Natpro Research

Natpro research

Below are some articles which discuss the role of progesterone in woman’s health.

1. – 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

2. – Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. Sayeed I, Stein DG.  Prog Brain Res. 2009;175:219-37.  This review describes the effectiveness of Progesterone in the treatment of traumatic brain injury, and then focuses on its potential role in the treatment of ischemic stroke. Progesterone and its natural metabolites act through numerous mechanisms to exert their neuroprotective activity, and these are described in the review. The authors recommend testing progesterone in clinical trials as a compelling natural treatment for nervous system injuries such as traumatic brain injury and stroke.  Article on Pubmed

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

4. – Transdermal Progesterone: effects on menopausal symptoms and on thrombotic, anticoagulant, and inflammatory factors in postmenopausal women. Stephenson K, Neuenschwander PF, Kurdowska AK, Pinson B, Price C.  Int J Pharm Compounding 2008;12(4):295-304.  In this randomized, placebo-controlled, double-blinded, crossover study, 30 postmenopausal women received either 20 mg/day transdermal Progesterone or placebo for 4 weeks. Menopausal symptoms were significantly improved by the progesterone treatment compared to placebo, and no detrimental effects on any of the clotting or inflammatory factors were seen. This is in contrast to conventional hormone replacement with conjugated equine estrogens and synthetic progestins, which have been found to increase risk of thrombosis and inflammation and thereby impact cardiovascular risk. The authors conclude that transdermal progesterone is a safe alternative for the treatment of menopausal symptoms.  Link to Abstract

5. – Hormone therapy – it’s time for a second opinion. Collins JJ, Ahlgrimm M.  Int J Pharm Compounding 2008;12(7):123-127.  This paper highlights some counterarguments to an opinion piece by the American College of Obstetrics and Gynecologists, which has been widely quoted as evidence against the use of bioidentical hormones. The authors urge clinicians reading the ACOG opinion piece to ask themselves whether it really reflects clinical advances in the use of compounded and FDA-approved bioidentical hormones that have transformed the practice of hormone replacement therapy. They recommend that people read the original research, rather than quoting reviews and opinions that are not well founded in the literature.  Link to Abstract

6. – Cardiovascular effects of medroxyProgesterone acetate and progesterone: a case of mistaken identity? Hermsmeyer RK, Thompson TL, Pohost GM, Kaski JC.  Nat Clin Pract Cardiovasc Med 2008;5(7):387-95.  The authors present the current state of knowledge about the cardiovascular effects of Progesterone compared to medroxyprogesterone acetate (MPA). They caution that the beneficial effects of natural progesterone on cardiovascular risk have been obscured by the negative results of large trials involving hormone therapy that included MPA, in which cardiac risk was seen to increase. The review covers the evidence that natural progesterone actually improves cardiovascular function, and compares oral and transdermal delivery.  Article on Pubmed

7. – Could transdermal estradiol + Progesterone be a safer postmenopausal HRT? A review. L’Hermite M, Simoncini T, Fuller S, Genazzani AR.  Maturitas 2008;60(3-4):185-201.  This detailed review examines the way different types of hormone replacement therapy (HRT) affect the cardiovascular system, the brain, and the risk of breast cancer. It discusses the research that shows that non-oral estrogens have more favorable cardiovascular effects, such as improved blood pressure control and lower risk of thrombosis. It discusses the benefits of using natural Progesterone rather than synthetic progestins in association with estrogens in HRT. Natural progesterone has a beneficial effect on blood vessels and the brain, and confers less or even no risk of breast cancer, compared with synthetic progestins.  Article on Pubmed

8. – Novel perspectives for Progesterone in hormone replacement therapy, with special reference to the nervous system. Schumacher M, Guennoun R, Ghoumari A, Massaad C, Robert F, El-Etr M, Akwa Y, Rajkowski K, Baulieu EE.  Endocr Rev. 2007;28(4):387-439.  The authors describe in detail the neuroprotective effects of Progesterone when used in postmenopausal hormone replacement therapy. They emphasize that natural progesterone has very different properties than synthetic progestins. Medroxyprogesterone acetate actually inhibits the beneficial effects of estradiol on the nervous system and also exerts damaging effects, whereas progesterone does neither. Progesterone is known to have neuroprotective, neurotrophic, and promyelinating effects.  Article on Pubmed

9. – Correcting misconceptions about compounding bioidentical hormones: a review of the literature. Paoletti J.  Int J Pharm Compounding 2007;11(4):269-272.  The author proposes that any physician prescribing compounded bioidentical hormones should be aware of current information published in the scientific literature. There is much published evidence for the afety of bioidentical Progesterone and estrogens, compared to their synthetic alternatives. Unfortunately, some expert advisory groups ignore the published evidence and state opinion rather than fact.  Link to Abstracts

10. – Is Bio-Identical Hormone Replacement Therapy Safer than Traditional Hormone Replacement Therapy? A Critical Appraisal of Cardiovascular Risks in Menopausal Women. Curcio JJ, Wollner DA, Schmidt JW, Kim LS.  Treat Endocrinol. 2006;5(6):367-374.  This review examines currently used bioidentical hormones used as alternatives to conventional hormone replacement therapy. The authors acknowledge that the clinical evidence shows natural Progesterone to be superior to synthetic progestins, because of its more beneficial effects on lipids, the nervous system, and overall quality of life. Oral estriol has been associated with similar adverse effects to oral synthetic estrogens with respect to cardiovascular risks, but there is evidence that transdermal application of estrogens offers a safer alternative that “should be explored”. The authors recommend longer term clinical trials of topical estriol to confirm its cardiovascular safety.  Article on Pubmed

11. – A comprehensive review of the safety and efficacy of bioidentical hormones for the management of menopause and related health risks. Moskowitz D.  Altern Med Rev. 2006 Sep;11(3):208-23.  This review describes the various synthetic estrogens and progestins used in hormone replacement therapy and discusses their safety in relation to natural alternatives. Natural estrogens and Progesterone are being increasingly used in clinical practice and have demonstrated effectiveness in treating menopausal symptoms. They also have improved safety profiles with respect to breast cancer risk and cardiovascular effects.  Article on Pubmed

12. – 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

13. – Over-the-counter Progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product. Hermann AC, Nafziger AN, Victory J, Kulawy R, Rocci ML Jr, Bertino JS Jr.  J Clin Pharmacol 2005; 5(6):614-9.  In 12 healthy, postmenopausal women, steady state levels of Progesterone in the blood were measured in a randomized crossover study comparing topical progesterone cream (Pro-gest®, 40 mg twice daily x 12 days ) with oral micronized progesterone (Prometrium®, 200 mg daily x 12 days). There was no significant difference noted in mean steady state levels between the two products as measured by area under the curve (AUC) of progesterone levels in whole blood. This indicates that equivalent blood levels of progesterone can be achieved with substantially lower doses of topical progesterone cream than with oral micronized progesterone.  Article on Pubmed

14. – 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

15. – The relationship of longitudinal change in reproductive hormones and vasomotor symptoms during the menopausal transition. Randolph JF, Sowers MF, Bondarenko I, Gold EB, Greendale GA, Bromberger JT, Brockwell SE, Matthews KA.  J Clin Endocrinol Metab 2005;90(11):6106-12.  Vasomotor symptoms are experienced by 65-76% of women going through menopause. This study examined longitudinal changes in estradiol, FSH, testosterone, DHEA, sex hormone binding globulin, free estrogen index and free testosterone index, and found that only FSH levels were associated with the prevalence and frequency of vasomotor symptoms.  Article on Pubmed

16. – 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

17. – Transdermal Progesterone cream as an alternative progestin in hormone therapy. Leonetti HB, Landes J, Steinberg D, Anasti JN.  Altern Ther Health Med 2005; 11(6):36-38.  This study evaluated the endometrial effects and determined patients’ acceptance of transdermal Progesterone cream (PC) compared to standard hormone therapy. Healthy menopausal women were recruited and received a pretreatment endometrial biopsy (EMB). They were randomized to 0.625 mg conjugated equine estrogen (CEE) daily and 2.5 mg medroxyprogesterone acetate (MPA) (PremproTM) or daily 0.625 mg CEE and twice daily 20 mg transdermal PC (Pro-gest®). At the end of 6 months, a repeat EMB was obtained, and the women were crossed over to other treatment. A final EMB was performed after the final 6 months. Twenty-six women completed both arms of the study. Seventy-seven percent of women preferred the CEE/PC to the CEE/MPA (P<.001). Of the 52 post-treatment endometrial biopsies: 40 revealed atrophic endometrium and 12 proliferative endometrium (7 in the oral progestin group and 5 in the PC group). There was no evidence of endometrial hyperplasia in any of the specimens. The incidence of vaginal spotting was similar in both groups. Conclusion: Patients preferred transdermal PC over oral MPA. These preliminary data indicate that CEE/PC has a similar effect on the endometrium as standard (CEE/MPA) oral HT over a 6-month period.  Article on Pubmed

18. – Effects of conventional or lower doses of hormone replacement therapy in postmenopausal women. Koh KK, Shin MS, Sakuma I, Ahn JY, Jin DK, Kim HS, Kim DS, Han SH, Chung W-J, Shin EK.  Arterioscler Thromb Vasc Biol 2004; 24:1516-21.  Progesterone together with lower dose conjugated equine estrogens (CEE) had comparable beneficial effects to conventional high dose CEE on flow mediated dilation, high density lipoproteins, and triglycerides, which may suggest that peripheral vascular function in postmenopausal women is markedly improved by direct actions on the vascular wall.   Article on Pubmed

