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Bioidentical Progesterone helps sleep, hair & lower risks cancer

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Comments

  • Spoonie77
    Spoonie77 Member Posts: 532

    So would I, Salamandra. Gotta say, you are really doing an amazing job giving it all you can on those brands of Tamoxifen. I sure hope one of them works out for you soon.

  • macb04
    macb04 Member Posts: 756

    Thanks so much for sharing that article Marijen. Information about Bioidentical Progesterone lowering risks of breast cancer is why I started this thread.

    I know that my hormone levels tested just prior to diagnosis showed elevated Estrogen, and low levels of Progesterone, exactly what is known as Estrogen Dominance.

    I also feel so much better on a daily dose of Bioidentical Progesterone, 100mg at bedtime. My sleep improved immensely when I started it. I usually sleep through the entire night since being on the Progesterone.

  • macb04
    macb04 Member Posts: 756

    bump

  • GiddyupGirl
    GiddyupGirl Member Posts: 196

    Salamandra - check out lower dose Tamoxifen trials and research. Looks really promising.

  • macb04
    macb04 Member Posts: 756

    Uncovering the Role of Progesterone in the Treatment of Breast Cancer

      July 15, 2015

      Clinicians have long observed that breast cancer patients who are both estrogen receptor (ER) positive and progesterone receptor (PR) positive have better clinical outcomes. These patients tend to respond better to treatment and have a lower risk of relapse, even though they are treated with the same hormone therapy as their ER-positive, PR-negative counterparts.

      Now, researchers from the United Kingdom and Australia have uncovered the molecular underpinnings of why upregulation of both hormone receptors results in better tumor control. Their results, published in Nature, suggest that hormone therapy with progesterone could be used in the treatment of ER-positive, PR-positive disease, which makes up about half of all diagnosed breast cancers.

      Using ER-positive, PR-positive cell-line xenografts, as well as primary ER-positive breast tumor cells excised from patients and grown in a lab, Jason S. Carroll, PhD, of the Cancer Research UK Cambridge Institute, and colleagues observed that the receptors for estrogen and progesterone physically interacted within the cell. They also found that the global gene expression profile of these cells was different when the cells were exposed to estrogen alone vs estrogen plus progesterone and, in the presence of both hormones, was linked to better clinical outcomes.

      Adding progesterone to tamoxifen, the researchers found that the ER is redirected to different transcriptional targets, and its activity is blocked, said Jacqueline F. Bromberg, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, who was not involved in the study.

      Moreover, the use of progesterone with tamoxifen slowed tumor growth compared with either hormone alone in both cells grown in the lab and in breast cancer tumors implanted into mice.

      "[This study] beautifully elucidates a previously unknown function for the PR in modulating the behavior of the ER in breast cancer," said Bromberg.

      While important, the preclinical study cannot yet be directly translated into clinical trials, said Bromberg. All of the experiments in mouse and human models required the addition of estrogen, as well as tamoxifen and progesterone, which is not clinically relevant. Additionally, the type of progesterone used in the study is not one used in clinical practice.

    • WC3
      WC3 Member Posts: 658

      Here's a repost of what I originally wrote on the subject with an important update on the subject of progesterone and HER2 status:

      Progesterone and breast cancer is an interest of mine. I've discovered that it's a complex subject that is not yet very straight forward.

      Certain progestins had been used in the past to treat breast cancer but I can find little information on it. One of them was medroxyprogesterone acetate, which is ironic because that is the progestin implemented in an increase of breast cancer rates in post menopausal women who took HRT to alleviate symptoms of menopause.

      Here is one of the few studies I found on the use of medroxyprogesterone in the treatment of breast cancer.

      Oral medroxyprogesterone acetate in the treatment of metastatic breast cancer.

      As an aside...it seems that not all progestins affect breast cancer risk and breast cancer proliferation equally. Unfortunately many studies do not differentiate between different progestins, but here is a study that sought to distinguish the risk from micronized progesterone (bio identical) from synthetic progestins if you are interested.

      The impact of micronized progesterone on breast cancer risk: a systematic review

      It should be noted they are talking about risk of developing breast cancer, and not the actual effect on already existing breast cancer.

      To continue with using progestins to treat breast cancer...

      There is renewed interest in treating ER+/PR+ breast cancer with progestins, this time I believe bio identical progesterone and there are three clinical trials planned or already under way. The idea is that in hormone receptor positive breast cancer, the progesterone receptors are attached to the estrogen alpha receptors, and when activated, interfere with the ability of the estrogen alpha receptors to be activated.

      Progesterone receptor modulates ERα action in breast cancer

      Here is a nice article on that paper.

      Solving a breast cancer mystery – why do 'double-positive' women do better?

      Here is a link to one of the clinical trials involving progesterone therapy in breast cancer. They are not including people with stsge IV in it but those running the trial might have some information or resources that could be of help.

      A trial looking at progesterone to treat early breast cancer in premenopausal women

      While progesterone may have an inhibitory effect on ER/PR positive breast cancer, it has been implicated in Herceptin resistance in HER2 positive breast cancer.

      Progesterone impairs Herceptin effect on breast cancer cells

      The above study found that the progesterone activated the HER2/HER3 signaling pathway (HER2 receptors are activated and cause cell proliferation by the activation of other HER receptors).

      While the study only briefly mentions it, HER1 which is also called EGFR can also activate HER2.

      Though the above study does not mention it, one of the things that activates HER1 is a compound called amphiregulin, and one of the things that causes the expression of/interacts with amphiregulin is progesterone.

      The only thing I have on that right now are a few papers on amphiregulin, progesterone, estrogen, and breast development and a paper that concluded that amphiregulin confers herceptin resistance in HER2 positive breast cancer.

      Amphiregulin confers trastuzumab resistance via AKT and ERK activation in HER2-positive breast cancer.

      I think we will see studies that better investigate the relation between these things in the future but until then it is difficult to say who progesterone will help and who it will hurt.

