Re: Progesterone questions

[Guest guest]

Hi, Marie,

Thank you, Marie, for sharing your thoughtful progesterone questions.

Here are more progesterone questions...

In a May 2010 study, researchers, exploring why women who have a

late menopause have a higher risk for breast cancer, found that progesterone

might be a factor. Progesterone induces adult mammary stem cell expansion .

In fact, stem cell expansion was 14-fold during the reproductive cycle in

mice. Do people who have a high risk for breast cancer have an even higher

risk that they will get breast cancer upon stem cell expansion?

In another May 2010 study, researchers found that natural

progesterone, MPA, and other synthetic progestins stimulated the growth of

xenograft

tumors in mice. Progestins stimulated vascular endothelial growth factor

elaboration and increased tumor vascularity. Will women who ingest

progestins for hormone therapy or oral contraception be more at risk for

developing

breast cancer because of proliferation of existing latent tumor cells?

All of this is new research .... Who would know that, prompted by

progesterone, stem cells, historically thought to be inactive, would lose

their quiesence during the menstrual period? And who would know that

progestins would increase the number of blood vessels?

Again, thank you, Marie for your questions.

Sally

(STUDIES BELOW.)

------------------------------------------------------STUDIES---------------

------------------------------------------------

_Nature._ (javascript:AL_get(this, 'jour', 'Nature.') 2010 May 5. [Epub

ahead of print]

Progesterone induces adult mammary stem cell expansion.

_Joshi PA_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Joshi%20PA " [Author]) , _

HW_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " %20HW " [Author]) ,

_Beristain AG_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Beristain%20AG " [Author]) , _Di

Grappa MA_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Di%20Grappa%20MA " [Author]) , _Mote

P_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Mote%20P " [Author]) , _e C_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " e%20C " [Author]) , _Stingl J_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Stingl%20J " [Author]) , _Waterhouse

PD_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Waterhouse%20PD " [Author]) ,

_Khokha R_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Khokha%20R " [Author]) .

Ontario Cancer Institute, Department of Medical Biophysics and Department

of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5G

2M9, Ontario, Canada.

Abstract

Reproductive history is the strongest risk factor for breast cancer after

age, genetics and breast density. Increased breast cancer risk is entwined

with a greater number of ovarian hormone-dependent reproductive cycles, yet

the basis for this predisposition is unknown. Mammary stem cells (MaSCs)

are located within a specialized niche in the basal epithelial compartment

that is under local and systemic regulation. The emerging role of MaSCs in

cancer initiation warrants the study of ovarian hormones in MaSC homeostasis.

Here we show that the MaSC pool increases 14-fold during maximal

progesterone levels at the luteal dioestrus phase of the mouse.

Stem-cell-enriched

CD49f(hi) cells amplify at dioestrus, or with exogenous progesterone,

demonstrating a key role for progesterone in propelling this expansion. In aged

mice, CD49f(hi) cells display stasis upon cessation of the reproductive

cycle. Progesterone drives a series of events where luminal cells probably

provide Wnt4 and RANKL signals to basal cells which in turn respond by

upregulating their cognate receptors, transcriptional targets and cell cycle

markers. Our findings uncover a dynamic role for progesterone in activating

adult

MaSCs within the mammary stem cell niche during the reproductive cycle,

where MaSCs are putative targets for cell transformation events leading to

breast cancer

_Menopause._ (javascript:AL_get(this, 'jour', 'Menopause.') 2010 May 7.

[Epub ahead of print]

Synthetic progestins induce growth and metastasis of BT-474 human breast

cancer xenografts in nude mice.

_Liang Y_ (http://preview.ncbi.nlm.nih.gov/pubmed?term= " Liang%20Y " [Author])

, _Benakanakere I_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Benakanakere%20I " [Author]) ,

_Besch-Williford C_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Besch-Williford%20C " [Author]) ,

_Hyder RS_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Hyder%20RS " [Author]) , _Ellersieck

MR_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Ellersieck%20MR " [Author]) , _Hyder

SM_

(http://preview.ncbi.nlm.nih.gov/pubmed?term= " Hyder%20SM " [Author]) .

From the 1Department of Biomedical Sciences, 2Dalton Cardiovascular

Research Center, 3Department of Pathobiology, and 4Agriculture Experiment

Station, University of Missouri, Columbia, MO.