19. – Progesterone enhances functional recovery after middle cerebral artery occlusion in male mice. Gibson CL, Murphy SP.  J Cereb Blood Flow Metab. 2004;24(7):805-13.  Differences in outcomes following ischemia have been noted between men and women, and this is thought to be attributed to sex steroids. This study investigated the potential benefits of Progesterone administration after focal cerebral ischemia of the middle cerebral artery of male mice. Male mice undergoing 60-minute middle cerebral artery occlusion (MCAO) received either progesterone or vehicle following occlusion. The mice receiving progesterone had significantly reduced lesion volume (p< 0.05) when compared with the vehicle treated mice (control). Progesterone treatment also improved survival rate, weight recovery, and motor ability when compared to the control group. In addition, mice treated with progesterone demonstrated motor ability comparable to mice that did not undergo MCAO. The authors suggest the need to further investigate the mechanisms of progesterone action on recovery from cerebral injury.  Article on Pubmed

20. – Effects of Progesterone on the inflammatory response to brain injury in the rat. Grossman KJ, Goss CW, Stein DG.  Brain Res. 2004;1008(1):29-39.  Progesterone has a known anti-inflammatory effect. In this study, male rats treated with progesterone (4 mg/kg) and/or vehicle, were examined with respect to cellular inflammatory response to frontal cortex injury on postsurgical days 1, 3, 5, 7 and 9. The treated mice suffered significantly less edema than untreated mice, as well as showed an increase in the accumulation of activated microglia, demonstrating a neuroprotective effect on the rat brain.  Article on Pubmed

21. – Chronic treatment with Progesterone but not medroxyprogesterone acetate restores the endothelial control of vascular tone in the mesenteric artery of ovariectomized rats. Chataigneau T, Zerr M, Chataigneau M, Hudlett F, Hirn C, Pernot F, Schini-Kerth VB.  Menopause 2004;11(3):255-63.  This study helps explain the more beneficial effects on the cardiovascular system of Progesterone compared with MPA because of its enhancement of the protective effects of endothelial cells on the arterial walls.  Article on Pubmed

22. – 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

23. – Effects of specific post-menopausal hormone therapies on bone mineral density in post-menopausal women: a meta-analysis. Doren M, Nilsson J-A, Johnell O.  Human Reprod 2003;18(8):1737-46.    Article on Pubmed

24. – A perspective on HRT for women: picking up the pieces after the Women’s Health Initiative trial – Part 2. Gillson GR, Zava DT.  Int J Pharm Compounding 2003;7(5):330-8.  The authors review clinical evidence for the benefits of bioidentical Progesterone over synthetic progestins. While both protect the uterine lining from proliferation caused by estrogens, progesterone has beneficial effects on cardiovascular health. The synergy between progesterone and estradiol , each “turning on” the other’s receptors, has the added benefit of allowing the estradiol dosage to be reduced. Oral and transdermal dosing of bioidentical progesterone are discussed.  Link to Abstract

25. – A perspective on HRT for women: picking up the pieces after the Women’s Health Initiative trial – Part 1. Gillson GR, Zava DT.  Int J Pharm Compounding 2003;7(4):250-6.  This article discusses some fundamental aspects of safer hormone replacement therapy that may have been overlooked in the debate surrounding bioidentical versus synthetic hormones: Oral delivery of hormones is not optimal; application of hormones to the skin (transdermal application) has many important advantages; and synthetic progestins are not acceptable as a substitute for natural Progesterone. The evidence for and principles behind these factors are presented.  Link to Abstract

26. – Topical Progesterone cream has antiproliferative effect on estrogen-stimulated endometrium. Leonetti HB, Wilson KJ, Anasti JN.  Fertil Steril 2003;79(1):221-2  This randomized, controlled study involving 58 postmenopausal women demonstrated that topically applied Progesterone cream (Pro-gest®) had an antiproliferative effect in postmenopausal women who had been given oral estrogens x 14 days prior to progesterone treatment. Treatment with topical progesterone did not differ in effects from vaginally applied progesterone (Crinone®), and both progesterone applications demonstrated a significant effect over placebo. Patients preferred the topical application of progesterone cream.  Article on Pubmed

27. – 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

28. – All progestins are not created equal. Stanczyk FZ.  Steroids 2003; 68:879-90.  This paper describes the molecular and pharmacokinetic differences between various progestins and Progesterone. Orally administered progestins require relatively high doses for therapeutic use because of extensive first pass metabolism in the liver. Also, the various molecules show profound differences in progestational activity between human and animal tissues, particularly with respect to androgenicity, which has led to erroneous conclusions being drawn from animal studies regarding androgenicity in humans. The author classifies the various molecules by chemical structure and concludes that they differ widely in metabolism, pharmacokinetics, and potency.  Article on Pubmed

29. – Progestogens in hormonal replacement therapy: new molecules, risks, and benefits. Sitruk-Ware R.  Menopause 2002;9(1):6-15.  The classifications of various progestogens (natural and synthetic) are reviewed in terms of their risks and benefits. This review clearly elucidates the differences in the mode of action of various synthetic progestins as well as Progesterone.  Article on Pubmed

30. – 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

31. – Part 2 – The science behind bioidentical hormone replacement therapy. Wepfer ST.  Int J Pharm Compounding 2002;6(1):50-54  The author describes the differences between natural Progesterone and the synthetic progestin medroxyprogesterone acetate (MPA), saying that the number 1 problem in women’s health care today is a lack of understanding about progesterone and a belief that it is the same thing as MPA. The benefits of progesterone on the heart and bone are discussed.  Link to Abstract

32. – Pharmacokinetic comparison of Progesterone capsules with a progesterone gel after vaginal administration. Kleinstein J, Schlegelmilch R, Mazur D, Vens-Cappell B.  Arzneimittelforschung 2002; 52(8):615-21.  Twenty-four women participated in this randomized controlled, crossover study comparing the bioavailability and pharmacokinetics of a vaginal Progesterone capsule (200 mg/dose) vs a progesterone vaginal gel (90 mg/dose). Both were well tolerated, and no differences were noted with respect to safety. The vaginal capsule delivered more progesterone, however peak concentrations between the two preparations didn’t differ.  Article on Pubmed

33. – Distribution and metabolism of topically applied Progesterone in a rat model. Waddell BJ, O’Leary PC.  J Steroid Biochem Mol Biol 2002; 80(4-5): 449-55.  Following topical application of a commercially available Progesterone cream, concentrations of fat and water-soluble metabolites of progesterone were measured in various tissues (uterus, kidney, salivary gland, liver) as well as plasma and urine. The topically applied progesterone was demonstrated to be well absorbed and had distribution and metabolism patterns similar to that seen with intravascular progesterone delivery.  Article on Pubmed

34. – Intrauterine Progesterone treatment of early endometrial cancer. Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ.  Am J Obstet Gynecol 2002;186(4):651-7.  This study evaluated the use of a Progesterone-releasing IUD as a feasible treatment for early stage endometrial cancer (IA, grade 1). Twelve subjects were followed for 36 months. Results suggested IUD progesterone appeared to resolve some cases of early endometrial cancer.  Article on Pubmed

35. – Twice-weekly transdermal estradiol and vaginal Progesterone as continuous combined hormone replacement therapy in postmenopausal women: a 1-year prospective study. Cicinelli E, de Ziegler D, Galantino P, Pinto V, Barba B, Morgese S, Schonauer S.  Am J Obstet Gynecol 2002;187(3):556-60.  In this study of 35 postmenopausal women, twice-weekly administration of a Progesterone vaginal gel (45 mg P4/day) sufficiently protected the endometrium in women receiving transdermal estradiol (0.05 mg/d) as revealed by endometrial thickness and histology. The authors present vaginally applied progesterone as a viable option for hormone replacement therapy at menopause.  Article on Pubmed

36. – The effects of short-term medroxyProgesterone acetate and micronized progesterone on glucose metabolism and lipid profiles in patients with polycystic ovary syndrome: a prospective randomized study. Bagis T, Gokcel A, Zeyneloglu HB, Tarim E, Kilicdag EB, Haydardedeoglu B.  J Clin Endocrinol Metab 2002;87(10):4536-40.  This randomized prospective study evaluated and compared the effects of ten days treatment with oral and vaginal micronized Progesterone (MP) and medroxyprogesterone acetate (MPA) on glucose metabolism, lipid profiles, and hormonal parameters in 28 patients with polycystic ovary syndrome (PCOS). Oral MPA and oral MP decreased luteinizing hormone (P = 0.028, P = 0.009, respectively) and total testosterone (P = 0.013, P = 0.037, respectively) levels. There was no change in hormonal parameters with vaginal MP. Basal insulin decreased (P = 0.021) and insulin sensitivity increased significantly in the oral MPA group. Low density lipoprotein cholesterol (LDL) and lipoprotein (a) levels decreased only in the MPA group. This study concluded that MPA and oral MP may reduce insulin sensitivity in patients with PCOS. Vaginal MP had no effect on glucose metabolism and lipid profiles.  Article on Pubmed

37. – Effects of progestogens on the postmenopausal breast. De Lignieres B.  Climacteric 2002; 5(3):229-35.  In this review, the author highlights the differences between Progesterone and synthetic progestins in the breast and cautions that progestogens not be “all put in the same bag” with respect to safety and risk of breast cancer. A strong case is made for the protective effect of progesterone on the breast.  Article on Pubmed

38. – Vaginal micronized Progesterone in continuous hormone replacement therapy. A prospective randomized study. Ferrero S, Gerbaldo D, Fulcheri E, Cristoforoni P.  Minerva Ginecol 2002; 54(6):519-30.  Transvaginal micronized Progesterone (100 mg/day for 12 days/month) effectively promoted a functional, secretory endometrium, while cyclic oral medroxyprogesterone acetate or transdermal norethisterone acetate more often produced endometrial atrophy, in women receiving continuous transdermal estradiol.  Article on Pubmed

39. – Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells. Otsuki M, Saito H, Xu X, Sumitani S, Kouhara H, Kishimoto T, Kasayama S.  Arterioscler Thromb Vasc Biol 2001 Feb;21(2):243-8.  This study utilizing human umbilical vein endothelial cells (HUVEC’s) demonstrated that Progesterone, but not medroxyprogesterone acetate (MPA) inhibited expression of vascular cell adhesion molecule-1 (VCAM-1), demonstrating a role for progesterone in the prevention of atherosclerosis. The differing effects of progesterone and MPA are clinically important, as MPA is widely used in hormone replacement therapy, when, as this research suggests, progesterone might be a more appropriate option.  Article on Pubmed

40. – Part 1 – The science behind bioidentical hormone replacement therapy. Wepfer ST.  Int J Pharm Compounding 2001;5(6):10-12  The author defines bioidentical hormone therapy and reviews the scientific literature supporting its use to treat menopausal symptoms, focusing on the 3 estrogens: estrone, estradiol, and estriol, as well as Progesterone and testosterone.  Link to Abstract

41. – Progesterone treatment during the early follicular phase of the menstrual cycle: effects on smoking behavior in women. Sofuoglu M, Babb DA, Hatsukami DK.  Pharmacol Biochem Behav 2001;69(1-2):299-304.  In this unique randomized controlled study, administration of Progesterone (200 mg oral) demonstrated a decrease in craving for and subjective effects of cigarette smoking in female smokers. With progesterone treatment, there was a noted trend to decrease smoking.  Article on Pubmed

42. – Efficacy of Progesterone and progestogens in management of premenstrual syndrome: systematic review. Wyatt K, Dimmock P, Jones P, Obhrai M, O’Brien S.  BMJ 2001;323(7316):776-80.  This systematic review of published studies of Progesterone or progestogens for treatment of PMS found a small positive effect of oral micronized progesterone over placebo in the 3 trials that studied this. No published studies of progesterone cream were found. A statistically, but not clinically, significant improvement was seen with progestogen treatment.  Article on Pubmed

43. – Natural vaginal Progesterone is associated with minimal psychological side effects: a preliminary study. Shantha S, Brooks-Gunn J, Locke RJ, Warren MP.  J Womens Health Gend Based Med 2001;10(10):991-7.  This 3 month, multicenter randomized study evaluated the psychological side effects of a vaginally applied Progesterone gel in reproductive aged women treated for hypothalamic amenorrhea or premature ovarian failure. No differences were noted in psychometric measures as evaluated by the Hopkins Symptom Checklist. Natural progesterone in a vaginal gel can be an effective treatment for women requiring hormone therapy.  Article on Pubmed

44. – Progesterone and progestins: applications in gynecology. de Ziegler D, Fanchin R.  Steroids 2000;65(10-11):671-9.  This paper reviews the use of a transvaginal Progesterone gel as a viable option to other routes of application of natural progesterone (intramuscular, oral micronized), and offered it as a viable option to synthetic progestins given the low incidence of side effects noted in existing studies.  Article on Pubmed

45. – 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

46. – 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

47. – Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination. Baulieu E, Schumacher M.  Steroids 2000;65(10-11):605-12.  This paper reviews the effects of Progesterone on the brain, with special focus on its role in the formation of the myelin sheath surrounding nerve fibers. Other roles of progesterone in the brain include activating GABA receptors, which induces a calming effect.  Article on Pubmed

48. – Salivary, but not serum or urinary levels of Progesterone are elevated after topical application of progesterone cream to pre-and postmenopausal women. O’Leary P, Feddema P, Chan K, Taranto M, Smith M, Evans S.  Clin Endocrinol (Oxf) 2000;53(5):615-20.  Absorption of Progesterone as provided in a topical preparation of “natural” progesterone cream to 6 premenopausal and 6 postmenopausal women was demonstrated via salivary hormone levels. Salivary progesterone concentrations reached their peak 1-4 hrs after application. A five-fold increase in mean levels was seen in the premenopausal group. Serum progesterone levels were not significantly different from baseline in either group, and serum progesterone was not seen as an effective measure of absorption of topically applied progesterone.  Article on Pubmed

49. – Natural Progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, de Ziegler D, Collins P.  J Am Coll Cardiol 2000;36(7):2154-9.  This randomized crossover study compared the effects of estradiol (E2) (2mg/day), estradiol + Progesterone (P4) vaginal gel (2 mg/day + 90 mg on alternate days), and estradiol + medroxyprogesterone acetate (MPA) (2 mg/day + 10 mg/day) on exercise-induced myocardial ischemia in eighteen postmenopausal women with coronary artery disease (CAD) or previous myocardial infarction (MI). Utilizing treadmill testing, patients were evaluated for exercise tolerance after each estradiol phase and at day 10 of each progestogen phase. The results demonstrated an increase in exercise tolerance with both E2 alone and E2 + progesterone, but not by E2 + MPA as compared to baseline. Furthermore, E2 + P4 demonstrated a significant increase in exercise tolerance when compared to MPA. The results suggest that progesterone may be preferred to progestins for hormone replacement therapy in women at risk for cardiovascular disease.  Article on Pubmed

50. – Progestins and cardiovascular risk markers. Sitruk-Ware R.  Steroids 2000; 65(10-11):651-8.  This article reviews the effects of various synthetic progestins and Progesterone on cardiovascular health. Many synthetic progestins, especially 19-nortestosterone and some 17-hyroxyprogesterones, have negative effects on cardiovascular risk factors, whereas natural progesterone does not. Further studies utilizing natural and other steroids should be considered.  Article on Pubmed

51. – Micronized Progesterone in the treatment of imminent necrosis of a myoma during pregnancy. Ultrasound changes during treatment. Hajek Z, Uhlir M.  Ceska Gynekol 1999;64(3):189-92.  Progesterone has a role in increasing blood flow to the uterus during pregnancy. As such, these researchers studied the effect of progesterone treatment to resolve imminent necrosis of a myoma in two cases. Both resolved within several days following oral and vaginal doses of progesterone (300-600 mg/day). Both women went on to deliver healthy, full-term infants.  Article on Pubmed

52. – Progestogens used in menopause. Side effects, mood and quality of life. Sherwin BB.  J Reprod Med 1999;44(2 Suppl):227-32.  This review summarizes the effects of Progesterone on mood and other brain functions. Progesterone receptors are present in many of the same areas of the brain as estrogen receptors, including the limbic system and hypothalamus. The limbic system plays a prominent role in regulating mood and emotion. As a comparison, progesterone decreases brain excitability, while estrogens increase it. This relates to why women with epilepsy have a higher frequency of seizures during the part of the cycle when estrogen levels are high, and a reduced frequency when progesterone levels are high. Estrogen and progesterone may also have differing effects on MAO, thereby affecting concentration of serotonin (a mood elevator) in the brain.  Article on Pubmed

53. – 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

54. – Oral micronized Progesterone. De Lignieres B.  Clin Ther 1999; 21(1):41-60.  This review article examines the rationale for selecting oral micronized Progesterone over synthetic progestins. It reviews research regarding efficacy and safety and concludes that oral micronized progesterone has fewer side effects than synthetic progestins and is a convenient way to deliver natural progesterone.  Article on Pubmed

55. – Percutaneous absorption of Progesterone in postmenopausal women treated with transdermal estrogen. Burry KA, Patton PE, Hermsmeyer K.  Am J Obstet Gynecol 1999;180(6 Pt 1):1504-11.  This pilot study demonstrated a significant increase in serum Progesterone levels in 6 women receiving topical progesterone cream (Pro-gest®; 30-60 mg P4/day) and 17beta estradiol (0.05mg patch). The absorption of progesterone via a topical cream correlated well with estrogen absorption (p< 0.001). They concluded that progesterone cream appeared to be a safe and effective route of application.  Article on Pubmed

56. – Preregistration study on the safety and contraceptive efficacy of a Progesterone-releasing vaginal ring in Chilean nursing women. Massai R, Miranda P, Valdes P, Lavín P, Zepeda A, Casado ME, Silva MA, Fetis G,Bravo C, Chandía O, Peralta O, Croxatto HB, Díaz S.  Contraception 1999;60(1):9-14.  In this long-term controlled study, the safety and efficacy of a Progesterone-releasing vaginal contraceptive device was compared to that of the copper-T 380A IUD in nursing mothers. There was no difference in breastfeeding performance or infant growth between groups. The participants using the progesterone-releasing ring had a longer period of lactational amenorrhea than did the group using the copper T. Women were tracked for over 2000 women-months of exposure in both groups. The Chilean government found the progesterone-releasing ring to be a safe and effective contraceptive alternative.  Article on Pubmed

57. – Micronized Progesterone: clinical indications and comparison with current treatments. Fitzpatrick LA, Good A.  Fertil Steril 1999;72(3):389-97.  The literature reviewed in this tutorial indicates a potential use for oral micronized Progesterone for the treatment of secondary amenorrhea, dysfunctional uterine bleeding, luteal phase disorders, premenopausal bleeding disorders, and as a component of hormone replacement therapy that may provide a better safety profile than commonly utilized synthetic progestins.  Article on Pubmed

58. – Micronized Progesterone: a new option for women’s health care. Wetzel W.  Nurse Pract 1999;24(5):62-6, 71, 75-6.  This paper discusses the use of micronized Progesterone as a safe, effective, and well-tolerated therapy and reviews indications for use. It also includes case studies and issues of patient compliance and the need for an individualized treatment plan for women receiving hormone therapy.  Article on Pubmed

