone receptors Mother Nature shows a high variability in biological systems for competition and adaption. The former interpretation of endocrinology, that one hormone exerts only one effect has been replaced by the knowledge that an incredible amount of hormonal compounds exert several effects on several tissues of the human body. Steroid hormones can be converted into many other steroids that occupy different receptors and sometimes even show antagonistic effects to the precursor. Similarly to cytoplasmatic receptors for steroids, connected to different second messengers, also nuclear receptors have different, sometimes dialectic effects as the nuclear progesterone receptors. The progesterone receptor (PR) gene is transcribed from one gene by two alternative promoters and translated into two different zinc-finger containing proteins, PR-A and PR-B differing by a 165-amino-acid part in the NH2-terminal region. PR-B is a potent transcriptional activator, whereas PR-A, the shorter isoform, is necessary to oppose the effects of PR-B. In normal endometrium, different steroid receptors are differentially expressed. PR-A and PR-B decline significantly in glandular epithelium from proliferative to late secretory phase. Interestingly, also estrogen receptors display different expression, comparable with progesterone receptors; the estrogen-receptor  immunohistochemical reactions show a similar significant declining pattern [56]. Not only in regard to breast cancer the existence of specific receptors for progesterone metabolites is of importance. Distinct and separate receptors for 3␣-dihydroprogesterone and 5␣-dihydroprogesterone have been identified in human breast cells [57,58]. This is of special interest as these two progesterone metabolites exert opposing effects with respect to cell proliferation and adhesion [13]. A general tendency for progesterone resistance within eutopic and ectopic endometrium and also a downregulation of PRB, but not PR-A has been demonstrated for endometriosis [59]. The molecular endocrinological basis of progesterone resistance in endometriotic patients may be related to the reduction of progesterone receptors and the lack of progesterone receptor B. In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factors for the expression of 17-hydroxysteroid-dehydrogenase type 2, which metabolizes the biologically active estrogen E2 to estrone [60]. In endometriosis, progesterone does not stimulate epithelial 17-hydroxysteroid-dehydrogenase type 2 expression in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate 17betaHSD-2 may be due to the lack of PR-B observed in vivo in endometriotic tissue leading to high paracrine levels of this local mitogen.
5. Epigenetics in progesterone receptors Endocrine reactions are modulated by epigenetics. Hypermethylation in the promoter area is associated with a silencing effect in the given genes. These mechanisms hold true for regulation of PR-receptor expression. It was reported that PR-B is silenced by a DNA methylation mechanism and PR-B expression was upregulated by aza-deoxycytidine treatment [61]. In addition, relatively low concentrations of aza-deoxycytidine and trichostatin A have been demonstrated to induce significant PR-B expression following a relatively short treatment duration in endometrioid cancer cell lines [62]. There is some evidence for aberrant methylation in the endometrium of women with endometriosis compared to those without endometriosis. For example, the aberrant methylation of HOXA10 gene may be responsible for the aberrant gene expression in the endometrium of women with endometriosis. This finding suggests a new interpretation for endometriosis—it may be an epigenetic disease [63]. Epigenetic mechanisms modulate steroid receptors activity and progesterone resistance in endometriosis in general and the downregulation of PR-B in particular, that may be a result of promoter hypermethylation of PR-B. Aromatase activity seems to be modulated by epigenetic procedures, too. An aberrant expression of aromatase gene in endometriotic stromal cells may be caused by an epigenetic disorder [64]. Recently, successful epigenetic therapy was published. Following the hypothesis, that endometriosis is an epigenetic disease, the authors conducted a pilot study on the off-label use of valproic acid to treat adenomyosis. By the end of the 3-month treatment it could be shown all three recruited patients reported complete relief from dysmenorrhea and an average of one-third reduction in uterine size [65]. 6. Conclusion The dilemma of hormone replacement therapy is a dilemma of our knowledge in endocrinology. Endogenous and exogenous substituted steroids have a long history in the female organism. There is a high genetic variability in genes for metabolization and synthesis of new steroids with different biological effects. These factors must be also taken into account as well as epigenetic mechanisms in endocrinology. Thus natural steroids should not be disparaged as treatment options for gender-specific diseases in hormone replacement therapy. An update on endocrinological knowledge and experience is rather mandatory for gynaecologists and practitioners. However, as our knowledge on endocrinology and hormonal therapy seems to be quite in an early stage, many efforts will have to be made in order to disclose all the secrets of its dangers and benefits. Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript. References [1] Huber JC. Endokrine Gynäkologie – Einführung in die frauenspezifische Medizin. Wien – München – Bern: Wilhelm Maudrich Verlag; 1998. [2] Marrone BL, Karavolas HJ. Progesterone metabolism by the hypothalamus, pituitary, and uterus of the rat during pregnancy. Endocrinology 1981;109: 41–5. [3] Redmond AF, Pepe GJ. Uterine progesterone metabolism during early pseudopregnancy in the rat. Biol Reprod 1986;35:949–55. [4] Glasier MA, Wiebe JP, Hobkirk R. Progesterone metabolism by guinea pig intrauterine tissues. J Steroid Biochem Mol Biol 1994;51:199–207.