Abstract

OBJECTIVE:: Previous studies have shown that sequential exposure to

estrogen and progesterone or medroxyprogesterone acetate (MPA) stimulates v

ascularization and promotes the progression of BT-474 and T47-D human breast

cancer cell xenografts in nude mice (Liang et al, Cancer Res 2007, 67:9929). In

this follow-up study, the effects of progesterone, MPA, norgestrel (N-EL),

and norethindrone (N-ONE) on BT-474 xenograft tumors were compared in the

context of several different hormonal environments. N-EL and N-ONE were

included in the study because synthetic progestins vary considerably in their

biological effects and the effects of these two progestins on the growth of

human tumor xenografts are not known. METHODS:: Estradiol-supplemented

intact and ovariectomized immunodeficient mice were implanted with BT-474

cells. Progestin pellets were implanted simultaneously with estradiol pellets

either 2 days before tumor cell injection (ie, combined) or 5 days after

tumor cell injections (ie, sequentially). RESULTS:: Progestins stimulated the

growth of BT-474 xenograft tumors independent of exposure timing and

protocol, MPA stimulated the growth of BT-474 xenograft tumors in

ovariectomized

mice, and progestins stimulated vascular endothelial growth factor

elaboration and increased tumor vascularity. Progestins also increased lymph

node

metastasis of BT-474 cells. Therefore, progestins, including N-EL and N-ONE,

induce the progression of breast cancer xenografts in nude mice and promote

tumor metastasis. CONCLUSIONS:: These observations suggest that women who

ingest progestins for hormone therapy or oral contraception could be more

at risk for developing breast cancer because of proliferation of existing

latent tumor cells. Such risks should be considered in the clinical setting.

[Guest guest]

Hi Marie,

I think you have asked some interesting questions. I don't actually have any

answers, just wanted to comment on a few things.

As you have discovered yourself, it is important to look at an issue from all

angles. Who is to say that one source is more balanced than another? It's one

of my complaints with The China Study. Lots of great info on why eating vegan

is good for a person - but no data on the disease rates of vegans and

vegetarians.

Anyway, I wanted to also say that I am a member of an online group for young

women with breast cancer. Many of the women are suffering horribly from

menopausal symptoms, but none of them have been offered HRT, nor would any of

them take any hormones.

And, there is no way to tell if all the cancer cells are gone, of course.

ar

>

> I think the biggest problem with the book What Your Doctor May Not Tell You

About Breast Cancer: How Hormone Balance Can Save Your Life by Drs. Lee and Zava

is the scarcity of data. What, for instance, is the percentage of women who got

breast cancer while taking progesterone compared to those who did not? If

someone can find the answer in this book, I would appreciate it if they would

let me know.

>

> We are often told that there are no studies on natural progesterone because

drug companies are unwilling to spend money on things they can't patent. Why

then don't the authors of the books on natural progesterone, the saliva testing

labs and the manufacturers get together and set aside some of their profits for

research?

>

> In a recent letter, physician and researcher Dr. Barry Wren stated that while

" ... women experiencing severe menopausal symptoms following treatment of breast

cancer may be prescribed HRT without increasing their risk of recurrence or

death - the problems of secondary spread of the disease still existed. If viable

cancer cells were still present, HRT would promote the growth of these cells,

but if the intervention had removed or destroyed the cells then that woman was

not at increased risk. "

>

> How, I wonder, can anyone be sure that all of cancer cells have been removed

or destroyed?

>

> Marie

>

[Guest guest]

Hi Sally,

 

I see one of these studies used natural progesterone, MPA as well as other

synthetic progestins and found that all of them acted the same and stimulated

the growth of xenograft tumors in mice.  I hope other researchers will include

natural progesterone in their studies so people can make an informed decision

about this product. Thanks.

 

Marie

________________________________

From: " Gould018@... " <Gould018@...>

Sent: Mon, June 14, 2010 1:39:08 PM

Subject: [ ] RE: Progesterone Questions

Hi, Marie, 

Thank you, Marie, for  sharing your thoughtful progesterone questions.

      Here are more  progesterone questions...

      In a May 2010 study,  researchers, exploring why women who have a

late menopause have a higher risk  for breast cancer, found that progesterone

might be a factor.  Progesterone induces adult mammary stem cell expansion .

In fact, stem  cell expansion was 14-fold during the reproductive cycle in

mice.  Do  people who have a high risk for breast cancer have an even higher

risk that they  will get breast cancer upon stem cell expansion?

      In another May 2010  study, researchers found that natural

progesterone, MPA, and other synthetic  progestins stimulated the growth of

xenograft

tumors in mice.  Progestins  stimulated vascular endothelial growth factor

elaboration and increased tumor  vascularity.  Will women who ingest

progestins for hormone therapy or oral  contraception be more at risk for

developing

breast cancer because of  proliferation of existing latent tumor cells?

      All of this is new  research ....  Who would know that, prompted by 

progesterone, stem cells, historically thought to be inactive, would lose 

their quiesence during the menstrual period?  And who would know that 

progestins would increase the number of blood vessels?

    Again, thank you, Marie for  your questions.

                        Sally

[Guest guest]

A technology called " CELL SEARCH " is able to detect circulating

tumor cells in the blood after surgery...

karla

Ann Oncol. 2010 Apr;21(4):729-33. Epub 2009 Oct 22.

Single circulating tumor cell detection and overall survival in nonmetastatic

breast cancer.

Bidard FC, Mathiot C, Delaloge S, Brain E, Giachetti S, de Cremoux P, Marty M,

Pierga JY.

CirCe laboratory, Institut Curie, 26 rue d'Ulm, Paris, France.