      One more thing. One study I found observed a bi phastic effect of progesterone on breast cancer. In some instance they observed cell proliferation and in other inhibition.

      Biphasic Regulation of Breast Cancer Cell Growth by Progesterone: Role of the Cyclin-Dependent Kinase Inhibitors, p21 and p27Kip

      A general disclaimer for the general public: As always, take these studies with a grain of salt. We aren't mice or petri dishes. Research is a discovery process. Conclusions are tentative and sometimes subjective. Biology is complex. And researchers aren't infallible. And make sure your doctor is aware of and onboard with any treatments, medical or alternative that you embark on.

      Edit: I just noticed that the website the paper on medroxyprogesterone as a treatment for metastatic breast cancer has links to more papers on the matter. One details it's use in ER+/PR+ breast cancer specifically.

    • macb04
      macb04 Member Posts: 756

      Nice compilation of studies WC3.

      One thing that seems to be done with some regularity, even in the research studies, is to list Progestins as Progesterone. I have seen the terms used interchangeably, as if a "progestin" is in any way the same molecule, with the same effects as " Bioidentical Progesterone ".

      Are they just being disingenuous, or are they merely sloppy, interchanging the terms that way??? Progestins all seem to have some degree of increased bc risk because they have artificial estogen like effects. That's why HRT, using progestins, was stopped because they increased bc risk substantially.

      I have never seen studies of actual "Bioidentical Progesterone " causing bc or other hormone driven cancers.

    • WC3
      WC3 Member Posts: 658

      macb04:

      I'm not sure why the authors of these studies often use progesterone interchangeably with progestin but it forces me to do it as well when talking about the studies because I don't know of a term that I can use when the authors switch off that encompasses both of them.

      I'm also kind of curious to know why progestins are more commonly used than progesterone but that might be why we don't see many studies on it or hear about it causing cancer to the extent that we hear about progestins causing it.


    • alicebastable
      alicebastable Member Posts: 1,946

      My goodness, with all those claims to curing or alleviating this, that, and the other, will it rotate my tires and walk my dog, too?

      The longer the list of things a drug/compound claims to do, the higher my skepticism rises.

      IMHO.

    • WC3
      WC3 Member Posts: 658

      AliceBastable:

      It actually does do at least a few of those things. It can be a godsend for women who have estrogen dominance. I kind of hate to use the term because it's not widely accepted by the medical community but that is due to lack of peer reviewed studies on the matter and I believe lack of peer reviewed studies is due to the medical community not really caring to illuminate what is referred to as "hormone problems" that so many women face. I really hope that changes in the future. I would like hormone profile monitoring to be a thing in women's health care and when a woman is having "hormone problems", I would like her to know exactly which hormones and how.

      Anyway that's my little rant about that.



    • macb04
      macb04 Member Posts: 756

      Only Progestins ( artificial Progesterone compounds) are used in the manufacturing of Birth Control or mainstream HRT ( an example is Provera).

      These artificial Progestins are able to be patented because of a change in their chemical structure that makes them different than Progesterone.

      The real deal , Progesterone, can not ever be owned as an exclusive product by any one company. Basically, it's all about the money.

    • WC3
      WC3 Member Posts: 658

      That's true. There are generics now which negate patent advantage but maybe the historical precedent persists.

    • macb04
      macb04 Member Posts: 756

      Drug manufacturing is a Billion Dollar Business. I doubt the incentive to patent new formulations ( that differ by only a single chemical bond sometimes) that they can advertise as being somehow " better" ever stops. Remember they've got to keep the Stockholders happy and keep the 6 plus figure saleries coming for their CEO.'s.

      Considerations about my health, your health and that of millions and millions of women will never improve profit margins, and so will never become part of the equation.

    • WC3
      WC3 Member Posts: 658

      I think a lot of doctors are also just uninformed about it. To obtain progesterone cream in the U.S., you either have to buy it online, or have it compounded at a compounding pharmacy which requires a prescription. In my experience, most doctors have never written a prescription for anything that has to be compounded and the idea is a novel one for them. They are often hesitant to recommend natural alternatives to synthetic compounds; for example, Armour or Naturethroid instead of Synthroid, because of concerns over the consistency of the dosing.


    • macb04
      macb04 Member Posts: 756

      WC3, I think you are right about the limitations of their knowledge. It's a damn shame thay sre so poorly educated about how our bodies work, and are instead propagandized into only considering meds from Big Pharma as bioequivalent and effective.

      In reality, these artificial progestins have always been a train wreck waiting to happen. The drug companies could have applied the same diligence to coming up with Bioidentical Progesterone and other hormones, in consistent, reliable dosing.

      Put where is the profit in that?

    • macb04
      macb04 Member Posts: 756


      https://europepmc.org/article/MED/27456847

      Search worldwide, life-sciences literature

      Search

      E.g. "breast cancer" HER2 Smith J

      Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis.

      Asi N1,

      Mohammed K1,

      Haydour Q1,

      Gionfriddo MR2,

      Vargas OL3,

      Prokop LJ4,

      Faubion SS5,

      Murad MH1

      Author information

      Systematic Reviews, 25 Jul 2016, 5(1):121
      DOI: 10.1186/s13643-016-0294-5PMID: 27456847PMCID: PMC4960754

      ReviewFree to read & use

      Share this article Share with emailShare with twitterShare with linkedinShare with facebook