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Hackenberg R, Lüttchens S, Hofmann J, Kunzmann R, Hölzel F, Schulz KD. Androgen sensitivity of the new human breast cancer cell line MFM-223. Cancer Res 1991;51:5722–7. Lapointe J, Labrie C. Role of the cyclin-dependent kinase inhibitor p27(Kip1) in androgen-induced inhibition of CAMA-1 breast cancer cell proliferation. Endocrinology 2001;142:4331–8. Boccuzzi G, Tamagno E, Brignardello E, Di Monaco M, Aragno M, Danni O. Growth inhibition of DMBA-induced rat mammary carcinomas by the antiandrogen flutamide. J Cancer Res Clin Oncol 1995;121:150–4. Pluchino N, Luisi M, Lenzi E, et al. Progesterone and progestins: effects on brain, allopregnanolone and beta-endorphin. J Steroid Biochem Mol Biol 2006;102:205–13. Mylonas I, Jeschke U, Shabani L, et al. Steroid receptors ER-alpha, ER-beta PR-A and PR-B are differentially expressed in normal and atrophic human endometrium. Histol Histopathol 2007;22:169–76. Laduron PM. Criteria for receptor sites in binding studies. Biochem Pharmacol 1984;33:833–9. Limbird LE. Identification of receptors using direct radiogland techniques. In: Cell surface receptors: a short course on theory and methods. 2nd edn Norwell, MA: Klewer Academic Publishers; 1996. Wu Y. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosis. Epigenetics 2006;1:106–11. Bulun SE, Cheng YH, Yin P, et al. Pogesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol 2006;248:94–103. Sasaki M, Kaneuchi M, Fujimoto S, Tanaka Y, Dahiya R. Hypermethylation can selectively silence multiple promoters of steroid receptors in cancers. Mol Cell Endocrinol 2003;202:201–7. Xiong Y, Dowdy SC, Gonzalez Bosquet J, et al. Epigenetic-mediated upregulation of progesterone receptor B gene in endometrial cancer cell lines. Gynecol Oncol 2005;99:135–41. Wu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo SW. Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. Am J Obstet Gynecol 2005;193:371–80. Izawa M, Harada T, Taniguchi F, Ohama Y, Takenaka Y, Terakawa N. An epigenetic disorder may cause aberrant expression of aromatase gene in endometriotic stromal cells. Fertil Steril 2008;89:1390–6. Liu X, Guo SW. A pilot study on the off-label use of valproic acid to treat adenomyosis. Fertil Steril 2008;89:246–50.