59. – Transdermal Progesterone cream for vasomotor symptoms and postmenopausal bone loss. Leonetti HB, Longo S, Anasti JN.  Obstet Gynecol 1999;94(2):225-8.  In this randomized controlled trial, 102 menopausal women were treated with topical Progesterone (Pro-gest®, 20 mg daily) or placebo and monitored for 1 year. Improvement in vasomotor symptoms was seen in 83% of the women in the treatment group who had experienced hot flashes, compared to 19% in the placebo group (p< .001). There was no difference noted in bone mineral densities between groups after one year. All women studied received a daily multivitamin and 1200 mg calcium.  Article on Pubmed

60. – 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

61. – 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

62. – Progestogen metabolism. Lobo RA.  J Reprod Med 1999; 44(2 Suppl):148-52.  This review clearly elucidates what’s known about the differences in metabolism of various progestins as compared with endogenous or natural Progesterone. Not only are there different pathways for metabolism, but the route of administration also has a significant effect. The physiologic and pathologic state of the patient further influences the metabolism, and there are measurable variations between patients. The authors also review the differences expressed by various tissues in metabolizing progestogens as well as the different biologic potencies of the various progestogens. Most importantly, the authors state the lack of knowledge about the synthetic progestins as compared to natural progesterone, which has a much better understood effect in the body.  Article on Pubmed

63. – 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

64. – Ovarian steroid protection against coronary artery hyperreactivity in rhesus monkeys. Minshall RD, Stanczyk FZ, Miyagawa K, Uchida B, Axthelm M, Novy M, Hermsmeyer K.  J Clin Endocrinol Metab 1998; 83(2):649-59.  MedroxyProgesterone acetate, but not natural progesterone, negated the protective effects of estradiol against coronary artery hyperreactivity.  Article on Pubmed

65. – 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

66. – Urinary ovarian and gonadotropin hormone levels in premenopausal women with low bone mass. Sowers M, Randolph JF Jr, Crutchfield M, Jannausch ML, Shapiro B, Zhang B, La Pietra M.  J Bone Miner Res 1998;13(7):1191-202.    Article on Pubmed

67. – 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

68. – MedroxyProgesterone interferes with ovarian steroid protection against coronary vasospasm. Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K.  Nat Med 1997; 3(3): 324-7.  Ovariectomized rhesus monkeys were treated with physiological levels of 17-beta estradiol in combination with either medroxyProgesterone or progesterone (oral micronized) for four weeks. Following pathophysiological stimulation without injury to induce coronary vasospasm, it was shown that progesterone plus estradiol was protective against vasospasm, whereas estradiol plus medroxyprogesterone allowed vasospasm, concluding that medroxyprogesterone increases risk of coronary vasospasm, while progesterone does not.  Article on Pubmed

69. – Diverse modes of action of Progesterone and its metabolites. Mahesh VB, Brann DW, Hendry LB.  Steroid Biochem Mol Biol 1996;56(1-6):209-19.  A review of the actions of Progesterone and its metabolites demonstrates physiological significance in such biological activities as may have importance in the regulation of stress, post-partum depression, memory, cognition, PMS, and depression, to name a few.  Article on Pubmed

70. – Morphometric, immunohistological and three-dimensional evaluation of the endometrium of menopausal women treated by oestrogen and Crinone®, a new slow-release vaginal Progesterone. Casanas-Roux F, Nisolle M, Marbaix E, Smets M, Bassil S, Donnez J.  Hum Reprod 1996;11(2):357-63.  Twenty estrogen-deprived women were given oral estrogen for 12 days followed by oral estrogen- vaginal Progesterone gel for 12 days. Endometrial evaluation occurred before treatment, after the estrogen-only phase and after estrogen-progesterone gel treatment. Atrophy was present before treatment in all patients. Typical proliferative changes occurred after estrogen-only treatment, and secretory transformation occurred after estrogen-progesterone treatment, indicating that sustained-release progesterone gel can effectively counteract the proliferative effects of estrogen treatment in postmenopausal women.  Article on Pubmed

71. – Luteal support after in-vitro fertilization: Crinone® 8%, a sustained release vaginal Progesterone gel, versus Utrogestan, an oral micronized progesterone. Pouly JL, Bassil S, Frydman R, Hedon B, Nicollet B, Prada Y, Antoine JM, Zambrano R, Donnez J.  Human Reprod 1996;11:2085-89.  90 mg of vaginal estrogen gel daily was compared to 300 mg oral Progesterone daily in a randomized open-label trial of 283 IVF patients. Delivery rates, safety parameters, frequency of spontaneous abortion, ratio of newborn babies to embryo transfer were nearly identical for both groups. The oral progesterone group reported more drowsiness.  Article on Pubmed

72. – 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

73. – 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

74. – An alternative method of hormone replacement therapy using the natural sex steroids. Hargrove JT, Osteen KG.  Menopause 1995;6(4):653-674  The authors present a protocol for hormone replacement therapy in postmenopausal women with low levels of estradiol, testosterone, and DHEA. They advocate individualizing therapy for each woman according to her needs, and monitoring blood levels closely. All postmenopausal women are deficient in Progesterone, so this should also be given unless contraindicated. Hormones should be replaced only up to the levels found in premenopausal women. Natural hormones are preferable to their synthetic counterparts.  Not available on Pubmed

75. – 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

76. – Prevention of endometrial hyperplasia by Progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes. Moyer DL, de Lignieres B, Driguez P, Pez JP.  Fertil Steril 1993;59(5):992-7.  It is often presumed that Progesterone levels must be high enough to induce endometrial bleeding by withdrawal in order to convey protection during estrogen replacement therapy. In this expanded observational study, the authors sought to determine the influence of withdrawal bleedings, secretory transformation, and reduction of mitosis on the prevention of endometrial hyperplasia during long-term estrogen-replacement therapy. Hysteroscopy and endometrial biopsies were utilized to establish maturation patterns, glandular epithelial mitosis rates, and macroscopic endometrial appearance. The results showed an increase in withdrawal bleeding with higher levels of progesterone, with those levels producing distinct secretory responses. However, incidence of endometrial hyperplasia after 5 years of E2/P therapy was independent of secretory changes and withdrawal bleeding, and was more related to the control of mitosis, which was seen even with low doses of progesterone. The authors conclude that a relatively low dose of P may be offered to women seeking hormone replacement therapy with similar levels of endometrial safety.  Article on Pubmed

77. – Low-dose Progesterone therapy in oestrogenised postmenopausal women: effects on plasma lipids, lipoproteins and liver function parameters. Bolaji II, Grimes H, Mortimer G, Tallon DF, Fottrell PF, O’Dwyer EM.  Eur J Obstet Gynecol Reprod Biol 1993;48(1):61-8.  This 12 month prospective, open, non-comparative study measured the effects Progesterone (oral micronized 100mg/day) paired with 0.625 mg conjugated equine estrogens (CEE) and found progesterone had no adverse effects on the lipid profile when combined with CEE. This lack of effect differs from other studies that noted adverse effects on lipid profiles when synthetic progestins were utilized with CEE.  Article on Pubmed

78. – Differentiating between natural Progesterone and synthetic progestogens: clinical implications for premenstrual syndrome management. Martorano JT, Ahlgrimm M, Meyers D.  Compr Ther 1993; 19(3):96-8.  Clinical observations demonstrate that patients suffering from PMS respond to treatment with natural Progesterone, whereas synthetic progestins may exacerbate the condition. The authors review the differences between natural progesterone and synthetic progestins.  Article on Pubmed

79. – 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

80. – Progesterone and the prevention of osteoporosis. Prior JC, Vigna Y, Alojado N.  Canadian Journal of Obstetrics/Gynecology and Women’s Health Care 1991; 3(4):178-84.  In this review article, the authors propose that cyclic Progesterone both prevents bone loss and acts as a bone-builder. The studies discussed focus on abnormal menstrual cycles as an important risk factor for osteoporotic fractures. Their conclusion is that the first step in preventing osteoporosis is treating ovulation disorders.  Not available on Pubmed

81. – Absorption of micronized Progesterone from a nonliquefying vaginal cream. Kimzey LM, Gumowski J, Merriam GR, Grimes GJ Jr, Nelson LM.  Fertil Steril 1991; 56(5):995-6.  The pharmacokinetics are compared between orally administered micronized Progesterone, and that administered through a vaginal cream. Oral progesterone is extensively metabolized prior to reaching the target tissues, and progesterone metabolites may comprise a significant amount of progesterone measured in the serum. When compared, vaginal application sustained progesterone levels over a longer period of time than orally administered progesterone.  Article on Pubmed

82. – Progesterone as a bone-trophic hormone. Prior JC.  Endocr Rev 1990; 11(2):386-98.    Article on Pubmed

83. – Transdermal administration of oestrogen/progestogen hormone replacement therapy. Whitehead MI, Fraser D, Schenkel L, Crook D, Stevenson JC.  Lancet 1990; 335(8685):310-2.  Sixteen estrogen-deficient women were evaluated on a course of transdermal estradiol and transdermal progestogen for five cycles. Regular withdrawal bleeding was noted in all but one patient. Fourteen endometrial biopsies were performed after the fifth cycle, with no evidence of endometrial hyperplasia.  Article on Pubmed

84. – Osteoporosis reversal; the role of Progesterone. Lee JR.  International Clinical Nutrition Review 1990;10(3):384-91.  Transdermal Progesterone supplementation with and without conjugated estrogens was evaluated in a clinical setting using 100 women aged 38 to 83 years. The average time from onset of menopause was 16 years. 63 women were followed for three years with dual photon absorptiometry. Treatment also included dietary changes, nutritional supplements, and exercise. All individuals followed showed an increase in bone mineral density over the three years, with the greatest increase occurring in the first year. There was no difference noted between estrogen/progesterone and progesterone only groups. Subjective changes included increased libido, diminished hot flushes, reduced joint pain, and increased mobility and energy. No side effects were noted during treatment protocol.  Not available on Pubmed

