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Categories available are: Androgens; Estrogens; Progesterone; Bone: Brain; Breast; Cardiovascular; Formulations; Menopausal Symptoms; Premenopause; Progestin; Safety; Uterus.
1. - The physiologic role and use of estriol. Paoletti J.
Int J Pharm Compounding 2009;13(4)270-275.
Estriol has an important physiological role in the prevention of Breast cancer by balancing the effects of the stronger estrogens, estradiol and estrone, effectively acting as an anti-estrogen. The author explains this phenomenon and explains a rationale for appropriate dosing of estriol relative to estradiol in bioidentical hormone replacement therapy.
Link to Abstract
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2. - The Bioidentical Hormone Debate: Are Bioidentical Hormones (Estradiol, Estriol, and Progesterone) Safer or More Efficacious than Commonly Used Synthetic Versions in Hormone Replacement Therapy? Holtorf K.
Postgrad Med 2009;121(1):1-13.
This literature review presents the substantial evidence for the safety and efficacy of bioidentical hormone therapy, including estradiol, estriol, and progesterone, which shows that it presents lower risks for Breast cancer and cardiovascular disease than synthetic or animal-derived hormones. Studies show that progestins have a number of negative effects on the cardiovascular system and an association with breast cancer risk that can be avoided by using bioidentical progesterone.
Not available on Pubmed
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3. - Progesterone receptor A-regulated gene expression in mammary organoid cultures. Santos SJ, Aupperlee MD, Xie J, Durairaj S, Miksicek R, Conrad SE, Leipprandt JR, Tan YS, Schwartz RC, Haslam SZ.
J Steroid Biochem Mol Biol. 2009;115(3-5):161-72.
This experimental study used Breast cells from mice, cultured in vitro. First, the behavior of the cells was compared after exposure to either progesterone or the synthetic progestin, promogestone. After seeing similar proliferation with both progestogens, they then went on to conduct gene expression studies (again in the mouse mammary cells) using only the promogestone. They found that certain genes were activated by the promogestone, and these were regulated by progesterone receptor A, which is increased relative to progesterone receptor B in more aggressive breast cancers in humans. The researchers imply that the expression of these genes in the cultured mouse breast cells may translate to growth-promoting actions of progesterone in the breast tissue in humans. However, human tissue was not studied here, and the mouse cells under investigation were in an environment very different to that under which they would be growing in the intact mouse. Any conclusions regarding the possibility that progesterone in itself could promote breast cancer in a living human can, therefore, not be inferred from this study. In addition, synthetic progestins are already known to have very different actions to those of progesterone itself in clinical studies. Progesterone has not been shown to cause or exacerbate breast cancer in women; on the contrary, it has been found in clinical studies to be associated with a lower breast cancer risk.
Article on Pubmed
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4. - Unequal risks for Breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Fournier A, Berrino F, Clavel-Chapelon F.
Breast Cancer Res Treat 2008;107(1):103-11.
This large multicenter study in France followed 80,377 postmenopausal women for up to 12 years, and looked in particular at whether the type of progestogen used in combination with estrogen made a difference to the risk of developing Breast cancer in those women who used hormone replacement therapy (HRT). The estrogen in HRT is primarily transdermal estradiol in France. Compared with those women who did not use HRT at all, women using estrogen alone had a 1.29-fold increased risk of developing breast cancer; women using estrogen plus natural progesterone had the same risk as women using no HRT. In women using synthetic progestins in combination with estrogen, the particular progestin used made a difference to breast cancer risk; women using dydrogesterone had a 1.16-fold increased risk of breast cancer, but those using other progestins had a 1.69-fold increased risk of breast cancer, compared to women not using HRT. The authors note that dydrogesterone is the progestin most similar to natural progesterone in its chemical structure and pharmacological effects.
Article on Pubmed
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5. - Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F.
Int J Cancer 2005; 114(3):448-54.