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Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
The dialectic role of progesterone Johannes C. Huber ∗ , Johannes Ott Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
a r t i c l e
i n f o
Article history: Received 1 August 2008 Received in revised form 10 December 2008 Accepted 15 December 2008 Keywords: Progesterone receptor Progesterone metabolites Breast cancer Hormone replacement therapy
a b s t r a c t Progesterone is known to be metabolized into various metabolites exerting various effects, predominantly into 5␣-pregnanes and 4-pregnenes. Studies on uterine tissues showed numerous progesteroneconverting enzymes such as 5␣-reductase (5␣R), 5-reductase, 3␣-, 3-, 20␣-, and 20-hydroxysteroid oxidoreductases and others. The main progesterone-metabolizing enzymes in human breast tissues are 5␣R, 3␣-HSO 3-HSO, and 20␣-HSO. Tumor genesis in the breast has been shown to be enhanced by high 5␣R activity and suppression of 3␣-HSO and 20␣-HSO. A major determinant of 5␣R, the breast’s gate-keeping enzyme activity is the genetic variation in the enzyme’s gene. Two polymorphisms within the steroid 5␣R type 2 gene, Ala > Thr at codon 49 and Val > Leu at codon 89 have been reported to strongly affect the enzyme’s activity, even in regard to breast cancer risk. As steroid hormones are known to be converted into many other steroids occupying different receptors and thereby exerting various different effects, progesterone receptors are important factors when mediating the hormone’s effects. The progesterone receptor (PR) gene is transcribed from one gene by two alternative promoters and translated into PR-B, a potent transcriptional activator, and PR-A, the shorter isoform, necessary to oppose the effects of PR-B. In addition, endocrine reactions are modulated by epigenetics. The expression of progesterone receptors has been shown to be up- and downregulated by various epigenetic mechanisms. Many factors must be also taken into account in hormonal (replacement) therapy. Thus natural steroids should not be disparaged as treatment options for gender-specific diseases. An update on endocrinological knowledge and experience is rather mandatory for gynaecologists. © 2009 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Progesterone metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic variation in progesterone metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The dialectic in progesterone receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epigenetics in progesterone receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Steroid biogenesis is connected to the evolution of the atmosphere. The evolution of oxygen led to the association of this single atom to the former aliphatic compound squalene in position 3. According to biophysical principles, steroids were born.
∗ Corresponding author. Tel.: +431 40400 2816; fax: +431 40400 2817. E-mail address: [email protected] (J.C. Huber). 0378-5122/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2008.12.009
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Until now, adding and removing of oxygen or a hydroxyl group remain important principles in metabolism and generation of new steroids. Hydroxylation of the estradiol-molecule in different positions leads to generation of hormones with various biological effects: for example, 2-hydroxy-estrogen exerts angiostasis and has a low affinity to estrogen-receptor alpha (ER-␣), whereas 4hydroxyestradiol has a high ER-␣ affinity and strong angiogenetic and mitotic power, also generating the dangerous depurinated DNA adducts. As this metabolic switch is needed for nidation and implantation and thus contributes to reproductive processes, endocrine related tissues in the female organism developed into
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highly vascularized organs in order to guarantee these early events of reproduction [1]. Testosterone, produced in the ovarian theca cells, can also be converted into different androgenic metabolites with different functions in the female breast as well as in the brain [1]. 2. Progesterone metabolites As estradiol and testosterone are transformed into various metabolites exerting various effects, progesterone can also be converted into other progesteronic steroids. Progesterone is predominantly converted along two biochemical highways—(i) 5␣-pregnanes and (ii) 4-pregnenes. 