Intracrinology: role of the family of 17 beta-hydroxysteroid dehydrogenases in human physiology and disease.

In women and men, an important proportion of estrogens and androgens are synthesized locally at their site of action in peripheral target tissues. This new field of endocrinology has been called intracrinology. In postmenopausal women, 100% of active sex steroids are synthesized in peripheral target tissues from inactive steroid precursors while, in adult men, approximately 50% of androgens are made locally in intracrine target tissues. The last and key step in the formation of all estrogens and androgens is catalyzed by members of the family of 17beta-hydroxysteroid dehydrogenases (17 beta-HSDs) while different 17 beta-HSDs inactivate these steroids in the same cell where synthesis takes place. To date, seven human 17 beta-HSDs have been cloned, sequenced and characterized. The 17 beta-HSDs provide each cell with the means of precisely controlling the intracellular concentration of each sex steroid according to local needs.

[1]  L. Bernstein,et al.  Endogenous hormones and breast cancer risk. , 1993, Epidemiologic reviews.

[2]  F. Labrie.  Intracrinology , 1991, Molecular and Cellular Endocrinology.

[3]  H. Bonkhoff,et al.  [Morphogenesis of benign prostatic hyperplasia and prostatic carcinoma]. , 1998, Der Pathologe.

[4]  M. Ghilchik,et al.  A comparison of the in vivo uptake and metabolism of 3H‐oestrone and 3H‐oestradiol by normal breast and breast tumour tissues in post‐menopausal women , 1986, International journal of cancer.

[5]  P. Soucy,et al.  Characteristics of a Highly Labile Human Type 5 17β-Hydroxysteroid Dehydrogenase1. , 1999, Endocrinology.

[6]  N. Davidson,et al.  The role of estrogens in growth regulation of breast cancer. , 1989, Critical reviews in oncogenesis.

[7]  J. Simard,et al.  Intracrinology: the basis for the rational design of endocrine therapy at all stages of prostate cancer. , 1993, European urology.

[8]  K. Davidson,et al.  THE RELATIONSHIP BETWEEN 17β‐HYDROXYSTEROID DEHYDROGENASE ACTIVITY AND OESTROGEN CONCENTRATIONS IN HUMAN BREAST TUMOURS AND IN NORMAL BREAST TISSUE , 1983, Clinical endocrinology.

[9]  J. Simard,et al.  Interleukin-4 and interleukin-13 inhibit estrogen-induced breast cancer cell proliferation and stimulate GCDFP-15 expression in human breast cancer cells , 1996, Molecular and Cellular Endocrinology.

[10]  R. Vihko,et al.  Two 17β-hydroxysteroid dehydrogenases (17HSDs) of estradiol biosynthesis: 17HSD type 1 and type 7 , 1999, The Journal of Steroid Biochemistry and Molecular Biology.

[11]  M. Poutanen,et al.  17 beta-hydroxysteroid dehydrogenase gene expression in human breast cancer cells: regulation of expression by a progestin. , 1992, Cancer research.

[12]  M. Takahashi,et al.  Distribution of 17β-hydroxysteroid dehydrogenase gene expression and activity in rat and human tissues , 1992, The Journal of Steroid Biochemistry and Molecular Biology.

[13]  E. Thiel,et al.  Inhibition of proliferation and clonal growth of human breast cancer cells by interleukin 13. , 1996, Cancer research.

[14]  G. Hodgen,et al.  Adrenarche: a survey of rodents, domestic animals, and primates. , 1978, Endocrinology.

[15]  R. Vihko,et al.  Expression cloning of a novel estrogenic mouse 17 beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase (m17HSD7), previously described as a prolactin receptor-associated protein (PRAP) in rat. , 1998, Molecular endocrinology.

[16]  C. Labrie,et al.  Androgenic activity of dehydroepiandrosterone and androstenedione in the rat ventral prostate. , 1988, Endocrinology.

[17]  W. Pangborn,et al.  Crystallization and preliminary X-ray diffraction analysis of the complex of human placental 17 beta-hydroxysteroid dehydrogenase with NADP+. , 1993, Journal of molecular biology.

[18]  F. Leenders,et al.  Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV. , 1995, The Biochemical journal.