Combined HRT with estrogen (either oral or transdermal) and synthetic progestins was found to carry a significantly increased risk of Breast cancer compared with estrogens plus oral micronized progesterone. In fact, no increase in breast cancer risk was seen in the estrogen plus oral micronized progesterone group compared with estrogen alone. This large multicenter study therefore suggests that there is a dramatic difference between the effects of bioidentical progesterone versus synthetic progestins on breast cancer risk.
Article on Pubmed
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6. - Pregnancy, progesterone and progestins in relation to Breast cancer risk. Campagnoli C, Abba C, Ambroggio S, Peris C.
J Steroid Biochem Mol Biol 2005; 97(5):441-50.
The authors review recent findings that show that the production of progesterone during pregnancy and the use of bioidentical progesterone in hormone therapy do not increase Breast cancer risk, and can even protect against the development of breast cancer.
Article on Pubmed
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7. - Serum sex steroids in premenopausal women and Breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). Kaaks R, Berrino F, Key T, Rinaldi S, Dossus L, Biessy C, Secreto G, Amiano P, Bingham S, Boeing H, Bueno de Mesquita HB, Chang-Claude J, Clavel-Chapelon F, Fournier A, et al.
J Natl Cancer Inst 2005; 97:755-65.
In this large multicenter study, higher serum progesterone levels were associated with a significant reduction in Breast cancer risk.
Article on Pubmed
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8. - Bio-identical steroid hormone replacement: selected observations from 23 years of clinical and laboratory practice. Wright JV.
Ann N Y Acad Sci. 2005;1057:506-24.
This review discusses the types of estrogens used in bioidentical hormone replacement, including their dosages and routes of administration. The author advocates the use of natural hormones because of the problems with using non-human identical synthetic hormones, highlighted largely by the Women's Health Initiative trial. However, bioidentical estrogens must be properly monitored to ensure appropriate dosing, just as is common for thyroid hormone replacement. The metabolism of estradiol to estrone and estriol is discussed. The author advocates the use of iodine supplements, which stimulate the metabolism of estradiol towards estriol. The amount of circulating estriol relative to estradiol and estrone is important in Breast cancer risk: the greater the relative amount of estriol, the lower the breast cancer risk.
Article on Pubmed
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9. - Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone. Friel PN, Hinchcliffe C, Wright JV.
Altern Med Rev 2005;10(1):36-41.
Studies have shown increased Breast cancer risk in women with high levels of estradiol and estrone in their urine. This study therefore investigated urinary estrone and estradiol concentrations in 35 women taking between 0.025 and 2.0 mg/day oral estradiol. Urinary levels of both estrogens increased as the estradiol dosage increased. At doses of 0.25 mg/day or higher, urine estrone levels were higher than seen in non-pregnant premenopausal women, while at doses of 0.5 mg/day or higher, urine estradiol was higher than in non-pregnant premenopausal women. Estradiol given at a dose of 1 mg/day resulted in excessive serum estrone levels. To minimize breast cancer risk, the authors recommend oral estradiol doses no higher than 0.25 mg/day.
Article on Pubmed
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10. - Endogenous estrogen, androgen, and progesterone concentrations and Breast cancer risk among postmenopausal women. Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE.
J Natl Cancer Inst 2004; 96(24):1856-65.
Blood progesterone levels were found not to be related to Breast cancer risk in this first study to investigate this in postmenopausal women. The occurrence of progesterone receptor positive tumors was the tumor type most strongly affected by all the circulating steroid hormones measured except for progesterone. Higher levels of endogenous estrogens and androgens were significantly correlated with increasing breast cancer incidence. This suggests that circulating natural progesterone does not increase breast cancer risk.
Article on Pubmed
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11. - Postmenopausal hormone therapy and change in mammographic density. Greendale GA, Reboussin BA, Slone S, Wasilauskas C, Pike MC, Ursin G.