85. – Spinal bone loss and ovulatory disturbances. Prior JC, Vigna YM, Schecter MI, Burgess AE.  N Engl J Med 1990; 323(18):1221-7.  A review of the available data indicates that Progesterone acts to promote bone metabolism. It appears to be independent of estrogen by either acting directly at progesterone receptors, or indirectly through competition at glucocorticoid receptors in the osteoblasts.  Article on Pubmed

86. – Sequential use of norethisterone and natural Progesterone in pre-menopausal bleeding disorders. Saarikoski S, Yliskoski M, Penttila I.  Maturitas 1990; 12(2):89-97.  This randomized controlled study evaluated the effects of norethisterone (NET) and micronized Progesterone (MP) on bleeding disorders in pre-menopausal women. 80 patients were randomized to the trial and all were found via endometrial morphology to need progestogen therapy. They were subsequently treated with NET or MP. In both treatment groups, hyperplastic changes disappeared during the first three cycles, with the duration of treatment being 6 months. NET decreased follicle-stimulating hormone, luteinizing hormone, estradiol and sex-hormone-binding globulin levels (P < 0.001) whereas no changes were seen during MP treatment. High-density-lipoprotein cholesterol and triglyceride levels were also lowered by NET (P< 0.001-0.02) slightly decreased phospholipids. MP treatment had no effect on lipid profiles suggesting it may be a preferred progestogen for the treatment of bleeding disorders.  Article on Pubmed

87. – Transdermal delivery of steroids. Sitruk-Ware R.  Contraception 1989; 39(1): 1-20.  This review summarizes the advantages of delivering steroids through the skin, as well as reviews skin biology. The authors make a strong case for the choice of transdermal delivery of hormones (especially estrogen, Progesterone, and testosterone) for both male and female patients with respect to safety, efficacy, and ease of use and predict this delivery method to make a significant impact on the quality of care for both male and female patients.  Article on Pubmed

88. – Absorption of oral Progesterone is influenced by vehicle and particle size. Hargrove JT, Maxson WS, Wentz AC.  Am J Obstet Gynecol 1989;161(4):948-51.  This small sample study shows that significant serum Progesterone levels can be achieved by oral administration of progesterone. Efficacy of absorption is improved using micronization in oil formulations.  Article on Pubmed

89. – Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and Progesterone. Hargrove JT, Maxson WS, Wentz AC, Burnett LS.  Obstet Gynecol 1989; 73( 4):606-12.  Fifteen menopausal subjects were studied to determine the efficacy and safety of hormone replacement therapy with micronized estradiol (E2) and Progesterone. Ten subjects were given 0.7-E2 (1.05 mg daily) and progesterone (200-300 mg daily) and evaluated over one year at month 0, 1, 3, 6 and 12. Five subjects were administered conjugated estrogens (0.625mg daily) and medroxyprogesterone acetate (10 mg daily) and evaluated at the same intervals. Results showed all 10 women on E2 and progesterone had a decrease in total cholesterol with an increase in HDLs and sustained amenorrhea with no endometrial hyperplasia or withdrawal bleeding after six months of observation. Four of five women in the conjugated estrogen group continued to have withdrawal bleeding without endometrial hyperplasia. HDLs also increased in this group but no significant change in total cholesterol was found.  Article on Pubmed

90. – Sedative and hypnotic effects of oral administration of micronized Progesterone may be mediated through its metabolites. Arafat ES, Hargrove JT, Maxson WS, Desiderio DM, Wentz AC, Andersen RN.  Am J Obstet Gynecol 1988;159(5):1203-9.  This small pilot study evaluated Progesterone and its metabolites following administration of oral micronized progesterone in eight postmenopausal women. Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-mass spectrometry. Evaluation of serial blood samples showed elevated levels of serum progesterone and its metabolites from baseline, reaching a peak between 2 and 6 hours after oral administration. The following compounds: progesterone, 5 beta-pregnan-3 alpha, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 20 beta-diol, and 5 beta-pregnan-3 alpha-ol-11,20-dione, were identified. These compounds have reported anesthetic qualities, which may contribute to the sedative and hypnotic effects seen with oral administration of progesterone. The authors reported that, in one subject, 400 mg of oral micronized progesterone induced a hypnotic state lasting approximately 2 hours.  Article on Pubmed

91. – Oral micronized Progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications–a review. Sitruk-Ware R, Bricaire C, De Lignieres B, Yaneva H, Mauvais-Jarvis P.  Contraception 1987; 36(4): 373-402.  This paper reviews the effects and benefits of oral micronized Progesterone. Progesterone exhibits anti-estrogenic effects, anti-androgenic effects, and anti-mineralocorticoid effects in addition to its progestational effects. No side effects have been reported for micronized progesterone with respect to lipid profile, coagulation, or blood pressure, leading the authors to recommend micronized progesterone as suitable for treatment of PMS, menopause, irregular cycles, and pregnancy maintenance.  Article on Pubmed

92. – 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

93. – Progesterone and the premenstrual syndrome: a double blind crossover trial. Dennerstein L, Spencer-Gardner C, Gotts G, Brown JB, Smith MA, Burrows GD.  Br Med J (Clin Res Ed) 1985; 290(6482): 1617-21.  In this double-blind, placebo-controlled, randomized, crossover trial, oral micronized Progesterone demonstrated effectiveness in alleviating premenstrual complaints. Twenty-three women completed a Beck, et al depression inventory, Moos’s menstrual distress questionnaire, Spielberger, et al state anxiety inventory, and daily symptom diary before and during each treatment. There was an overall benefit of treatment for all variables, except positive moods, restlessness, and interest in sex. For most parameters, maximum benefit was seen within the first month of treatment, demonstrating an effectiveness of progesterone as a viable treatment option for women with PMS.  Article on Pubmed

94. – Natural Progesterone and antihypertensive action. Rylance PB, Brincat M, Lafferty K, De Trafford JC, Brincat S, Parsons V, Studd JW.  Br Med J (Clin Res Ed) 1985;290(6461):13-4.  In a placebo controlled, double blind crossover study, increasing doses of natural Progesterone was given orally to six men and four postmenopausal women with mild to moderate hypertension who were not receiving any other antihypertensive drugs. Compared to before treatment values and to placebo, progesterone caused a significant reduction in blood pressure, suggesting that progesterone has an antihypertensive action rather than a hypertensive one as has been previously thought. The authors suggest this protective effect of progesterone should be investigated further.  Article on Pubmed

95. – Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: A comparison between progestogens and natural Progesterone. Ottosson UB, Johansson BG, von Schoultz B.  Am J Obstet Gynecol 1985;151(6):746-50.  Fifty-eight postmenopausal women were followed with respect to subfractions of high-density lipoprotein during 3 cycles of unopposed estrogen. The women received either levonorgestrel, medroxyProgesterone acetate, or natural progesterone during the last ten days of the treatment period. Both progestogens significantly lowered HDL cholesterol, whereas natural progesterone had no effect on HDL levels.  Article on Pubmed

96. – Oral administration of micronized natural Progesterone in late human pregnancy. Effects on progesterone and estrogen concentrations in the plasma, placenta, and myometrium. Ferre F, Uzan M, Janssens Y, Tanguy G, Jolivet A, Breuiller M, Sureau C, Cedard L.  Am J Obstet Gynecol 1984; 148(1): 26-34.  Levels of Progesterone, 17 beta-estradiol, and estrone were measured in the plasma, in the placenta, and at different sites in myometrium following a single dose of micronized oral progesterone administered to 15 pregnant women immediately prior to elective cesarean section. In comparison to a control group, progesterone levels in the treated women increased in the plasma and myometrium 150 minutes after administration. Placenta progesterone levels did not demonstrate any change. No change was seen in 17 beta-estradiol levels in the plasma or the myometrium, however placental levels were increased. Estrone levels were decreased in the myometrium and in the placenta, and unchanged in the plasma.  Article on Pubmed

97. – 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

98. – The effect of Progesterone and progestogens on the foetus. Dalton K.  Neuropharmacology 1981; 20(12B):1267-9.  This article looks at the differing effects of Progesterone and synthetic progestogens on the fetus. Of note in this article is evidence that progesterone supplementation may reduce episodes of pre-eclampsia. Synthetic progestogen supplementation during pregnancy may produce a variety of side effects. Several references are made to articles documenting cases of masculinization of external genitalia in female babies. There are two known cases of true hermaphroditism and several cases of behavioral problems developing in adolescent girls whose mothers took oral synthetic progestogens during pregnancy. More problematic may be administration of oral estrogen-progestogen preparations. Side effects may include spina bifida, esophageal anomalies, heart defects and limb reduction deformities.  Article on Pubmed

99. – Prenatal Progesterone and educational attainments. Dalton K.  Br J Psychiatry 1976; 129:438-42.  This study compares educational attainments of 34 children whose mothers received prenatal Progesterone with 37 normal and 12 toxemic controls. Results at ages 17-24 showed that progesterone children were more likely to continue schooling after 16 years, a higher number left school with ‘O’ and ‘A’ level grades and more obtained entrance to university. The best academic results were found for children whose mothers had received over 5 grams of progesterone for a minimum of eight weeks, with treatment beginning before week sixteen.  Article on Pubmed

100. – Plasma levels of Progesterone after vaginal, rectal or intramuscular administration of progesterone. Nillius SJ, Johansson ED.  Am J Obstet Gynecol 1971;110(4):470-7.  Plasma levels of Progesterone equivalent to normal luteal phase levels were obtained using 25 mg of injected progesterone or 100 mg via rectal or vaginal administration at 8 hours after administration.  Article on Pubmed

Neuroendocrinology 1998;67:269-274 (DOI: 10.1159/000054322)
Acute Estradiol and Progesterone Administration Reduced Cardiovascular and Catecholamine Responses to Mental Stress in Menopausal Women

Vol. 288, Issue 2, 679-684, February 1999
Finasteride, a 5 -Reductase Inhibitor, Blocks the Anticonvulsant Activity of Progesterone in Mice

J Am Coll Cardiol, 2000; 36:2154-2159
Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise- induced myocardial ischemia in postmenopausal women.