[19]  R. Campbell,et al.  3D-structure of human estrogenic 17β-HSD1: binding with various steroids , 1999, The Journal of Steroid Biochemistry and Molecular Biology.

[20]  R. King.  A discussion of the roles of oestrogen and progestin in human mammary carcinogenesis , 1991, The Journal of Steroid Biochemistry and Molecular Biology.

[21]  M. Reed,et al.  Multiple forms of 17β-hydroxysteroid oxidoreductase in human breast tissue , 1989 .

[22]  J. Simard,et al.  Potent stimulatory effect of interleukin‐1α on apolipoprotein D and gross cystic disease fluid protein‐15 expression in human breast‐cancer cells , 1994, International journal of cancer.

[23]  A. Purohit,et al.  Breast cancer and the role of cytokines in regulating estrogen synthesis: an emerging hypothesis. , 1997, Endocrine reviews.

[24]  D. Linzer,et al.  Cloning and Characterization of an Ovarian-specific Protein That Associates with the Short Form of the Prolactin Receptor* , 1996, The Journal of Biological Chemistry.

[25]  B. Rafferty,et al.  Interleukin 6 is secreted by breast fibroblasts and stimulates 17β‐oestradiol oxidoreductase activity of MCF‐7 cells: Possible paracrine regulation of breast 17β‐oestradiol levels , 1991, International journal of cancer.

[26]  H. Inoko,et al.  Physical mapping 220 kb centromeric of the human MHC and DNA sequence analysis of the 43-kb segment including the RING1, HKE6, and HKE4 genes. , 1997, Genomics.

[27]  F. Labrie,et al.  Localization of Type 5 17β-Hydroxysteroid Dehydrogenase, 3β-Hydroxysteroid Dehydrogenase, and Androgen Receptor in the Human Prostate by in Situ Hybridization and Immunocytochemistry. , 1999, Endocrinology.

[28]  J. Simard,et al.  Structure, function and tissue-specific gene expression of 3β-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase enzymes in classical and peripheral intracrine steroidogenic tissues , 1992, The Journal of Steroid Biochemistry and Molecular Biology.

[29]  F. Labrie,et al.  Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology. , 1997, The Journal of clinical endocrinology and metabolism.

[30]  M. Dumont,et al.  Expression of human 17β-hydroxysteroid dehydrogenase in mammalian cells , 1992, The Journal of Steroid Biochemistry and Molecular Biology.

[31]  D. Russell,et al.  Expression Cloning and Characterization of Oxidative 17β- and 3α-Hydroxysteroid Dehydrogenases from Rat and Human Prostate* , 1997, The Journal of Biological Chemistry.

[32]  R. Vihko,et al.  Genomic organization and DNA sequences of human 17 beta-hydroxysteroid dehydrogenase genes and flanking regions. Localization of multiple Alu sequences and putative cis-acting elements. , 1992, European journal of biochemistry.

[33]  S. Cummings,et al.  The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. , 1999, JAMA.

[34]  Candaş,et al.  Long-Term Combined Androgen Blockade Alone for Localized Prostate Cancer. , 1999, Molecular urology.

[35]  M. Baker,et al.  Characterization of Ke 6, a New 17β-Hydroxysteroid Dehydrogenase, and Its Expression in Gonadal Tissues* , 1998, The Journal of Biological Chemistry.

[36]  W. Pangborn,et al.  Structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase at 2.20 A resolution. , 1995, Structure.

[37]  F. Labrie,et al.  Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after castration: unique importance of extratesticular androgens in men. , 1989, Journal of steroid biochemistry.

[38]  Sheng-Xiang Lin,et al.  Subunit identity of the dimeric 17 beta-hydroxysteroid dehydrogenase from human placenta. , 1992, The Journal of biological chemistry.

[39]  F. Labrie,et al.  New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen. , 1982, Clinical and investigative medicine. Medecine clinique et experimentale.

[40]  J. Simard,et al.  Androgen receptor-mediated stimulation of 17 beta-hydroxysteroid dehydrogenase activity by dihydrotestosterone and medroxyprogesterone acetate in ZR-75-1 human breast cancer cells. , 1993, Endocrinology.

[41]  H. Bonkhoff,et al.  Morphogenese der benignen Prostatahyperplasie und des Prostatakarzinoms , 1998, Der Pathologe.