J Natl Cancer Inst 2003; 95(1):30-7.
Breast cancer risk independently increases with mammographic density. Use of hormone replacement therapy (HRT) postmenopausally is associated with an increase in mammographic density, but the extent of the density increase is unknown. This study evaluated mammograms from 571 of the 875 women enrolled in the PEPI trial at baseline and after 12 months HRT. The women had been randomized to receive placebo, conjugated equine estrogens (CEE) + medroxyprogesterone acetate (MPA) in a continuous or cyclic fashion, or CEE + micronized progesterone (MP). Mammograms were analyzed digitally and a linear regression analysis was utilized to quantify breast density change in all four treatment arms. The adjusted absolute mean changes in mammographic percent density over 12 months were 4.76% (95% confidence interval [CI] = 3.29% to 6.23%), 4.58% (95% CI = 3.19% to 5.97%), and 3.08% (95% CI = 1.65% to 4.51%) for women in the CEE+MPA-cyclic, CEE+MPA-continuous, and CEE-MP groups, respectively. Each of those absolute mean changes was statistically significantly different from the adjusted absolute mean change in mammographic percent density for women in the placebo group, which was -0.07% (95% CI = -1.50% to 1.38%). Greater mammographic density was associated with the use of estrogen/progestin combination therapy, although the micronized progesterone containing arm appeared to induce a smaller increase that that with MPA.
Article on Pubmed
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12. - Part 3 - The science behind bioidentical hormone replacement therapy. Wepfer ST.
Int J Pharm Compounding 2002;6(2):142-6
Differences between synthetic progestins and bioidentical progesterone in terms of their effects on Breast cancer risk, estrogen dominance, and vasomotor symptoms are discussed. The review also covers the use of testosterone for postmenopausal women who have androgen deficiency because of surgically induced menopause. Androgen deficiency is also seen in women receiving estrogen replacement therapy, which reduces bioavailable testosterone because it increases levels of sex hormone binding globulin in the blood. The author concludes that bioidentical hormones are more effective and safer than the synthetic alternatives, but hopes that large trials will soon be conducted to confirm their promising effects.
Link to Abstract
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13. - Progesterone receptor activation - an alternative to SERMs in Breast cancer. Desreux J, Kebers F, Noel A, Francart D, Van Cauwenberge H, Heinen V, Thomas JL, Bernard AM, Paris J, Delansorne R, Foidart JM.
Eur J Cancer 2000;36 Suppl 4:S90-1.
This review emphasizes progesterone’s role in supporting healthy Breast homeostasis and opposing the proliferative effects of estradiol in the breast, unlike synthetic progestins.
Article on Pubmed
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14. - Progesterone effect on cell growth, ultrastructural aspect and estradiol receptors of normal human Breast epithelial (HBE) cells in culture. Malet C, Spritzer P, Guillaumin D, Kuttenn F.
J Steroid Biochem Mol Biol 2000; 73: 171-81.
In a culture system, progesterone was found to have an inhibitory effect on Breast cell growth. When given following estradiol (E2), it limited the stimulatory effect of E2 on cell growth.
Article on Pubmed
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15. - Bcl-2, survivin and variant CD44 v7-v10 are downregulated and p53 is upregulated in Breast cancer cells by progesterone: inhibition of cell growth and induction of apoptosis. Formby B, Wiley TS.
Mol Cell Biochem 1999;202(1-2):53-61.
This study sought to elucidate the mechanism by which progesterone inhibits the proliferation of Breast cancer cells. Utilizing breast cancer cell lines with and without progesterone receptors (T47-D and MDA-231, respectively) in vitro, the authors looked at apoptosis (programmed cell death) in response to progesterone exposure as a possible mechanism. The genetic markers for apoptosis - p53, bcl-2 and surviving, were utilized to determine whether or not the cells underwent apoptosis. The results demonstrated that progesterone does produce a strong antiproliferative effect on breast cancer cell lines containing progesterone receptors, and induced apoptosis. The relatively high levels of progesterone utilized were similar to those seen during the third trimester of human pregnancy.