Obstetrics & Gynecology 2000;95:403-406
Direct Transport of Progesterone From Vagina to Uterus

Acta Obstet Gynecol Scand 2001; 80: 972-973
Substantial relief of myopathic disability by progesterone therapy. Myopathy delineates all disorders affecting the human musculature. Myopathies are known to be associated with endocrinological disorders like hypo- and hyperthyroidism, hypo- and hyperparathyroidism and glucocorticoid excess (1). To this date there exists no information of an association between luteal insufficiency and myopathic disorders. We describe here the progesterone treatment of a patient with a most likely congenital myopathy and we show that interdisciplinary cooperation can be fruitful.
(Original in pdf format, no web address available)

American Journal of Obstetrics and Gynecology
Volume 188, Issue 2 , February 2003, Pages 419-424
Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebo-controlled double-blind study.

Exp Clin Endocrinol Diabetes 2003; 111: 267-273
One Year Follow-Up of Hormone Replacement Therapy with Percutaneous Estradiol and Low-Dose Vaginal Natural Progesterone in Women with Mild to Moderate Hypertension

University of Missouri 2010

Breast Cancer Risk Varies Among Different Progestins Used in Hormone Replacement Therapy, MU Researchers Finds

JAMA. 2010;304(15):1719-1720
Postmenopausal Hormone Therapy and Breast Cancer: An Uncertain Trade-off

Medscape October 19, 2010
11-Year WHI Data Show Increase in More Advanced Breast Cancers

Cancer Research October 19, 2010
Tissue-Specific Pathways for Estrogen Regulation of Ovarian Cancer Growth and Metastasis

JAMA. 2010;304(15):1684-1692
Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in Postmenopausal Women

JAMA. 2010;304(15):1719-1720
Postmenopausal Hormone Therapy and Breast Cancer

Medscape October 12, 2010
Hip Fractures Soar When Hormone Therapy Stops

Medscape October 12, 2010
Hormone Therapy Raises CHD Risk in Women With Metabolic Syndrome

Medscape October 13, 2010
Lower Doses of Estrogen in Hormone Therapy Carry Less Cardiovascular Risk

Arch Intern Med. 2010;170(18):1678-1685
Postmenopausal Hormone Use and the Risk of Nephrolithiasis

Arch Intern Med. 2010;170(18):1678-1685
Postmenopausal Hormone Use and the Risk of Nephrolithiasis

Cancer Prevention Research August 10, 2010
Synthetic Progestins Differentially Promote or Prevent 7,12-Dimethylbenz(a)anthracene–Induced Mammary Tumors in Sprague-Dawley Rats

American Association for Cancer Research August 10, 2010 New Findings Further Clarify Breast Cancer Risk With Hormone Therapy

BMJ 2010;340:c2519
Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study

AIM 2010 vol. 152 no. 4 211-217
Coronary Heart Disease in Postmenopausal Recipients of Estrogen Plus Progestin Therapy: Does the Increased Risk Ever Disappear?

ScienceDaily Feb. 19, 2010
Short-Term Heart Disease Risks of Combination Menopausal Hormone Therapy Confirmed

Endocrine-Related Cancer 2009, 16 (1) 85-98
Regression of progestin-accelerated 7,12-dimethylbenz[a]anthracene-induced mammary tumors in Sprague-Dawley rats by p53 reactivation and induction of massive apoptosis: a pilot study

Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD001405
Oestrogen therapy for urinary incontinence in post-menopausal women

The Lancet, Volume 374, Issue 9697, Pages 1243 – 1251, 10 October 2009
Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): a post-hoc analysis of a randomised controlled trial

Hormone Replacement Therapy and Cardiovascular Health in the United States.
Medical Care:May 2009 – Volume 47 – Issue 5 – pp 600-606

The New England Journal of Medicine, Volume 360:573-587 February 5, 2009 Number 6
Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women

ScienceDaily (June 20, 2008)
Complex Changes In The Brain’s Vascular System Occur After Menopause

Arch Intern Med. 2008;168(8):861-866.
Postmenopausal Hormone Therapy and Stroke
Role of Time Since Menopause and Age at Initiation of Hormone Therapy

Medscape March 11, 2008
Estrogen Levels Linked to Risk for Breast Cancer Recurrence

From Heart wire – a professional news service of WebMD March 5, 2008
Breast Cancer Risk Remains After Stopping HRT

ScienceDaily (Apr. 9, 2008
Estrogen Therapy Increases Benign Breast Disease Risk, Study Suggests

University of Oxford 19 April 2007
HRT increases incidence of, and deaths from, ovarian cancer

Medscape Medical News April 24, 2007
Hormone Replacement Therapy Linked to Ovarian Cancer

Metabolism Volume 56, Issue 6, June 2007, Pages 830-837
Addition of medroxyprogesterone acetate to conjugated equine estrogens results in insulin resistance in adipose tissue

JAMA. 2007 Apr;297(13):1465-77
Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.

The FASEB Journal 2007;21:2285-2293.
Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer

CANCERactive Published 2007
HRT increases cancer risk – confirmed yet again

CANCERactive Published 2007
Dramatic fall in Breast Cancer rates points finger at HRT again

BREAST CANCER RESEARCH AND TREATMENT 2006, Volume 101, Number 2, 125-134
Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys

Recent Declines in Hormone Therapy Utilization and Breast Cancer
Incidence: Clinical and Population-Based Evidence

Arch Intern Med 2006;166:772-780.
Postmenopausal Estrogen Use Linked to Elevated Clot Risk in Clinical Trial

Maturitas Volume 52, Issue 1, 16 September 2005, Pages 1-10
New evidence regarding hormone replacement therapies is urgently required. Transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits

JNCI Journal of the National Cancer Institute 2005 97(8):595-602;
Plasma Sex Hormone Concentrations and Subsequent Risk of Breast Cancer Among Women Using Postmenopausal Hormones

Cellular and Molecular Life Sciences (CMLS)
Volume 62, Number 3 / February, 2005
Alzheimer’s disease: the impact of age-related changes in reproductive hormones

Maturitas Volume 49, Issue 4, 10 December 2004, Pages 315-320
Effects of progestins on estrogen-induced increase in C-reactive protein in postmenopausal women

JAMA. 2004;291:47-53.
National Use of Postmenopausal Hormone Therapy
Annual Trends and Response to Recent Evidence

Biological Psychiatry
Volume 55, Issue 4, 15 February 2004, Pages 406-412
Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial

BMJ 2004;328:357-358 (14 February), doi:10.1136/bmj.328.7436.357
Where are we now with hormone replacement therapy?

Annals of Internal Medicine
3 February 2004 | Volume 140 Issue 3 | Pages 184-188
Changes in the Use of Postmenopausal Hormone Therapy after the Publication of Clinical Trial Results

Medscape Dec. 15, 2003
Estrogen Plus Progestin Doubles Risk of Venous Thrombosis

The Lancet Volume 362, Issue 9382, 9 August 2003, Pages 428-432
Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk

The Lancet, Volume 362, Issue 9382, 9 August 2003, Pages 414-415
Breast cancer and hormone-replacement therapy in the Million Women Study

Cancer Causes and Control
Volume 14, Number 2 / March, 2003 , 195-201
Patterns of postmenopausal progestin use with estrogen in relation to endometrial cancer

Maturitas. 2002 Sep 30;43(1):35-9.
Effect of hormone replacement therapy on uterine fibroids in postmenopausal women–a 3-year study.

BJOG: An International Journal of Obstetrics and Gynaecology
Volume 109 Issue 9 Page 1056 – September 2002
A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study

Clinical Therapeutics Volume 21, Issue 1, January 1999, Pages 41-60
Oral micronized progesterone

Contraceptives references

Cochrane Fertility Regulation Group Issue 6, 2010
Copper containing intra-uterine devices versus depot progestogens for contraception

University of Missouri 2010
Breast Cancer Risk Varies Among Different Progestins Used in Hormone Replacement Therapy, MU Researchers Finds

Endocrine-Related Cancer 2009, 16 (1) 85-98
Regression of progestin-accelerated 7,12-dimethylbenz[a]anthracene-induced mammary tumors in Sprague-Dawley rats by p53 reactivation and induction of massive apoptosis: a pilot study

ScienceDaily (Mar. 11, 2008)
Certain Oral Contraceptives May Pose Health Risks, Study Suggests

The Global Library of Women’s Medicine 2008
Pharmacology of Contraceptive Steroids

Medscape November 16, 2007
Oral Contraceptive Use Linked to Small Increase in Cervical Cancer Risk

Metabolism Volume 56, Issue 6, June 2007, Pages 830-837
Addition of medroxyprogesterone acetate to conjugated equine estrogens results in insulin resistance in adipose tissue

Diabetes Care 29:613-617, 2006
Long-Acting Injectable Progestin Contraception and Risk of Type 2 Diabetes in Latino Women With Prior Gestational Diabetes Mellitus

Maturitas Volume 49, Issue 4, 10 December 2004, Pages 315-320
Effects of progestins on estrogen-induced increase in C-reactive protein in postmenopausal women