      Abstract

      Use of menopausal hormonal therapy (MHT)-containing estrogen and a synthetic progestin is associated with an increased risk of breast cancer. It is unclear if progesterone in combination with estrogen carries a lower risk of breast cancer. Limited data suggest differences between progesterone and progestins on cardiovascular risk factors, including cholesterol and glucose metabolism. Whether this translates to differences in cardiovascular outcomes is uncertain. We conducted a systematic review and meta-analysis to synthesize the existing evidence about the effect of progesterone in comparison to synthetic progestins, each in combination with estrogens, on the risk of breast cancer and cardiovascular events.We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus through 17 May 2016 for studies that enrolled postmenopausal women using progesterone vs. synthetic progestins and reported the outcomes of interest. Study selection and data extraction were performed by two independent reviewers. Meta-analysis was conducted using the random effects model.We included two cohort studies and one population-based case-control study out of 3410 citations identified by the search. The included studies enrolled 86,881 postmenopausal women with mean age of 59 years and follow-up range from 3 to 20 years. The overall risk of bias of the included cohort studies in the meta-analysis was moderate. There was no data on cardiovascular events. Progesterone was associated with lower breast cancer risk compared to synthetic progestins when each is given in combination with estrogen, relative risk 0.67; 95 % confidence interval 0.55-0.81.Observational studies suggest that in menopausal women, estrogen and progesterone use may be associated with lower breast cancer risk compared to synthetic progestin.

      Occurrences of search terms within full text

      1. ... from native progesterone and from each other [3]. Micronized progesterone is a bioidentical hormone with...
      2. ... progestins, progesterone in combination with estrogen has not been associated with increased breast cancer [8]...

      Figures (2)

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      Free full text

      Logo of sysrevSyst Rev. 2016; 5: 121.

      Published online 2016 Jul 26.doi: 10.1186/s13643-016-0294-5

      PMCID: PMC4960754

      PMID: 27456847

      Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis

      Noor Asi,corresponding author1,7 Khaled Mohammed,1 Qusay Haydour,1,2 Michael R. Gionfriddo,3 Oscar L. Morey Vargas,4 Larry J. Prokop,5 Stephanie S. Faubion,6 and Mohammad Hassan Murad1Author information Article notes Copyright and License informationThis article has been cited by other articles in PMC.

      Abstract

      Background

      Use of menopausal hormonal therapy (MHT)-containing estrogen and a synthetic progestin is associated with an increased risk of breast cancer. It is unclear if progesterone in combination with estrogen carries a lower risk of breast cancer. Limited data suggest differences between progesterone and progestins on cardiovascular risk factors, including cholesterol and glucose metabolism. Whether this translates to differences in cardiovascular outcomes is uncertain. We conducted a systematic review and meta-analysis to synthesize the existing evidence about the effect of progesterone in comparison to synthetic progestins, each in combination with estrogens, on the risk of breast cancer and cardiovascular events.

      Methods

      We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus through 17 May 2016 for studies that enrolled postmenopausal women using progesterone vs. synthetic progestins and reported the outcomes of interest. Study selection and data extraction were performed by two independent reviewers. Meta-analysis was conducted using the random effects model.

      Results

      We included two cohort studies and one population-based case-control study out of 3410 citations identified by the search. The included studies enrolled 86,881 postmenopausal women with mean age of 59 years and follow-up range from 3 to 20 years. The overall risk of bias of the included cohort studies in the meta-analysis was moderate. There was no data on cardiovascular events. Progesterone was associated with lower breast cancer risk compared to synthetic progestins when each is given in combination with estrogen, relative risk 0.67; 95 % confidence interval 0.55–0.81.

      Conclusions

      Observational studies suggest that in menopausal women, estrogen and progesterone use may be associated with lower breast cancer risk compared to synthetic progestin.

      Electronic supplementary material

      The online version of this article (doi:10.1186/s13643-016-0294-5) contains supplementary material, which is available to authorized users.

      Keywords: Progesterone, Synthetic progestins, Breast cancer, Cardiovascular events, Systematic review, Meta-analysis

      Background

      Menopausal hormone therapy (MHT) is highly effective for the treatment of symptoms related to menopause [1]. MHT regimens typically include estrogen and, for women with an intact uterus, a progestin to protect the endometrium from hyperplasia caused by unopposed estrogen. A number of US Food and Drug Administration (FDA)-approved hormone preparations are available for treatment of women with menopausal symptoms [2]. The biochemistry, metabolism, and both beneficial and harmful effects of the various synthetic progestins differ widely from native progesterone and from each other [3].

      Micronized progesterone is a bioidentical hormone with a molecular structure identical to that of endogenous progesterone produced by the ovary. Synthetic progestins have a different chemical structure from progesterone. These compounds mimic some of the effects of progesterone but may have different actions on progesterone receptors [4]. Synthetic progestins may be structurally related to progesterone (e.g., medroxyprogesterone acetate (MPA), dydrogesterone) or to testosterone (e.g., levonorgestrel, drospirenone) with differing potency and pharmacokinetics. The physiologic effects of a particular progestin depend not only on these properties but also on receptor binding. In addition to binding to progesterone receptors, these compounds may also have an affinity for androgen, glucocorticoid, and mineralocorticoid receptors [5].

      Although some data suggest that MHT increases the risk of breast cancer [6], the risk of breast cancer may differ depending on the type of MHT used. For example, MHT containing conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) has been associated with increased risk of breast cancer compared to CEE alone [7]. Further, breast cancer risk may vary between regimens containing different progestins, with some synthetic progestins exhibiting greater risk than others [8]. The effects of progesterone have been shown to be growth-promoting, neutral, or anti-proliferative in breast cells, whereas in women, synthetic progestins, especially the combination of CEE and MPA, have been found to be growth-promoting [9]. In contrast to progestins, progesterone in combination with estrogen has not been associated with increased breast cancer [8]. Emerging evidence suggests that the progesterone receptor acts as a modulator of estrogen receptor α (ERα) binding and transcription, blocking estrogen-mediated cell proliferation. The presence of progesterone receptors in breast cancer that are positive for ERα is associated with positive clinical outcomes [10].

      Progesterone and synthetic progestins also demonstrate varied effects on lipids, coagulation factors, glucose, and insulin and may therefore differentially impact cardiovascular risk, though data are sparse [11].