Article on Pubmed
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16. - Percutaneous progesterone use and risk of Breast cancer: results from a French cohort study of premenopausal women with benign breast disease. Plu-Bureau G, Le MG, Thalabard JC, Sitruk-Ware R, Mauvais-Jarvis P.
Cancer Detect Prev 1999;23(4):290-6.
This cohort study followed 1150 premenopausal French women diagnosed with benign Breast disease. Topical progesterone cream, a common treatment for mastalgia in Europe, had been prescribed to 58% of the women. Follow-up accumulated 12,462 person-years. There was no association noted between progesterone cream use and breast cancer risk. Furthermore, women who had used both progesterone cream and an oral progestogen had a significant decrease in breast cancer risk (RR= 0.5) as compared to women who did not use progesterone cream. There was no significant difference in the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users. These results suggest there are no deleterious effects caused by percutaneous progesterone use in women with benign breast disease.
Article on Pubmed
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17. - Progestins inhibit the growth of MDA-MB-231 cells transfected with progesterone receptor complementary DNA. Lin VC, Ng EH, Aw SE, Tan MG, Ng EH, Chan VS, Ho GH.
Clin Cancer Res 1999;5(2):395-403.
Progesterone is mainly thought to exert its effects via the estrogen-dependent progesterone receptor (PR), the effects of which may be overshadowed by the presence of estrogen. In order to study the independent effects of progesterone on Breast cancer cell lines, PR expression vectors were transfected into a PR and ER negative cell line (MDA-MB-231). The growth of these cells was then studied in response to progesterone and several progestins. Progesterone was found to significantly inhibit DNA synthesis and cell growth in a dose-dependant fashion. The results of this study indicate that progesterone and progestins independent of estrogen have an antiproliferative effect on breast cancer cells via the progesterone receptor. This suggests a possible role in the treatment of PR negative breast cancer via re-activation of the PR receptor.
Article on Pubmed
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18. - Progestins and Breast cancer. Pasqualini JR, Paris J, Sitruk-Ware R, Chetrite G, Botella J.
J Steroid Biochem Mol Biol 1998;65(1-6):225-35.
This review article outlines the many functions of progestogens in hormone-dependent and independent Breast cancer and suggests new clinical applications for their use in the treatment of breast cancer.
Article on Pubmed
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19. - Estradiol and progesterone regulate the proliferation of human Breast epithelial cells. Foidart JM, Colin C, Denoo X, Desreux J, Beliard A, Fournier S, de Lignieres B.
Fertil Steril 1998;69(5):963-9.
In this double-blind randomized study, to evaluate the effects of estrogen and progesterone on normal Breast cells, 40 postmenopausal women received daily topical application of a gel containing either placebo, estradiol, progesterone, or estradiol + progesterone for two weeks prior to esthetic breast surgery or the excision of a benign breast lesion. The results showed that increased estrogen concentration increased the number of cycling epithelial cells, whereas exposure to progesterone for 14 days reduced the estrogen-induced proliferation of normal breast epithelial cells.
Article on Pubmed
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20. - Progesterone inhibits growth and induces apoptosis in Breast cancer cells: inverse effects on Bcl-2 and p53. Formby B, Wiley TS.
Ann Clin Lab Sci 1998;28(6):360-9.
This study explored the mechanism by which progesterone inhibits Breast cancer cell proliferation (growth). In progesterone receptor positive T47-D breast cancer cells, the mechanism of apoptosis appeared to be through the regulation of the genes p53 and bcl-2 by progesterone. These genes control the apoptotic process. It was demonstrated that at progesterone levels that approximate the third trimester of pregnancy, there was a strong antiproliferative effect in at least 2 breast cancer cell lines.