[42]  F. Labrie,et al.  Stimulation of cell proliferation and estrogenic response by adrenal C19-delta 5-steroids in the ZR-75-1 human breast cancer cell line. , 1986, Cancer research.

[43]  J. Simard,et al.  Structure of two in tandem human 17β-hydroxysteroid dehydrogenase genes , 1990 .

[44]  Crawford,et al.  Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials , 2000, The Lancet.

[45]  J. Simard,et al.  Interleukin‐6 inhibits the potent stimulatory action of androgens, glucocorticoids and interleukin‐1α on apolipoprotein D and GCDFP‐15 expression in human breast cancer cells , 1995, International journal of cancer.

[46]  P. Stewart,et al.  Novel aspects of hormone action: Intracellular ligand supply and its control by a series of tissue specific enzymes , 1992, Molecular and Cellular Endocrinology.

[47]  S. Bulun,et al.  Expression of the CYP19 (aromatase) gene: an unusual case of alternative promoter usage , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  J. McGee,et al.  Macrophages in human breast disease: a quantitative immunohistochemical study. , 1988, British Journal of Cancer.

[49]  J. Simard,et al.  The 3β-Hydroxysteroid Dehydrogenase/Isomerase Gene Family: Lessons from Type II 3β-HSD Congenital Deficiency , 1996 .

[50]  K. O. Elliston,et al.  Expression cloning and characterization of human 17 beta-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20 alpha-hydroxysteroid dehydrogenase activity. , 1993, The Journal of biological chemistry.

[51]  A. Buzdar,et al.  Fadrozole HCL (CGS‐16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: Results of two randomized double blind controlled multiinstitutional trials , 1996, Cancer.

[52]  K. O. Elliston,et al.  Male pseudohermaphroditism caused by mutations of testicular 17β–hydroxysteroid dehydrogenase 3 , 1994, Nature Genetics.

[53]  Sheng-Xiang Lin,et al.  Human 17β-hydroxysteroid dehydrogenase: overproduction using a baculovirus expression system and characterization , 1994, The Journal of Steroid Biochemistry and Molecular Biology.

[54]  A. Purohit,et al.  Regulation of aromatase and sulphatase in breast tumour cells. , 1996, The Journal of endocrinology.

[55]  P. Goodman,et al.  A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. , 1989, The New England journal of medicine.

[56]  S. Bulun,et al.  Aromatase P450 Gene Expression in Human Adipose Tissue. ROLE OF A Jak/STAT PATHWAY IN REGULATION OF THE ADIPOSE-SPECIFIC PROMOTER (*) , 1995, The Journal of Biological Chemistry.

[57]  R. Breitling,et al.  Determination of cDNA, gene structure and chromosomal localization of the novel human 17β‐hydroxysteroid dehydrogenase type 7 , 1999, FEBS letters.

[58]  M. Ernstoff,et al.  Maximum androgen-blockade with medical or surgical castration in advanced prostate cancer: A meta-analysis of nine published randomized controlled trials and 4128 patients using flutamide , 1999, Prostate Cancer and Prostatic Diseases.

[59]  J. Simard,et al.  Molecular biology and genetics of the 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase gene family , 1996 .

[60]  J. Pasqualini,et al.  Importance of estrogen sulfates in breast cancer. , 1989, Journal of steroid biochemistry.

[61]  F. Labrie.  Intracrinology: its impact on prostate cancer , 1993 .

[62]  R. Osathanondh,et al.  The production of progesterone, androgens, and estrogens by granulosa cells, thecal tissue, and stromal tissue from human ovaries in vitro. , 1979, The Journal of clinical endocrinology and metabolism.

[63]  J. L. Napoli,et al.  Cloning of a cDNA for Liver Microsomal Retinol Dehydrogenase , 1995, The Journal of Biological Chemistry.

[64]  M. Reed,et al.  Paracrine influence of human breast stromal fibroblasts on breast epithelial cells: Secretion of a polypeptide which stimulates reductive 17β‐oestradiol dehydrogenase activity , 1988, International Journal of Cancer.

[65]  F. Leenders,et al.  Molecular cloning and amino acid sequence of the porcine 17β‐estradiol dehydrogenase , 1994 .

[66]  B. Brenner,et al.  Downregulation of Ke 6, a novel gene encoded within the major histocompatibility complex, in murine polycystic kidney disease , 1993, Molecular and cellular biology.