      The PEPI trial previously demonstrated that, when combined with CEE, progesterone, unlike MPA, did not negate the positive effects of CEE on high-density lipoprotein cholesterol (HDL-C) [7]. A recent randomized, double-blind, placebo-controlled trial utilizing 300 mg of progesterone daily showed no adverse changes in endothelial function, blood pressure, weight, or markers of inflammation or coagulation. Although HDL-C was decreased on treatment, the change was not believed to be clinically relevant [12]. We conducted a systematic review and meta-analysis to synthesize the existing evidence about the effect of progesterone compared to synthetic progestins on the risk of breast cancer and cardiovascular disease.

      Methods

      A predefined protocol was developed by experts from the Endocrine Society to conduct this systematic review. The protocol included explicit criteria for study selection and plans for the data extraction and analysis. We followed the standards set in the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) [13] statement for reporting this review as shown in Additional file 1. This systematic review was submitted for PROSPERO registration but it did not meet registration requirement.

      Eligibility criteria

      We included comparative/controlled studies that enrolled women aged 45–59 years who were within 10 years of menopause and received MHT. The studies had to compare estrogen with progesterone (crystalline progesterone preparations) with any of the synthetic progestins in combination with estrogen and report outcomes of interest for a follow-up period ≥6 months. The outcomes of interest were the risk of breast cancer and cardiovascular disease. We excluded non-comparative studies, case series, and non-original papers.

      Literature search

      The search included the electronic databases of MEDLINE, MEDLINE in-process and other non-indexed citations, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, and Scopus. We expanded the search to include all languages, with the latest date of inclusion to be 17 May 2016. The database search was conducted by an experienced Mayo Clinic reference librarian. Controlled vocabulary supplemented with keywords was used to search for comparative studies of progesterone vs. synthetic progestins and risk of breast cancer and cardiac events. A manual search for the included studies' bibliographies and previous relevant systematic review were also conducted. A detailed search strategy is described in the Additional file 2.

      Study selection

      Using an online reference management system DistillerSR (Distiller SR, Evidence Partners Incorporated, Ontario, Canada), abstracts and titles that resulted from the electronic search strategy were independently evaluated by two reviewers for potential eligibility, and the full-text versions of all potentially eligible studies were obtained. Two reviewers working independently considered the full-text reports for eligibility. The level of agreement between the two reviewers (k level) was 0.7 and 0.8 for abstract screening and full-text screening, respectively. Disagreements were harmonized by consensus and, if not possible, by consensus through arbitration by a third reviewer.

      Data extraction

      Using a standardized, piloted, and web-based form (Distiller SR; Evidence Partners Inc.), two reviewers independently extracted data from each study and later reconciled differences, if present. Reviewers determined the methodological quality of studies and collected descriptive, methodological, and outcome data. We extracted the following variables from the studies: study characteristics (study design, inclusion and exclusion criteria), baseline characteristics, and patient demographics, and outcome data.

      Risk of bias assessment

      We used a modified Newcastle-Ottawa Scale (NOS) [14] to appraise the risk of bias of the observational studies. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) [15] methods.

      Data synthesis and statistical analysis

      We extracted or calculated the relative risk (RR) of the outcomes of interest with 95 % confidence interval (CI). The I2 statistic was used to assess heterogeneity of the treatment effect among studies for each outcome. I2 value >50 % and p value <0.10 of the Cochrane Q test suggested substantial heterogeneity that is due to real differences in study populations, protocols, interventions, and/or outcomes. Publication bias was not assessed due to the small number of the studies included. The statistical analyses using DerSimonian and Laird random effects model were performed with CMA version 2 (Biostat, Englewood, New Jersey).

      Results

      The initial search resulted in 3410 citations. After screening the abstracts, this was limited to 46 potentially relevant articles. These were reviewed in full text by two authors and eventually two cohort studies and one population-based case-control study were included with 44 being excluded for the reasons shown in Fig. 1. The included studies enrolled 86,881 women with a mean age of 59 years and mean follow-up duration of 5 years. None of the studies evaluated the outcome of cardiovascular disease. The studies included are summarized in Table 1. The overall risk of bias of the included cohort studies was moderate. Samples were somewhat representative in the two studies with no baseline imbalance, and the studies were controlled for the most important factors. Table 2 describes the detailed risk of bias assessment of the two included cohort studies.

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      Fig. 1

      Study selection process. The initial search resulted in 3410 citations. After screening the abstracts, this was limited to 46 potentially relevant articles. These were reviewed in full text by two authors and eventually two cohort studies and one population-based case-control study were included with 44 being excluded

      Table 1

      Description of included studies

      StudyStudy populationAge (mean) ±SDLocationGroup 1Group 2Type and route of estrogenFollow-up (mean) in yearsOutcomes
      Espie et al. [16]4949 postmenopausal women were included in two groups: exposed group, 2693 postmenopausal women who were receiving MHT or who stopped <5 years, and unexposed group, 2256 postmenopausal women who had never received MHT or who had stopped >5 years.
      MHT regimes were estradiol alone (351 postmenopausal women), estradiol+natural progesterone and estradiol+synthetic progestins (excluding medroxyprogesterone acetate and 19-nortestosterone derivatives)
      60.6±6.3 for exposed group, 64.2±8.3 for unexposed groupFranceEstradiol+natural progesterone
      N1=999
      Estradiol+synthetic progestins (excluding medroxyprogesterone acetate and 19-nortestosterone derivatives)
      N2=1272
      Estradiol transdermal in 78 % and oral in 22 %2.5Breast cancer risk
      Fournier et al. 2008 [8]80,377 postmenopausal women were included in two groups: MHT never-users with 23,703 postmenopausal women and MHT ever-users with 56,674 postmenopausal women.
      MHT regimes were estrogen alone, estrogen+progesterone, estrogen+dydrogesterone, estrogen+other progestins, weak estrogens and other unknown MHT
      (almost exclusively estradiol compounds)
      55.0±4.8 for MHT never-users, 52.3±4.1 for MHT ever-usersFranceEstrogen+progesterone (almost exclusively estradiol compounds)Estrogen+synthetic progestins (almost exclusively estradiol compounds)Postmenopausal women received either oral or transdermal estrogen (% not reported)8.1Breast cancer risk
      Cordina-Duverger et al. 2013 [17]1555 postmenopausal woman, 739 cases treated with combined estrogen and progestagen. 816 controlsRange (25–75)FranceEstrogen+progesterone: 25 cases and 34 controlsEstrogen+synthetic progestins : 55 cases and 43 controlsNot specified4Breast cancer risk