5␣-pregnanes are known to enhance the mitotic rate in breast cells and are locally overrepresented in breast cancer. But why is progesterone metabolized via 5␣-reductase (5␣R) into such a steroid exerting a strong mitotic and antiapoptotic effect? Again, it’s all about reproduction: 5␣-pregnanes have a strong tocolytic effect. Thus 5␣R activity increases during pregnancy, whereas it declines during the postpartum period. Studies on uterine tissues from rats [2,3], guinea pigs [4,5], goats [6], and humans [7–11], as well as human placentae [12] showed numerous progesterone-converting enzymes as summarized by Wiebe in 2006 [13]. Similarly, incubations with ovarian tissues (especially granulosa cells) from rats [14–19], chickens [20,21], and humans [22] as well as incubations with testicular cells or homogenates from trouts [23], frogs [24], mouses [25], rats [26–30], rabbits [31], and humans [32,33] revealed various progesterone-converting enzymes. The group of progesteronemetabolizing enzymes includes 5␣R, 5-reductase (5R), 3␣-, 3-, 20␣-, and 20-hydroxysteroid oxidoreductases (3␣-HSO, 3-HSO, 20␣-HSO, 20-HSO, respectively), 6␣()-, 11-, 16-, 17-, and 21hydroxylase, and C17–20-lyase. These enzymes are encoded by their responsible genes, which exhibit a high genetic variability, associated with a high differentiation in enzyme activity and velocity, expressing an individual enzyme pattern in a given patient. A physiologically important enzyme with oncolcogical aspects in the breast is 5␣R converting progesterone into 5␣-pregnane3,20-dione. The reaction of 5␣R is irreversible. However, the further steps of metabolization are reversible: 5␣-pregnane-3,20-dione is converted into 3- and 20-hydroxy pregnanes by the action of 3␣HSO, 3-HSO, and 20␣-HSO, respectively. The second metabolic highway of progesterone in the breast is covered by the actions of 3␣-HSO and 20␣-HSO catalyzing the generation of 4-pregnen-3␣-ol-20-one (3␣HP) and 4-pregnen20␣-ol-3-one (20␣HP). In contrast to 5␣-pregnanes, expression of 4-pregnenes leads to increases in apoptosis and decreases in mitosis [13]. Thus, the main progesterone-metabolizing enzymes in human breast tissues are 5␣R, 3␣-HSO 3-HSO, and 20␣-HSO. Investigations and documentation of the individual enzyme activity might become important, maybe allowing an individual risk assessment for endocrine related cancers in the future. As in vitro studies suggest, tumor genesis in the breast may also be enhanced by high 5␣R activity and suppression of 3␣-HSO and 20␣-HSO. However, the gate-keeping enzyme in the breast is 5␣R; its activity depends on several endocrine and paracrine circumstances: for example, prolactin acts as a paracrine/autocrine mutagenic agent in breast cells and inhibits 20␣-HSO expression in corpora lutea [34]. Different cytokines such as interleukin-4, -6, or -13 regulate activity and expression of 3-HSO [35,36]. In addition, estrogen stimulates 5␣R activity as demonstrated in the uterus [37]. Cellular milieu such as temperature, pH, cofactors such as ions, phospholipids, and other molecules also modulate the enzyme’s activity and expression.
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3. Genetic variation in progesterone metabolism A major determinant of 5␣R activity is the genetic variation in the enzyme’s gene. Two polymorphisms within the steroid 5␣R type 2 (SRD5A2) gene, Ala > Thr at codon 49 (A49T) and Val > Leu at codon 89 (V89L) affect the activity of the SRD5A2 enzyme and have been investigated by several study groups. The Ala > Thr Codon 49 polymorphism increases the activity of SRD5A2, whereas the Val > Leu Codon 89 polymorphism decreases the activity of SRD5A2. The A49T polymorphism appears to result in a strongly increased enzymatic activity also in females, but this polymorphism is relatively rare, with the frequency of the Thr allele being <4% [38]. In regard to the V89L polymorphism, the Leu allele appears to be related to lower levels of 5␣-androstane-3,17-diol17-glucuronide, a metabolite of dihydrotestosterone, which is commonly used as an in vivo measure of 5␣R activity [39,40]. The V89L polymorphism is fairly common with the Leu allele frequency in Caucasian control populations being 30% [39–41]. This polymorphism has been examined in relation to breast cancer risk in one study [42], reporting a decreased risk for Japanese women with two Leu alleles. Another study examined this polymorphism in relation to breast cancer prognosis [43] and showed that the Leu allele was associated with lower breast tumor extract concentrations of prostate specific antigen, an earlier onset of breast cancer and a shorter disease-free and overall survival [43]. However, another trial found no evidence for a consistent relationship between the V89L SRD5A2 polymorphism and breast cancer risk. However, the Leu/Leu genotype was associated with larger tumor size, higher frequency of positive lymph nodes, higher TNM stage, and as a result, shorter survival than the Val/Val or Val/Leu genotypes [44]. These conflicting data can be explained by the dialectic role of 5␣R effect in the breast. On the one hand side, progesterone is metabolized in 5␣-pregnane-3,20-dione with tocolytic and anxiolytic effects, but also with stimulated proliferation rates, changed cell-to-cell and cell-to-substrate adhesion and cytoskeletal and adhesion molecules, enhancing growth regulating signals and mitogenic growth signaling pathways. On the other hand side, 5␣R converts testosterone into dihydrotestosterone that is further metabolized by hydroxysteroid-dehydrogenase