Info

ERT, estrogen-replacement therapy EPRT, estrogen-progestin-re-placement therapy GnRHA, gonadotropin-releasing hormone agonist. ERT, estrogen-replacement therapy EPRT, estrogen-progestin-re-placement therapy GnRHA, gonadotropin-releasing hormone agonist. graphic density, although the regimen used may determine the size of the effect. Kaufman et al.19 found that postmenopausal women (n 113) who were on HRT had higher mammographic density than women who had not taken HRT (n 50 odds ratio 2.0 of...

Formation of 5Androstene317Diol and Testosterone

5-Androstene-3j6,17jS-diol and testosterone are formed from DHEA and androstenedione, respectively, through the action of 17 -hydroxys-teroid oxidoreductase, which is commonly referred to as 17j6-hydroxysteroid dehydrogenase (17jS-HSD) the reactions are reversible. Five isoforms of the enzyme, encoded by the 17fi-HSD gene, have been described in humans, each having cell-specific expression, substrate specificity, regulatory mechanisms, and reductase or oxidative catalytic activities. They are...

Inhibition Of Aromatase

Inhibition of estrogen action is generally the first-line adjuvant therapy for patients with metastatic estrogen receptor (ER)-positive breast cancers. Recent trials have demonstrated superiority of aromatase inhibitors such as anas-trozole over traditional estrogen receptor antagonists in this setting,66 and there is therefore much interest in the development of more effective aromatase inhibitors, both as treatment and as preventive agents.67 Estrogen receptor antagonists and aromatase enzyme...

Hormonal Carcinogenesis

It was Furth9 who first tentatively suggested that hormones might be directly carcinogenic not by a genotoxic mechanism per se but by influencing the rate of cell division and thereby increasing the potential for spontaneous mutations. Drawing partially on the work of others, he suggested that while DNA molecules replicate, some copying mistakes might go unrepaired. In fact, the chromosomal instability at mitosis, could produce cells carrying new karyotypes, which are potential ancestors of...

Diethylstilbestrol

Diethylstilbestrol (DES) is a potent synthetic estrogen. Between the late 1940s and the early Figure 6.13 Comparison of the cumulative number of breast cancers expected among never-users of postmenopausal hormone therapy and women who had used it for durations of 5 and 10 years from age 50. Estimated numbers for 1000 women based on breast cancer rates typical of Europe and North America. (Adapted from the Collaborative Group on Hormonal Factors in Breast Cancer.5) Figure 6.13 Comparison of the...

Regulation Of 173hydroxysteroid Dehydrogenase 1 Expression

Besides genetic alterations, abnormal regulation of gene transcription can result in changed protein expression and biological response. An example is the mouse gene for 17HSD8, also known as the ke6 gene, in which no nucleotide alterations have been detected but lack of the regulatory protein of which probably results in recessive polycystic kidney disease.47 To elucidate the mechanisms resulting in the expression, or possible overexpression, of 17HSD1, regulation of HSD17B1 expression in...

John M Rosenfeld Hungying Kao Ronald M Evans

Lipophilic hormones, including steroids, thyroids, and retinoids, regulate complex processes in cellular differentiation, metabolic homeosta-sis, and animal development. Their ability to diffuse into target cells and bind with high affinity and specificity to their cognate intracellular receptors allows these molecules to coordinate physiological responses by regulating the expression of gene networks. The proteins directly involved in transducing these hormonal signals are known broadly as...

Hydroxysteroid Dehydrogenases In Ovarian Function

During the reproductive years of women, the ovary and placenta are the most important single sources of the estrogens secreted into the circulation. Estradiol is produced in the ovarian gran ulosa cells of developing follicles from androgenic precursors of thecal origin.40,41 The granulosa cells are rich in P-450 aromatase and 17HSD1, which convert A-dione to E1 and E1 to E2, respectively. Expression of P-450 aromatase and 17HSD1 is under strict control and associated with the developmental...