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      MHT menopausal hormone therapy

      Table 3

      The effect of progesterone vs. synthetic progestins in combination with estrogen on breast cancer incidence

      StudyGroup 1Incidence of breast cancer in group 1Group 2Incidence of breast cancer in group 2Relative risk (RR)95 % confidence interval (95 % CI)
      Espie et al. 2007 [16]Estradiol+progesterone4/999Estradiol+synthetic progestina12/12720.420.13–1.31
      Fournier et al. 2008 [8]Estrogen+progesterone (almost exclusively estradiol compounds)129/40,537 person-yearsEstrogen+synthetic progestin (almost exclusively estradiol compounds)635/135,288 person-years0.680.56–0.82
      Estrogen+progesterone (almost exclusively estradiol compounds)129/40,537 person-yearsEstrogen+synthetic progestinb (almost exclusively estradiol compounds)606/128,253 person-years0.670.76–0.81

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      aThis study excluded users of medroxyprogesterone acetate and 19-nortestosterone derivatives

      bThis is a partial cohort that does not include users of medroxyprogesterone acetate from the analysis

      Meta-analysis

      Based on the meta-analysis of the two included cohort studies, progesterone was found to be associated with lower breast cancer risk compared to synthetic progestins in combination with estrogen (RR=0.67, (95 % CI 0.55–0.81) I2=42 % with p value of <0.0001). The quality of evidence was low due to the observational nature of the study design, and Fig. 2 shows the results. Sensitivity analysis was done to exclude postmenopausal women receiving synthetic progestins other than medroxyprogesterone acetate. The number of breast cancer events in women receiving medroxyprogesterone acetate was 29 in 7035 person-years as reported in the study by Fournier et al. [8]. The sensitivity analysis shows no change in results (RR=0.67 (95 % CI 0.76–0.81) with p value of <0.0001).

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      Fig. 2

      Random effects model of breast cancer risk in postmenopausal women receiving estrogen with progesterone vs. synthetic progestins. This figure shows that progesterone was found to be associated with lower breast cancer compared to synthetic progestins in combination with estrogen

      The effect of combined estradiol and progesterone in comparison with estradiol and synthetic progestin on breast cancer incidence showed a RR 0.42 (95 % CI 0.13–1.31) in Espie [16], whereas Fournier [8] showed a RR 0.68 (95 % CI 0.56–0.82) when comparing postmenopausal women who received estrogen and progesterone to those who received estrogen and synthetic progestin as shown in Table 3.

      Table 4

      The relative risk (95 %) for breast cancer according to the route of administration of estradiol and the type of progestogen used

      Study nameType of MHTProgesteroneSynthetic progestins
      Espie et al. 2007 [16]Oral estradiolNR0.81 (0.23–2.85)
      Transdermal estradiol0.46 (0.13–1.62)1.07 (0.50–2.27)

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      NR not reported in the study

      The study by Espie [16] reported the route of administration of estradiol where 2101 patients (78 %) received transdermal estradiol and 592 (22 %) received oral estradiol. Subgroup analysis was done based on the route of administration, and no differential effect on the risk of breast cancer was apparent between oral and transdermal routes of administration as shown in Table 4.

      Table 2

      Risk of bias assessment of the included studies

      StudyRepresentativeness of the exposed cohortSelection of the non-exposed cohortAscertainment of exposureOutcome of interest was not present at start of studyComparability of cohortsAssessment of outcomeAdequacy of follow-up cohort
      Espie et al. 2007 [16]Somehow representativeDrawn from the same communityNo descriptionYesStudy control for most important factorsNo descriptionYes
      Fournier et al. 2008 [8]Somehow representativeDrawn from the same communityWritten self-report questionnairesYesStudy control for most important factorsSelf-report questionnaires or files of health insurance plan. (Pathology reports were obtained in 96 % of cases)Yes

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      We also identified a population-based case-control study that reported similar results. The study showed no significant increased risk of breast cancer among women treated with progesterone in combination with estrogen, odds ratio (OR) 0.80 (CI 95 % 0.44–1.43). However, there was a non-significantly increased risk of breast cancer among users of estrogen with synthetic progestins, OR 1.57 (95 % CI 0.99–2.49) [17].

      Discussion

      Based on this systematic review and meta-analysis, progesterone may be associated with lower breast cancer risk compared to synthetic progestins, when each is given in combination with estrogen. No studies have been found reporting on the risk of cardiovascular disease in postmenopausal woman receiving estrogen with progesterone vs. those who are receiving estrogen with synthetic progestins, and no previous systematic reviews have evaluated this question.

      Progestin is utilized in MHT regimens for women with an intact uterus to prevent endometrial hyperplasia. Progestins used for MHT regimens can be administered orally, transdermally (patch containing norethisterone/norethindrone), or directly to the endometrium (levonorgestrel intrauterine system). While the levonorgestrel intrauterine system has been shown to be adequate for endometrial protection [18], it is not currently approved by the US FDA for this indication.

      The potential role of progestins in increasing breast cancer risk associated with MHT has come under greater scrutiny after the Women's Health Initiative trial suggested increased risk of breast cancer with continuous use of CEE and MPA for greater than 5 years compared with CEE alone, which showed no increased risk [19]. In fact, CEE alone was associated with a lower risk of breast cancer than placebo after 11 years of observation [20].