into androstenedione, which cannot be aromatized to estrogen and thus a decrease in the substrate for aromatase takes place. In regard to the breast, 5␣R exerts a ying-yang mechanism. Metabolization of progesterone into 5␣-pregnane-3,20-dione burdens breast tissue, whereas conversion of testosteron to dihydrotestosterone protects the breast gland. Treatment with dihydrotestosterone not only completely reverses the stimulatory effect of estradiol on breast tumor growth but also decreases total tumor area to 48 ± 10% of its original size. The androgen dihydrotestosterone is thus a potent inhibitor of the stimulatory effect of estradiol on ZR-75-1 human breast carcinoma growth in in vivo athymic mice. Ovariectomized animals supplemented by exogenous estrogen were used in these studies. These data support the hypothesis of a direct inhibitory action of androgens on tumor growth under in vivo conditions [45,46]. Former studies with several human breast cancer cell lines such as ZR-75-1 [47–49], T47-D [48,50], MDA-MB-231 [50,51], MFM-223 [52], and CAMA-1 cells [53] and with DMBA-induced rat mammary tumors [54] have shown that both testosterone and dihydrotestosterone inhibit cell growth more or less to the same extent. However, testosterone is further metabolized into estradiol. 5␣-pregnane-3,20-dione has anaesthetic and analgesic effects via mechanisms involving calcium channels, gamma-aminobutyric
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acid (GABA), chloride complex and endogenous opioid systems [55]. In stress situations, 5␣R activity is upregulated; this may coexplain the oncogenic dimension of human stress on endocrine related cancers. Progesterone metabolites are neurosteroids with rapid physiological effects. There is growing evidence, that these steroids also use cytoplasmatic receptors. The possible location of the receptors for 5␣-pregnane-3,20-dione and 3␣-HP on the cell membrane suggests involvement of nongenomic mechanisms of action via cell signaling pathways. Thus the action of 5␣-pregnane3,20-dione on breast cancer cells may involve modulation of the mitogen-activated protein kinase (MAPK)-signaling pathway, that controls cell proliferation and adhesion and plays a central role in human cancer [13]. 4. The dialectic in progesterone receptors Mother Nature shows a high variability in biological systems for competition and adaption. The former interpretation of endocrinology, that one hormone exerts only one effect has been replaced by the knowledge that an incredible amount of hormonal compounds exert several effects on several tissues of the human body. Steroid hormones can be converted into many other steroids that occupy different receptors and sometimes even show antagonistic effects to the precursor. Similarly to cytoplasmatic receptors for steroids, connected to different second messengers, also nuclear receptors have different, sometimes dialectic effects as the nuclear progesterone receptors. The progesterone receptor (PR) gene is transcribed from one gene by two alternative promoters and translated into two different zinc-finger containing proteins, PR-A and PR-B differing by a 165-amino-acid part in the NH2-terminal region. PR-B is a potent transcriptional activator, whereas PR-A, the shorter isoform, is necessary to oppose the effects of PR-B. In normal endometrium, different steroid receptors are differentially expressed. PR-A and PR-B decline significantly in glandular epithelium from proliferative to late secretory phase. Interestingly, also estrogen receptors display different expression, comparable with progesterone receptors; the estrogen-receptor  immunohistochemical reactions show a similar significant declining pattern [56]. Not only in regard to breast cancer the existence of specific receptors for progesterone metabolites is of importance. Distinct and separate receptors for 3␣-dihydroprogesterone and 5␣-dihydroprogesterone have been identified in human breast cells [57,58]. This is of special interest as these two progesterone metabolites exert opposing effects with respect to cell proliferation and adhesion [13]. A general tendency for progesterone resistance within eutopic and ectopic endometrium and also a downregulation of PRB, but not PR-A has been demonstrated for endometriosis [59]. The molecular endocrinological basis of progesterone resistance in endometriotic patients may be related to the reduction of progesterone receptors and the lack of progesterone receptor B. In normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factors for the expression of 17-hydroxysteroid-dehydrogenase type 2, which metabolizes the biologically active estrogen E2 to estrone [60]. In endometriosis, progesterone does not stimulate epithelial 17-hydroxysteroid-dehydrogenase type 2 expression in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate 17betaHSD-2 may be due to the lack of PR-B observed in vivo in endometriotic tissue leading to high paracrine levels of this local mitogen.