International Journal of Obesity (2004) 28, 998-1003
Association between C-reactive protein, metabolic cardiovascular risk factors, obesity and oral contraceptive use in young adults

Journal of Thrombosis and Haemostasis Volume 2 Issue 9 Page 1594-1600, September 2004
Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives

Journal of Thrombosis and Haemostasis Volume 1, Issue 7, pages 1371&Mac226; 1380, July 2003
Estrogens, progestogens and thrombosis

Carcinogenesis, Vol. 24, No. 5, 991-1005, May 2003
Predictors of the plasma ratio of 2-hydroxyestrone to 16 – hydroxyestrone among pre-menopausal, nulliparous women from four ethnic groups

Volume 46, Supplement 1, Pages 7-16 (10 December 2003)
Classification and pharmacology of progestins

Diabetes Care 26:216-225, 2003
Effects of Injectable or Implantable Progestin-Only Contraceptives on Insulin-Glucose Metabolism and Diabetes Risk

Best Practice & Research Clinical Obstetrics & Gynaecology Volume 17, Issue 3, June 2003, Pages 509-528
Thrombophilias and gynaecology

Mutat Res. 2002 Nov 26;521(1-2):113-9
Assessment of DNA damage in women using oral contraceptives

Thorax 2001;56:613-616
Exogenous female sex steroid hormones and risk of asthma and asthma-like symptoms: a cross sectional study of the general population

BMJ 1999;318:96-100 (9 January)
Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46 000 women from Royal College of General Practitioners’ oral contraception study

J Microbiol Immunol Infect. 1998 Sep;31(3):197-9
Premenstrual asthma: report of a case with hormonal studies

Human Reproduction, 1998, Vol 13, 3379-3383
The effect of a levonorgestrel-releasing intrauterine system on uterine artery blood flow, hormone concentrations and ovarian cyst formation in fertile women

Annals of Allergy, Asthma and Immunology, Volume 81, Number 3, September 1998 , pp. 243-246(4)
Exacerbation of Premenstrual Asthma Caused by an Oral Contraceptive

BJOG Volume 105 Issue 10 Page 1082 – October 1998
A double-blind randomised placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression and serum hormones

ScienceDaily (Apr. 16, 1997)
Pregnancy, Oral Contraceptives, Hormone Replacement Therapy As Risk Factors For Stroke

J Natl Cancer Inst (1995) 87 (11): 827-835
Oral Contraceptives and Breast Cancer Risk Among Younger Women

The American Journal of Medicine 1995, Volume 98, Issue 1, Supplement 1, Pages S104-S110
The androgenicity of progestins

The Lancet, Volume 344, Issue 8934, Pages 1390 – 1394, 19 November 1994
Oral contraceptive use and adenocarcinoma of cervix

Journal of Internal Medicine Volume 231, Issue 5, pages 561&Mac226; 565, May 1992
Protracted cholestasis probably induced by oral contraceptive

Estrogens, progestogens and thrombosis
Departments of *Clinical Epidemiology, †Haematology, ‡Gynaecology and Reproductive Medicine, Leiden University Medical Center, the Netherlands

Contraceptives May Pose Health Risks, Study Suggests
ScienceDaily (Mar. 11, 2008) – The widely used synthetic progestin medroxyprogesterone acetate (MPA) decreased endothelial function in premenopausal women in a study done at the University of Oregon. The finding, researchers said, raises concerns about long-term effects of MPA and possibly other synthetic hormones on vascular health in young women.

Oral Contraceptive Use Linked to Small Increase in Cervical Cancer Risk November 16, 2007
The use of oral contraceptives is associated with an increase in the risk for invasive cervical cancer, researchers from the International Collaboration of Epidemiological Studies of Cervical Cancer report. An analysis of pooled data from 24 studies, published in the November 10 issue of The Lancet , found that for current users, the relative risk for cancer rises with increasing duration of oral contraceptive use.

Metabolism Volume 56, Issue 6, June 2007, Pages 830-837
Addition of medroxyprogesterone acetate to conjugated equine estrogens results in insulin resistance in adipose tissue

International Journal of Obesity (2004) 28, 998 -1003.
August 2004, Volume 28, Number 8, Pages 998-1003
Association between C-reactive protein, metabolic cardiovascular risk factors, obesity and oral contraceptive use in young adults
CONCLUSION: These findings suggest that obesity is associated with inflammation independent of other cardiovascular risk factors that may contribute to an increased risk for cardiovascular disease in men and women. Elevated CRP related to combined oral contraceptive use may influence the rate of cardiovascular events in young women.

Best Practice & Research Clinical Obstetrics & Gynaecology
Volume 17, Issue 3 , June 2003, Pages 509-528
Thrombophilias and gynaecology
In gynaecology, women are exposed to sex steroids when using oral contraceptives, hormone replacement therapy or when undergoing in vitro fertilization treatment and ovulation induction. Oral contraceptives and the use of hormone replacement therapy increase the risk of venous thrombosis.

Mutation Research/Genetic Toxicology and Environmental Mutagenesis
Volume 521, Issues 1-2 , 26 November 2002, Pages 113-119
Assessment of DNA damage in women using oral contraceptives
This study underscores the fact that prolonged and extensive use of these drugs in our daily life may be hazardous and also, that OC users should be aware of multifactorial risk factors (environmental, genetic and life style patterns) that may be responsible for additional DNA damage.

BJOG: An International Journal of Obstetrics and Gynaecology Volume 105 Issue 10 Page 1082 – October 1998
Norethisterone enanthate: the effect on postnatal depression and serum hormones
Conclusions Long-acting norethisterone enanthate given within 48 hours of delivery is associated with an increased risk of developing postnatal depression and causes suppression of endogenous ovarian hormone secretion.

BMJ 1999;318:96-100 ( 9 January )
Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46 000 women from Royal College of General Practitioners’ oral contraception study. Objective: To describe the long term effects of the use of oral contraceptives on mortality.

Pregnancy, Oral Contraceptives, Hormone Replacement Therapy As Risk Factors For Stroke
ScienceDaily (Apr. 16, 1997) – During the weeks immediately following delivery of a baby, new mothers are at increased risk of strokes, a University of Maryland School of Medicine neurology professor told the American Academy of Neurology meeting in Boston this week.

Journal of the National Cancer Institute 1995 87(11):827-835;
Oral Contraceptives and Breast Cancer Risk Among Younger Women. Among women younger than 45 years, oral contraceptive use for 6 months or longer was associated with an RR for breast cancer of 13 (95% CI = 1.1-1.5). Risks were enhanced for breast cancers occurring prior to age 35 years (RR = 1.7; 95% CI = 1.2-2.6), with the RR rising to 2.2 (95% CI = 1.2-4.1) for users of 10 or more years. The RR for breast cancer for those whose oral contraceptive use began early (before age 18 years) and continued long-term (>10 years) was even higher (RR = 3.1; 95% CI = 1.4-6.7). The RRs observed for those who used oral contraceptives within 5 years of cancer diagnosis were higher than for those who had not, with the effect most marked for women younger than age 35 years (RR = 2.0; 95% CI = 13-3.1). Oral contraceptive associations were also strongest for cancers diagnosed at advanced stages.

Cancer Epidemiology Biomarkers & Prevention
17, 614-620, March 1, 2008. Published Online First March 6, 2008;
Reproductive Steroid Hormones and Recurrence-Free Survival in Women with a History of Breast Cancer

British Journal of Nutrition
April 2008, Volume 99, Issue 04, pp 723-731
“Trans-fatty acids induce pro-inflammatory responses and endothelial cell dysfunction”

Diabetes Care 30:561-567, 2007
Prospective Study of Hyperglycemia and Cancer Risk

J. Biol. Chem, March 12, 2007 10.1074/jbc.M611370200
Epinephrine protects cancer cells from apoptosis via activation of PKA and BAD phosphorylation

Breast Cancer Research and Treatment
Volume 101, Number 2, January 2007 , pp. 125-134(10)
Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys

Eur Urol, 2006 Nov; 50(5):935-9.
Testosterone and Prostate Cancer

Cancer Research 65, 54-65, January 1, 2005
Xenoestrogen Action in Prostate Cancer: Pleiotropic Effects Dependent on Androgen Receptor Status

Reproductive Sciences, Vol. 12, No. 4, 285-292 (2005)
Progesterone-Induced Inhibition of Growth and Differential Regulation of Gene Expression in PRA- and/or PRB-Expressing Endometrial Cancer Cell Lines

JNCI Journal of the National Cancer Institute 2005 97(10):755-765
Serum Sex Steroids in Premenopausal Women and Breast Cancer Risk Within the European Prospective Investigation into Cancer and Nutrition

Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 441-450
Pregnancy, progesterone and progestins in relation to breast cancer risk

BIOLOGY OF REPRODUCTION 73, 586–590 (2005)
Carcinogenic Potential of Ovulatory Genotoxicity

JAMA. 2004;291:1701-1712, 1769-1771
Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy

International Journal of Cancer Volume 114, Issue 3 , Pages 448 – 454
Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort

J Endocrinol. 2003 Oct;179(1):55-62.
‘Overexpression of wild-type p53 gene renders MCF-7 breast cancer cells more sensitive to the antiproliferative effect of progesterone.’

Oncogene. 2003 Oct 9;22(44):6883-90.
‘Progesterone-induced apoptosis in immortalized normal and malignant human ovarian surface epithelial cells involves enhanced expression of FasL’.

BMJ Publishing Group Ltd 2003
‘Women need better information about routine mammography’

Clinical Chimica Acta, 2002; vol. 322: 21-8
‘Hyperhomocysteinemia is a risk factor for cancer and a new potential tumour marker’

Cancer. 2002 Mar 15;94(6):1867-75
‘An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B’ radiation.’