      Both progesterone and synthetic progestins and the dosing regimen may impact breast cancer risk. In the E3N cohort study, MHT regimens containing estrogen and progesterone or dydrogesterone were not associated with a statistically significant increase in breast cancer risk. All other progestins were associated with an increased risk, with no difference between various progestins [8]. The results of this meta-analysis (which includes the E3N study) are consistent with these findings and show a decreased risk of breast cancer associated with the use of progesterone compared with a progestin (RR=0.67 (95 % CI 0.76–0.81)).

      Progesterone and synthetic progestins may be administered continuously with estrogen or sequentially for 10–14 days per month. Some, but not all, studies comparing these regimens have shown increased risk of breast cancer with continuous dosing compared to sequential dosing [2123]. Randomized clinical trials are needed to clarify these findings.

      Clinical implications

      Accumulating evidence suggests that important differences in risks and benefits exist between various MHT regimens, making individualization of MHT essential. Women with an intact uterus require the use of progesterone for endometrial protection when using systemic estrogen therapy for the management of menopausal symptoms. While an additional study is needed to confirm these results, data suggest lower risk of breast cancer with progesterone and dydrogesterone and do not support a class effect of progestins on breast cancer risk [24]. More studies are needed to define a potential difference in cardiovascular risk between progesterone and synthetic progestins.

      Strengths and limitations

      The strength of our review relates to following a predefined protocol, rigorous database search, and duplicate study selection and data extraction. The main limitations are the observational nature of the evidence, which lowers the confidence in the estimates, and the small number of studies included. We were unable to ascertain the presence and impact of publication bias due to the small number of studies. In terms of the individual studies, the major strength of the Fournier study [8] was the inclusion of multiple menopausal hormonal therapies: the regular follow-up implemented in the study. It was the first epidemiological study to provide results indicating that estrogen-progesterone and estrogen-dydrogesterone combinations may be the least harmful MHT in terms of breast cancer risk. However, the results cannot be translated into firm clinical recommendations. The strength of the Espie study [16] was that they studied the previous use of progestins prior to menopause. They found that it had no influence on the risk of breast cancer irrespective of whether or not the women were subsequently exposed to MHT. One limitation of that study was that it was influenced by the common practice in France in which gynecologist avoided prescribing MHT to high-risk women. Lastly, the results of this review are largely influenced by a single large study.

      Conclusions

      Observational studies suggest that in menopausal women taking estrogen, progesterone use may be associated with lower breast cancer risk compared to synthetic progestin.

      Abbreviations

      MHT, menopausal hormone therapy; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate; HDL-C, high-density lipoprotein cholesterol; CI, confidence interval; RR, relative risk; OR, odds ratio; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analysis; NOS, Newcastle-Ottawa Scale; GRADE, Grading of Recommendations Assessment, Development and Evaluation

      Acknowledgements

      Michael Gionfriddo was supported by a CTSA Grant Number TL1 TR000137 from the National Center for Advancing Translational Science (NCATS). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

      Authors' contributions

      NA, QH, MG, and OM participated in the data collection. NA, KM, SF, and MM participated and drafted the manuscript. NA and KM performed the statistical analysis. NA, KM, and MM participated in the analysis and interpretation. SF and MM critically revised the article. SF and MM approved the final revision of the review. All authors approved the final manuscript.

      Competing interests

      This review was funded by a contract from the Endocrine Society. The Endocrine Society as the funder had no role in literature search, statistical analysis, or the wording of the final report. Michael Gionfriddo was supported by CTSA Grant Number TL1 TR000137 from the National Center for Advancing Translational Science (NCATS). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

      Additional files

      Additional file 1:(85K, pdf)

      PRISMA 2009 checklist. We followed the standards set in the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement for reporting this review. (PDF 84 kb)

      Additional file 2:(63K, pdf)

      Detailed search strategy. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus through August 2013 (updated search through 17 May 2016 yielded 457 additional abstracts) for studies that enrolled postmenopausal women using progesterone vs. synthetic progestins and reported the outcomes of interest. (PDF 63 kb)

      Contributor Information

      Noor Asi, Phone: (507) 266-2904, Email: ude.oyam@roon.isa, Email: moc.liamtoh@78isaroon.

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      References

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    • marijen
      marijen Member Posts: 2,181

      Bump

    • macb04
      macb04 Member Posts: 756

      Thanks for keeping the thread alive Marijen

    • jons_girl
      jons_girl Member Posts: 461

      I was high estrogen and progesterone receptor positive. I’m skeptical. I have tried natural progesterone in my lifetime. But I still got Br cancer.

      I agree tho the manufactured hormones aren’t good. My gma was free of breast cancer after taking tamoxifen for 7+yrs. she finished taking it and asked her gyn for hormones. Within a year she was dead. Cancer (Br) returned and metastasized. It was horrible to watch her go down so fast. This was due to the manufactured hrt she took I believe.

      I know your not speaking of that kind of hormone....

      I’ve just joined the menopause club. And I’d love to take natural hrt. I’m having joint pain. I’m just worried to try that....my grmas experience will be seared into my brain the rest of my life. Even tho it’s different it’s still hormones....

    • havefaithtoday
      havefaithtoday Member Posts: 88

      I just came across this post. Very interesting info. Thank you!

      Prior to being diagnosed with BC (ER+/PR+) I was on Bioidentical Progesterone pills and Bioidentical Testesterone cream that I got from a compounded pharmacy (my functional Dr prescribed). When I was diagnosed, my MO told me to immediately go off both and I asked her if the may have caused the BC, she said 'They certainly didn't help'.