Article on Pubmed
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21. - Serum progesterone and prognosis in operable Breast cancer. Mohr PE, Wang DY, Gregory WM, Richards MA, Fentiman IS.
Br J Cancer 1996;73:1552-5.
Higher blood levels of progesterone measured during surgical treatment of Breast cancers were associated with significantly better survival, especially in women who were node-positive (P<0.01). There was no significant relationship between estradiol levels and survival. This study demonstrated that a higher level of progesterone at time of excision is associated with improved prognosis in women with operable breast cancer.
Article on Pubmed
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22. - The proliferation of normal Breast tissue implanted into athymic nude mice is stimulated by estrogen, but not by progesterone. Laidlaw IJ, Clarke RB, Howell A, Owen AW, Potten CS, Anderson E.
Endocrinology 1995;136(1):164-71.
Normal human Breast tissue was implanted subcutaneously into athymic nude mice. The mice were then treated with estradiol or progesterone such that serum levels approximated those seen in normal menstruating women. Immunocytochemical measures were made of proliferative activity and steroid receptor expression of the tissue implants. It was found that physiologic levels of estradiol significantly stimulated the proliferation of human breast epithelial cells and increased progesterone receptor expression 10-20-fold. Progesterone failed to affect proliferation alone or after estradiol priming.
Article on Pubmed
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23. - Influences of percutaneous administration of estradiol and progesterone on human Breast epithelial cell cycle in vivo. Chang KJ, Lee TT, Linares-Cruz G, Fournier S, de Lignieres B.
Fertil Steril 1995; 63(4):785-91.
The effect of transdermal estradiol (1.5 mg), transdermal progesterone (25 mg), and combined transdermal estradiol and progesterone (1.5 mg and 25 mg) on human Breast epithelial cell cycles was evaluated in vivo. Results demonstrated that estradiol significantly increases cell proliferation, while progesterone significantly decreases cell replication below that observed with placebo. Transdermal progesterone was also shown to reduce estradiol-induced proliferation.
Article on Pubmed
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24. - Double-blind controlled trial of progesterone vaginal cream treatment for cyclical mastodynia in women with benign Breast disease. Nappi C, Affinito P, Di Carlo C, Esposito G, Montemagno U.
J Endocrinol Invest 1992;15(11):801-6.
Eighty regularly menstruating women with mastodynia were studied to evaluate the clinical effectiveness of vaginally administered micronized progesterone. Subjects were randomly assigned to one of two groups, with all participating in a control cycle prior to treatment. One group received 4 grams of vaginal cream containing 2.5% natural progesterone for six cycles from day 19 to day 25 of the cycle. The other group was similarly treated with placebo. Both subjective reporting on a daily basis and clinical examination revealed a significant reduction in Breast pain, defined as 50% reduction, in 64.9% of subjects receiving progesterone and 22.2% of subjects receiving placebo. Effects of breast nodularity were not significant. No side effects were detected.
Article on Pubmed
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25. - Antiestrogen action of progesterone in Breast tissue. Mauvais-Jarvis P, Kuttenn F, Gompel A.
Horm Res 1987;28(2-4):212-8.
In a review of international literature on the cellular effects of progesterone on both normal Breast cells and breast cancer cell lines, the authors conclude that most data indicate progesterone and progestins have an antiestrogenic effect on the breast, as reflected in the decrease in estradiol receptor content, the decrease in cell proliferation, and an increase in a marker of cell differentiation, 17 beta-hydroxysteroid activity, which is mediated by the progesterone receptor.
Article on Pubmed
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26. - Breast cancer incidence in women with a history of progesterone deficiency. Cowan LD, Gordis L, Tonascia JA, Jones GS.
Am J Epidemiol 1981; 114:209-17.
1083 infertile women were followed for 14-34 years. Those who were deficient in progesterone showed a five-fold greater incidence of premenopausal Breast cancer.
Article on Pubmed
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