Clinical Cancer Research September 2001 7; 2880
Effect of Progesterone on the Invasive Properties and Tumor Growth of Progesterone Receptor-transfected Breast Cancer Cells MDA-MB-23

J Cell Biochem. 2001;82(3):445-51.
‘Apoptosis induced by progesterone in human ovarian cancer cell line SNU-840.’

Anticancer Res. 2001 Nov-Dec;21(6A):3871-4.
‘Progesterone induces apoptosis in malignant mesothelioma cells.’

Int J Oncol. 2001 Jul;19(1):31-8.
Steroid receptors and hormones in relation to cell proliferation and apoptosis in poorly differentiated epithelial ovarian tumors.

Cancer 2000, Volume 83, Issue 1 , Pages 111 – 121
Progesterone therapy for endometrial carcinoma reduces cell proliferation but does not alter apoptosis

Molecular and Cellular Biochemistry
Volume 202, Numbers 1-2 / December, 1999 Pages 53-61
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

Journal of the National Cancer Institute, 1998, Vol. 90: 1774-86, No. 23,
Hormonal Etiology of Epithelial Ovarian Cancer, With a Hypothesis Concerning the Role of Androgens and Progesterone

Ann Clin Lab Sci. 1998 Nov-Dec;28(6):360-9.,
‘Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53.’

Cancer. 1997 May 15;79(10):1944-50.,
‘Progesterone induces apoptosis and up-regulation of p53 expression in human ovarian carcinoma cell lines.’

Cancer. 1995 May 1;75(9):2233-8.
Mutations of the p53 gene in male breast cancer.

J Am Diet Assoc. 1995 Jun; 95(6):693-7.
‘Implementing a ketogenic diet based on medium-chain triglyceride oil in pediatric patients with cancer.’

J Am Coll Nutr. 1995 Apri14(2):202-8.
‘Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports.’

New England Journal of Medicine 332:1589-1593 June 15, 1995 Number 24
‘The Use of Estrogens and Progestins and the Risk of Breast Cancer in Postmenopausal Women’

Web sites related to cancer and hormones

Research papers related to cancer and hormones…

1. Hormonal Etiology of Epithelial Ovarian Cancer, With a
Hypothesis Concerning the Role of Androgens and

Harvey A. Risch

Evidence for a possible protective role of progesterone in the etiology of ovarian cancer starts with consideration of the increased sex hormone activity during pregnancy. Over the first month of pregnancy, maternal LH and FSH decline strongly with the increase in trophoblast hCG (162). The hCG also stimulates the corpus luteum to continue producing progesterone and not regress (102). After the seventh week, the luteal-placental shift occurs in which the functional capacity of the corpus luteum of pregnancy drops, while the massive placental production of progesterone during pregnancy begins (102). In addition, the placenta extracts maternal (and later, fetal) adrenal androgens, which remain at stable maternal serum concentrations while both production and utilization rates increase; maternal serum estrone and estradiol are made from the adrenal androgens (102). During pregnancy, the placental synthesis thus causes 10-fold increases in maternal circulating progesterone levels (102). Maternal testosterone and androstenedione levels increase some twofold to threefold, although most of the testosterone is bound to the pregnancy-induced higher levels of sex hormonebinding globulin, preventing virilization of female fetuses (102). These maternal ovarian androgens are in any case dwarfed by the huge estrogen and progesterone concentrations. In terms of the pathogenesis of ovarian cancer, we suggest that the additional protective aspect of pregnancy not mediated through suppression of ovulation may be due to the 8–9 months of elevated progesterone. As we have noted, it seems unlikely to be due to the pregnancy estrogens, since most of the evidence relating estrogens to risk of ovarian cancer (as well as to endometrial cancer and perhaps breast cancer) points either to no effect or to increase in risk.”

2. Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 441–450
Pregnancy, progesterone and progestins in relation
to breast cancer risk
Carlo Campagnoli £™, Chiara Abb`a, Simona Ambroggio, Clementina Peris

In the last two decades the prevailing opinion, supported by the “estrogen augmented by progesterone” hypothesis, has been that progesterone contributes to the development of breast cancer (BC). Support for this opinion was provided by the finding that some synthetic progestins, when added to estrogen in hormone replacement therapy (HRT) for menopausal complaints, increase the BC risk more than estrogen alone. However, recent findings suggest that both the production of progesterone during pregnancy and the progesterone endogenously produced or exogenously administered outside pregnancy, does not increase BC risk, and could even be protective. The increased BC risk found with the addition of synthetic progestins to estrogen in HRT seems in all likehood due to the fact that these progestins (medroxyprogesterone acetate and 19-nortestosterone-derivatives) are endowed with some non-progesterone-like effects which can potentiate the proliferative action of estrogens. The use of progestational agents in pregnancy, for example to prevent preterm birth, does not cause concern in relation to BC risk.”
Available data suggest that progesterone produced during pregnancy does not have deleterious effects on BC risk; conversely, it could have a predominant role in the long term protective effect against BC shown by full-term pregnancies. Even outside pregnancy, the balance of the in vivo evidence is that progesterone does not have a cancer-promoting effect on breast tissue. The greater BC risk related to the use of HRT preparations containing estrogen and synthetic progestins seems in all likelihood to be due to the fact that many of the progestins used have several nonprogesterone like actions that potentiate the proliferative effect of estrogens on breast tissue and estrogen-sensitive cancer cells. Particularly relevant seem to be the metabolic and hepatocellular effects (decreased insulin sensitivity, increased levels and activity of IGF-I, and decreased levels of SHBG), which oppose the opposite effects induced by oral
estrogen. The use of progestational agents in pregnancy, e.g. to prevent preterm birth [107,108], does not cause concern in relation to BC risk. On the contrary, progestational agents could even be protective, especially when they succeed in avoiding preterm delivery, a well documented risk factor for the subsequent development of BC”

3. Int J Oncol. 2001 Jul;19(1):31-8.
Steroid receptors and hormones in relation to cell proliferation and apoptosis in poorly differentiated epithelial ovarian tumors.
Lindgren P ,Bäckström T ,Mählck CG ,Ridderheim M ,Cajander S .
Department of Obstetrics and Gynecology, Umeå University, Umeå, Sweden

4. Cancer Volume 83, Issue 1 , Pages 111 – 121
Published Online: 9 Nov 2000
Copyright © 1998 American Cancer Society
Progesterone therapy for endometrial carcinoma reduces cell proliferation but does not alter apoptosis
Makoto Saegusa, M.D. *, Isao Okayasu, M.D.
Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan

5. Reproductive Sciences, Vol. 12, No. 4, 285-292 (2005)
Progesterone-Induced Inhibition of Growth and Differential Regulation of Gene Expression in PRA- and/or PRB-Expressing Endometrial Cancer Cell Lines
Ellen Smid-Koopman, MD, PhD
Liesbeth C. M. Kuhne
Eline E. Hanekamp, PhD
Susanne C.J.P. Gielen, MD
Petra E. De Ruiter, BSc
J. Anton Grootegoed, PhD
Theo J.M. Helmerhorst, MD, PhD
Curt W. Burger, MD, PhD
Albert O. Brinkmann, PhD
Frans J. Huikeshoven, MD, PhD
Departments of Obstetncs and Gynecology, and Reproduction and Development, Erasmus Medical Center, Rotterdam; Department of Obstetncs and Gynecology, Ruwaard van Putten Hospital, Spijkemsse, The Netherlands

6. Source: Breast Cancer Research and Treatment , Volume 101, Number 2, January 2007 , pp. 125-134(10)
Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys
Authors: Wood, Charles 1; Register, Thomas; Lees, Cynthia; Chen, Haiying; Kimrey, Sabrina; Mark Cline, J.

7. International Journal of Cancer
Volume 114, Issue 3 , Pages 448 – 454
Published Online: 18 Nov 2004
Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort
Agnès Fournier 1, Franco Berrino 3, Elio Riboli 2, Valérie Avenel 1, Françoise Clavel-Chapelon 1*
1Equipe E3N, Institut National de la Santé et de la Recherche Médicale (INSERM), Villejuif, France
2Unit of Nutrition and Cancer, International Agency for Research on Cancer (IARC-WHO), Lyon, France
3Department of Preventive and Predictive Medicine, Istituto Nazionale Tumori, Milan, Italy

8. Brigham and Women’s Hospital, Harvard Medical School

Press Release – Jun 11, 2008

Low Melatonin Associated with Increased Risk of Breast Cancer in Postmenopausal Women

Researchers from Brigham and Women’s Hospital have shown in a new study that low melatonin levels are associated with an increased risk of breast cancer in postmenopausal women. This research is published in the June 11, 2008 issue of the Journal of the National Cancer Institute._Melatonin is primarily secreted during the dark hours of a light-dark cycle and has been shown to be low in some night workers. Previous research has found that low melatonin levels in premenopausal women are associated with an increased risk of breast cancer.

Schernhammer and colleagues compared melatonin levels in 178 postmenopausal women and 710 matched controls. All of the women were enrolled in the Hormones and Diet in the Etiology of Breast Cancer Risk study. Researchers report that women with the lowest levels of melatonin had a significantly higher incidence of breast cancer than those with the highest levels.

“Further studies are needed to confirm these data and investigate the mechanisms that underlie the association between melatonin levels and breast cancer risk,” concluded Schernhammer.

This research was funded through a grant from the Department of Defense.

Brigham and Women’s Hospital is a 747-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 860 physician-investigators and renowned biomedical scientists and faculty supported by more than $416 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses’ and Physicians’ Health Studies and the Women’s Health Initiative.

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