      Now I'm in Menopause (thanks to chemo) and I'm on Anastrazole. I'm struggling with the many Menopausal symptoms and side effects of Anastrazole. I'd love to be able to add back in the Bioidentical Progesterone. But my MO said NO hormones at all. Ughhhhh

    • macb04
      macb04 Member Posts: 756

      Estrogen has basically one roll, push cell growth. That's it. Pushes growth of uterine lining/ovarian follicles and breast cells for reproduction.

      Different Estrogens are more or less “ proliferative" on cells with ER receptors.

      Your body makes three main types of estrogen:

      • Estradiol (E2): the most common type in women of childbearing age.
      • Estriol (E3): the main estrogen during pregnancy.
      • Estrone (E1): the only estrogen your body makes after menopause (when menstrual periods stop)

      Aug 1, 2018imageHormone.org › hormones › estrogen

      Estrogen | Endocrine Society - Hormone.org

      So Estradiol is the type of Estrogen that is most likely to cause cell growth. That kind is what was used in HRT years ago, that caused so much death and destruction of Breast/Uterine and Ovarian Cancer. Too proliferative by far.

      Estriol, also known as E3, is the main Estrogen during pregnancy, and is by far the safest. It has been safely used intravaginally in Europe for years, with numerous supporting research. I won't add more of those links here.

      So HAVEFAITHTODAY, I think the Bioidentical Progesterone got a bum rap from your doctor as the culprit causing/exacerbating your BC.

      HOWEVER, the Bioidentical Testosterone might have been a contributing factor because it converts to E2 Estradiol, the most PROLIFERATIVE types of Estrogen.

      ———————————————————————————————————————————-

      So I know you are frightened, so am I at times. So are us all in actuality.

      I made a decision, an educated, scientifically logical decision to use the least proliferative Estrogen, Estriol, in Vaginal suppositories, along with Compounded Bioidentical Progesterone orally every night, to improve my vaginal and urethral health so I could have sex without crying in pain, so I can skip having course after course of antibiotics for UTI's.

      I have also gotten the lovely bonus of improved sleep, stronger bones and decreased anxiety.

      A Win/Win for me.

      You must decide for yourselves. I just am laying out the info for your perusal. That's all I can do.

      ———————————————————————————————————————————

      image


      September 06, 2017

      SAVE

      High estriol levels protect against breast cancer in pregnancy

      Source/Disclosures

      High levels of estriol may protect pregnant women in their third trimester from breast cancer, whereas elevated levels of estrone and estradiol may increase cancer risk, study data showed.


      ——————————————————-

      Estrogens are generated mainly by the action of aromatase, which converts testosterone to estradiol and androstenedione to estrone. However, in addition to estradiol and estrone, a variety of other steroids, whose synthesis is not dependent on aromatase, can stimulate the estrogenreceptor.imagehttps://pubmed.ncbi.nlm.nih.gov › ...

      Aromatase-independent Testosterone Conversion Into Estrogenic Steroids Is .

    • jojo0529
      jojo0529 Member Posts: 56

      is there a way to increase progesterone naturally? Does anyone know the preliminary results of the Pioneer study? I’m wondering if progesterone slows growth, does it also help prevent metastasis

    • macb04
      macb04 Member Posts: 756

      So the Pioneer Study isn't finished recruiting until July 31,2020. So no results yet.

      I just spent some time looking up Progesterone and Metastasis. Extremely frustrating as they lump together the effects of artificial Progestins and Bioidentical Progesterone as if they were one and the same.

      Apples are NEVER oranges. So how can doctors and researchers confuse the issue that way? Clarity and precision should be the Hallmarks of what they say, yet clearly that's not what happens.

      WHY?


      Artificial progestin are one of the biggest culprits in why HRT was such a big risk for hormone dependent cancers. That's wh it finally fell out of favor to give Provera to Post Menopausal women.

      Bioidentical Progesterone is biologically and structurally identical to the Progesterone we would produce in the Corpus Luteum following ovulation.

      Obviously Bioidentical Progesterone has the SAME regulateffects on endometrial/ovarian and breast tissue as Progesterone made by the Corpus Luteum.

      Whereas artificial progestins like Provera enhance cellular proliferation, rather like gasoline on a fire.

      So function follows structure. I posted studies showing Bioidentical Progesterone use reduces Breast Cancer, so people can look up those studies. I will add more research as it becomes available.

      ————————————————————————————————————————————

      In Defense of Progesterone: A Review of the Literature

      Allan Lieberman et al. Altern Ther Health Med.2017 Nov.Show detailsCite

      Abstract

      Context • The medical literature on the use of progesterone in postmenopausal women is often confusing and contradictory. Some physicians implicate natural progesterone in an increase in the risk of breast cancer. The chemical structure of natural progesterone (P4) is quite different from chemically altered, synthetic chemicals called progestins, which results in different actions at the cell level. Objective • The research team intended to review the literature to examine the benefits and safety of natural progesterone and determine whether it can cause an increase or decrease in breast cancer risk. Design • A review of the medical literature to examine the benefits and safety of natural progesterone as compared with synthetic progestins. Intervention • Studies examined compared controls not receiving hormone therapy with women receiving estrogen alone and in combination with natural progesterone and with various synthetic progestins, such as medroxyprogesterone acetate-the most commonly used synthetic progestin. Outcome Measures • Outcome measures included factors such as progression and survival of breast and other cancers and other epidemiological and laboratory data. Results • A meta-analysis of 3 studies involving 86 881 postmenopausal women reported that the use of natural progesterone was associated with a significantly lower risk of breast cancer compared with synthetic progestins. Anovulation and low levels of serum progesterone have been associated with a significantly higher risk of breast cancer in premenopausal women. Use of progesterone has been linked to lower rates of uterine and colon cancers and may also be useful in treating other cancers such as ovarian, melanoma, mesothelioma, and prostate. Progesterone may also be helpful in preventing cardiovascular disease and preventing and treating neurodegenerative conditions such a stroke and traumatic brain injury. Conclusions • Physicians should have no hesitation prescribing natural progesterone. The evidence is clear that progesterone does not cause breast cancer. Indeed, progesterone is protective and preventative of breast cancer.