5. Epigenetics in progesterone receptors Endocrine reactions are modulated by epigenetics. Hypermethylation in the promoter area is associated with a silencing effect in the given genes. These mechanisms hold true for regulation of PR-receptor expression. It was reported that PR-B is silenced by a DNA methylation mechanism and PR-B expression was upregulated by aza-deoxycytidine treatment [61]. In addition, relatively low concentrations of aza-deoxycytidine and trichostatin A have been demonstrated to induce significant PR-B expression following a relatively short treatment duration in endometrioid cancer cell lines [62]. There is some evidence for aberrant methylation in the endometrium of women with endometriosis compared to those without endometriosis. For example, the aberrant methylation of HOXA10 gene may be responsible for the aberrant gene expression in the endometrium of women with endometriosis. This finding suggests a new interpretation for endometriosis—it may be an epigenetic disease [63]. Epigenetic mechanisms modulate steroid receptors activity and progesterone resistance in endometriosis in general and the downregulation of PR-B in particular, that may be a result of promoter hypermethylation of PR-B. Aromatase activity seems to be modulated by epigenetic procedures, too. An aberrant expression of aromatase gene in endometriotic stromal cells may be caused by an epigenetic disorder [64]. Recently, successful epigenetic therapy was published. Following the hypothesis, that endometriosis is an epigenetic disease, the authors conducted a pilot study on the off-label use of valproic acid to treat adenomyosis. By the end of the 3-month treatment it could be shown all three recruited patients reported complete relief from dysmenorrhea and an average of one-third reduction in uterine size [65]. 6. Conclusion The dilemma of hormone replacement therapy is a dilemma of our knowledge in endocrinology. Endogenous and exogenous substituted steroids have a long history in the female organism. There is a high genetic variability in genes for metabolization and synthesis of new steroids with different biological effects. These factors must be also taken into account as well as epigenetic mechanisms in endocrinology. Thus natural steroids should not be disparaged as treatment options for gender-specific diseases in hormone replacement therapy. An update on endocrinological knowledge and experience is rather mandatory for gynaecologists and practitioners. However, as our knowledge on endocrinology and hormonal therapy seems to be quite in an early stage, many efforts will have to be made in order to disclose all the secrets of its dangers and benefits. Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript. References [1] Huber JC. Endokrine Gynäkologie – Einführung in die frauenspezifische Medizin. Wien – München – Bern: Wilhelm Maudrich Verlag; 1998. [2] Marrone BL, Karavolas HJ. Progesterone metabolism by the hypothalamus, pituitary, and uterus of the rat during pregnancy. Endocrinology 1981;109: 41–5. [3] Redmond AF, Pepe GJ. Uterine progesterone metabolism during early pseudopregnancy in the rat. Biol Reprod 1986;35:949–55. [4] Glasier MA, Wiebe JP, Hobkirk R. Progesterone metabolism by guinea pig intrauterine tissues. J Steroid Biochem Mol Biol 1994;51:199–207.
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