Regulation of Cholesterol to Pregnenolone Conversion

P450scc plays a key role in carrying out the conversion of cholesterol to pregnenolone and is subject to many levels of regulation. In the adrenal, gonads, and placenta, P450scc is regulated by various tropic hormones, utilizing cAMP or calcium as intracellular messengers.12 Steroid hormone biosynthesis in the adrenals is stimulated by the pituitary hormone corticotropin, which binds to its receptor at the cell surface and activates adenyl cyclase to increase intra-cellular cAMP. The latter...

Contributors

Department of Genetics and Medicine, Harvard Medical School Massachusetts General Hospital Director, Medical and Population Genetics, Whitehead MIT Center for Genome Research Boston, MA Emily Banks, M.B., B.S., B.Med.Sci., Ph.D. David J. Bentrem, M.D. Department of Surgery and Molecular Pharmacology Northwestern University Medical School Robert H. Luire Comprehensive Cancer Center Chicago, IL Philip Bretsky, M.P.H. Department of Preventive Medicine University of Southern California Keck School...

David J Bentrem V Craig Jordan

Prevention of disease is far superior to treating symptomatic illness. Until recently, the prevention of cancer focused on the identification of environmental carcinogens and the reduction of their exposure to the population. Education to avoid cigarette smoking is an example of primary prevention of lung cancer. Secondary prevention consists of screening individuals at increased risk for malignancy with the assumption that early detection and treatment will affect survival. Mammography and...

The 216aHydroxylated Estrogen Breast Cancer Risk Hypothesis

On the basis of the studies described above, which showed that increased formation of 16a-hydroxylated metabolites relative to 2-hydroxy-lated estrogen metabolites may be associated with an elevated risk of breast cancer, it was hypothesized that a low urinary 2-hydroxyestrone to 16a-hydroxyestrone ratio should be inversely associated with breast cancer risk.144 Development of a competitive-type enzyme immunoas-say (EIA) method for quantifying these metabolites in urine145 allowed the...

Hydroxysteroid Dehydrogenases In Breast Epithelial Cells

Both 17HSD1 and 17HSD2 are expressed in normal breast tissue,23,51 and recent investigations suggest that the oxidative (type 2) activity is the dominant form in nontumorous breast cells.51-53 In a study in which a total of 22 samples was analyzed, 17HSD1 protein was detected in most of the normal breast samples from women having regular menstrual cycles and in all samples from women using hormonal con-traception.23 The type 1 enzyme is expressed in epithelial cells of ducts and alveoli...

References

On the treatment of inoperable cases of carcinoma of the mamma suggestions for a new method of treatment with illustrative cases. Lancet 2 104, 1896. 2. Bittner JJ. The causes and control of mammary cancer in mice. Harvey Lect 42 221, 1946-1947. 3. Bittner JJ. The genesis of breast cancer in mice. Texas Rep Biol Med 10 160, 1952. 4. Rous P, Kidd JG. Conditional neoplasms and subthreshold neoplastic states. J Exp Med 73 365, 1941. 5. Berenblum I. Cocarcinogenesis. Br Med Bull 4 343,...

Italian Study

The third tamoxifen prevention study, performed in Italy, began in October 1992 and randomized 5408 women aged 35-70 to 20 milligrams of tamoxifen or placebo daily for 5 years.161 Originally, 20,000 volunteers without risk factors were sought, but the study was stopped prematurely because of poor recruitment and compliance. Women were required to have had a hysterectomy for a nonneoplastic condition to obviate concerns about an increased risk of endometrial carcinoma. There was no requirement...

Raloxifene

Figure 12.11 Comparison of the molecular structures of new and established selective estrogen receptor modulators. ance, 2 not be cross-resistant with tamoxifen, and 3 have fewer side effects such as a lower incidence of endometrial cancer observed with tamoxifen. Steroidal antiestrogens have been developed and have proven to be antiestrogenic in all target tissues206 through premature destruction of the ER.207,208 The pure antiestrogens are effective in laboratory models as second-line...