      =====================================

      Progesterone vs. Synthetic Progestins and the Risk of Breast Cancer: A Systematic Review and Meta-Analysis

      Noor Asi et al. Syst Rev. 2016.Free PMC articleShow detailsFull-text linksCite

      Abstract

      Background: Use of menopausal hormonal therapy (MHT)-containing estrogen and a synthetic progestin is associated with an increased risk of breast cancer. It is unclear if progesterone in combination with estrogen carries a lower risk of breast cancer. Limited data suggest differences between progesterone and progestins on cardiovascular risk factors, including cholesterol and glucose metabolism. Whether this translates to differences in cardiovascular outcomes is uncertain. We conducted a systematic review and meta-analysis to synthesize the existing evidence about the effect of progesterone in comparison to synthetic progestins, each in combination with estrogens, on the risk of breast cancer and cardiovascular events.

      Methods: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus through 17 May 2016 for studies that enrolled postmenopausal women using progesterone vs. synthetic progestins and reported the outcomes of interest. Study selection and data extraction were performed by two independent reviewers. Meta-analysis was conducted using the random effects model.

      Results: We included two cohort studies and one population-based case-control study out of 3410 citations identified by the search. The included studies enrolled 86,881 postmenopausal women with mean age of 59 years and follow-up range from 3 to 20 years. The overall risk of bias of the included cohort studies in the meta-analysis was moderate. There was no data on cardiovascular events. Progesterone was associated with lower breast cancer risk compared to synthetic progestins when each is given in combination with estrogen, relative risk 0.67; 95 % confidence interval 0.55-0.81.

      Conclusions: Observational studies suggest that in menopausal women, estrogen and progesterone use may be associated with lower breast cancer risk compared to synthetic progestin.

      ======================================

      Endocrine Abstracts (2017) 49 EP151 | DOI: 10.1530/endoabs.49.EP151

      Potential inhibitory effect of progesterone on breast cancer metastasis via the regulation on protein expression of apoptosis- and EMT-related genes

      Gyu-Sik Kim, So-Ye Jeon & Kyung-Chul Choi

    • I am new and recently diagnosed and trying to find info on Prometrium that I took during 2 pregnancies in the last 5 years - now I have sporadic aggressive BC seemingly out of nowhere at 37 with negative gene tests and no family history. This information reads like an info-mercial with the goal of selling its magic cream. I admit I need to read more on the science and that is what I plan to do but this just seems wrong.


      had anyone taken Prometrium as a suppository during pregnancy? I did for my second pregnancy in 2015 for 11 weeks after an emergency cerclage and during my 3rd pregnancy in 2019 after another cerclage. Now I have a fast growing ER+ (75%) PR low positive (3%), Her2 amplified tumor that has not spread.

      Any thoughts on Prometrium being a culprit or perhaps interacting with estrogen levels to promote the tumor? Or perhaps taking it gave me normal levels of Progesterone and now stopping it after pregnancies made the tumor grow fast? It doubled in size from Mach 2020 to October 2020 and I was diagnosed last month with IDC 4.8 cm.....any information or thoughts would be much appreciated as I plan to review with my MO and B

    • macb04
      macb04 Member Posts: 756

      2aT2N0M0ERHER2Pos I know you, like all of us, are looking for logical cause for this newly diagnosed misery of bc that has come your way.

      Our two main hormones, as you know, estrogen and progesterone, are meant to counterbalance each other mainly for the purposes of ovulation and pregnancy.

      The main biological role of Progesterone, is to stabilize the uterine lining during pregnancy, and to stop overgrowth of breast tissue. That's it. An essential stop/break to the tissue growth roles of Estrogen.

      That's why when women with a uterus used to get HRT, Progesterone ( in the form of Provera) was always given to prevent overgrowth of the uterine lining (endometrium).

      There are three main types of estrogen, Estradiol ( strongest, present during menstrual cycle and pregnancy) Estrone and Estriol ( mainly only present during pregnancy exclusively).

      Estrogens, especially Estradiol, are considered fuels for overgrowth of breast cells ( fibrocystic breast disease) and breast cancer, which is why treatment can include drugs like Tamoxifen, which drastically lower serum Estrogen levels.

      There is a big difference in cancer risks associated with Artificial Progestins like Provera (Medroxyprogesterone ) or the progestins, levonorgestrel, found in the Mirena IUD. Artificial progestins act in an Estrogenic way, so that in addition to having an ability to counteract Estrogen effects on uterine endometrium, they are also able to stimulate breast tissue.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923240/

      So you were on a Bioidentical Progesterone( Prometrium) during both of your pregnancies. That was the safest version of Progesterone you could possibly use during pregnancy.

      Pregnancy has a markedly increased level of Estradiol present, as compared to any other time during the menstrual cycle. As you can see in the chart I have attached, pregnancy can result in an estradiol increase of up to 20 times the amount present at any other point in the menstrual cycle.


      So to answer your question, I would say that the Prometrium likely only stopped overgrowth of Breast cells, while likewise stabilizing your uterine lining to help with pregnancy, because that is the natural role of Progesterone.



      image

      Estradiol (serum)

      Prepubertal children <10 pg /mL
      Male< 60 pg /mL
      Females ovulatingEarly follicularLate follicular Luteal phase
      pg /mL30 - 100 100 - 400 60 - 150
      PregnantFirst TrimesterSecond TrimesterThird Trimester
      pg /mL188 - 24971278 - 71926137 - 3460
      Postmenopausal< 18 pg /mL

      References:

      http://www.oxisresearch.com/pub/PDF/inserts/11110insert.pdf
      Accessed: 7/10/2007
      Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009 Dec;114(6):1326-31. PMID:19935037

    • macb04
      macb04 Member Posts: 756

      bump