[67]  John B. Adams.  Control of secretion and the function of C19-Δ5-steroids of the human adrenal gland , 1985, Molecular and Cellular Endocrinology.

[68]  J. Simard,et al.  DHEA and the Intracrine Formation of Androgens and Estrogens in Peripheral Target Tissues: Its Role during Aging , 1998, Steroids.

[69]  P. Vihko,et al.  Expression of Mouse 17β-Hydroxysteroid Dehydrogenase/17-Ketosteroid Reductase Type 7 in the Ovary, Uterus, and Placenta: Localization from Implantation to Late Pregnancy1. , 2000, Endocrinology.

[70]  G. Secreto,et al.  Testosterone, dihydrotestosterone and oestradiol levels in postmenopausal breast cancer tissues , 1995, The Journal of Steroid Biochemistry and Molecular Biology.

[71]  I. Cardinale,et al.  Decreased adherence of interleukin 6-treated breast carcinoma cells can lead to separation from neighbors after mitosis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[72]  R. Hobkirk.  Steroid sulfation Current concepts , 1993, Trends in Endocrinology & Metabolism.

[73]  M. Poutanen,et al.  Progestin induction of 17β‐hydroxysteroid dehydrogenase enzyme protein in the t‐47D human breast‐cancer cell line , 1990, International journal of cancer.

[74]  E. Adams,et al.  Steroidal regulation of oestradiol-17 beta dehydrogenase activity of the human breast cancer cell line MCF-7. , 1988, The Journal of endocrinology.

[75]  R. Vihko,et al.  Complete amino acid sequence of human placental 17β‐hydroxysteroid dehydrogenase deduced from cDNA , 1988, FEBS letters.

[76]  F. Labrie,et al.  Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in advanced prostate cancer: a marked improvement in response and survival. , 1985, Journal of steroid biochemistry.

[77]  D. Gagné,et al.  Widespread tissue distribution of steroid sulfatase, 3β-hydroxysteroid dehydrogenase/Δ5-Δ4isomerase(3β-HSD), 17β-HSD5α-reductase and aromatase activities in the rhesus monkey , 1994, Molecular and Cellular Endocrinology.

[78]  F. Labrie,et al.  Complete androgen blockade for the treatment of prostate cancer. , 1985, Important advances in oncology.

[79]  P. Sehgal,et al.  Interleukin 6 decreases cell-cell association and increases motility of ductal breast carcinoma cells , 1989, The Journal of experimental medicine.

[80]  J. Simard,et al.  Characterization of cDNAs for human estradiol 17 beta-dehydrogenase and assignment of the gene to chromosome 17: evidence of two mRNA species with distinct 5'-termini in human placenta. , 1989, Molecular endocrinology.

[81]  M. Toi,et al.  Inhibition of colon and breast carcinoma cell growth by interleukin-4. , 1992, Cancer research.

[82]  R. Campbell,et al.  Crystal structure of human estrogenic 17β-hydroxysteroid dehydrogenase complexed with 17β-estradiol , 1996, Nature Structural Biology.

[83]  F. Leenders,et al.  Molecular cloning and amino acid sequence of the porcine 17 beta-estradiol dehydrogenase. , 1994, European journal of biochemistry.

[84]  T. Tosteson,et al.  Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens. , 1997, Urology.

[85]  Sheng-Xiang Lin,et al.  Monte Carlo‐minimized energy profile of estradiol in the ligand‐binding tunnel of 17β‐hydroxysteroid dehydrogenase: Atomic mechanisms of steroid recognition , 2000, Proteins.

[86]  E. Mallon,et al.  Flow cytometric analysis of tumour infiltrating lymphocytes in breast cancer. , 1990, British Journal of Cancer.

[87]  R. Vihko,et al.  Genomic organization and DNA sequences of human 17β‐hydroxysteroid dehydrogenase genes and flanking regions , 1992 .

[88]  P. Vihko,et al.  Expression of mouse 17beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase type 7 in the ovary, uterus, and placenta: localization from implantation to late pregnancy. , 2000, Endocrinology.

[89]  J. Deslypere,et al.  Aromatase, 17 beta-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. , 1986, European journal of cancer & clinical oncology.