Abstract

BACKGROUND: Circulation of cancer cells in the blood is a mandatory step for

metastasis, but circulating tumor cells (CTC) have a low metastatic efficiency

in preclinical animal models. In this prospective study, we reported the

clinical outcome of nonmetastatic breast cancer patients according to CTC

detection. PATIENTS AND METHODS: In 115 nonmetastatic patients diagnosed with

large operable or locally advanced breast cancer, we prospectively detected CTC

using the CellSearch system before and after neoadjuvant chemotherapy in a phase

II trial (REMAGUS02). RESULTS: At baseline, 23% of patients were CTC positive,

but only 10% had >1 CTC/7.5 ml of blood. After a median follow-up of 36 months,

CTC detection before chemotherapy was an independent prognostic factor for both

distant metastasis-free survival [DMFS; P = 0.01, relative risk (RR) = 5.0, 95%

confidence interval (CI) 1.4-17] and overall survival (OS; P = 0.007, RR = 9,

95% CI 1.8-45). CTC detection after chemotherapy was of less significance (P =

0.07 and 0.09, respectively). Moreover, CTC detection showed interesting

characteristics as an individual predictive test for metastatic relapses

(sensibility 55%, specificity 81%, and global accuracy 77%). CONCLUSIONS:

Detection of > or =1 CTC/7.5 ml before neoadjuvant chemotherapy can accurately

predict OS. Our findings may change the clinical management of nonmetastatic

breast cancer and indicate that the metastatic efficiency of CTC could be higher

than previously reported.

PMID: 19850639 [PubMed - in process]

>

> I think the biggest problem with the book What Your Doctor May Not Tell You

About Breast Cancer: How Hormone Balance Can Save Your Life by Drs. Lee and Zava

is the scarcity of data. What, for instance, is the percentage of women who got

breast cancer while taking progesterone compared to those who did not? If

someone can find the answer in this book, I would appreciate it if they would

let me know.

>

> We are often told that there are no studies on natural progesterone because

drug companies are unwilling to spend money on things they can't patent. Why

then don't the authors of the books on natural progesterone, the saliva testing

labs and the manufacturers get together and set aside some of their profits for

research?

>

> In a recent letter, physician and researcher Dr. Barry Wren stated that while

" ... women experiencing severe menopausal symptoms following treatment of breast

cancer may be prescribed HRT without increasing their risk of recurrence or

death - the problems of secondary spread of the disease still existed. If viable

cancer cells were still present, HRT would promote the growth of these cells,

but if the intervention had removed or destroyed the cells then that woman was

not at increased risk. "

>

> How, I wonder, can anyone be sure that all of cancer cells have been removed

or destroyed?

>

> Marie

>

[Guest guest]

Marie,

1. The authors did not have many progesterone studies when they wrote the

book. After the book was published, this study was done.

_http://breastcancerchoices.org/files/BiosCouldTransdermalbeSafer.pdf_

(http://breastcancerchoices.org/files/BiosCouldTransdermalbeSafer.pdf)

The article may seem complex but that's because of the number of areas it

covers. You may want to try to locate what you are looking for and skip the

rest. Tho, I recommend the full article because it's so full of gems,

including insights into the Women's Health Initiative Study.

2. Regarding Dr. Barry Wren, while I've read almost every article Wren has

written, you have zeroed in on the one place he makes a PURELY SPECULATIVE

statement. There is no evidence for the statement you refer to. He is

theorizing, not observing actual patients. This is disappointing because of his

earlier work was so " just the facts, please. "

3. But even if what he says were true, according to more than 20 studies,

breast cancer patients taking hormones after diagnosis survive as long as

or longer than those who take no hormones. See:

_www.breastcancerchoices.org/hrt_ (http://www.breastcancerchoices.org/hrt)

Lynne

In a message dated 6/14/2010 12:02:10 P.M. Eastern Daylight Time,

everonward11@... writes:

In a recent letter, physician and researcher Dr. Barry Wren stated that

while " ... women experiencing severe menopausal symptoms following treatment

of breast cancer may be prescribed HRT without increasing their risk of

recurrence or death - the problems of secondary spread of the disease still

existed. If viable cancer cells were still present, HRT would promote the

growth of these cells, but if the intervention had removed or destroyed the

cells then that woman was not at increased risk. "

How, I wonder, can anyone be sure that all of cancer cells have been

removed or destroyed?

[Guest guest]

Lynne,

Dr. Barry Wren states that in certain cases, HRT can promote the growth of

cancer cells. When a well known researcher says that HRT may be dangerous for

some women, I think it is a good thing for them to learn about it.

In an earlier post, you recommended one of Dr. Lee's books and when I

looked at it, it seemed to me to be entirely anecdotal. I couldn't find any

data.

I recently tallied up some anecdotal information from a breast cancer discussion

group and discovered that all but one of the women who used natural progesterone

had had a recurrence of cancer. This made me look at some studies to try to

figure out what was going on. Then I noticed Dr. Wren's letter where he states

that " if viable cancer cells were still present after treatment, HRT would

promote the growth of these cells " .

For those who are interested, the full letter is printed below. In it you will

find a balanced view of hormone therapy that takes in many angles.

Marie

----------------------

Letter from Dr. Barry Wren:

In my earlier papers, I was reporting on the influence of hormone therapy on a

group of women who had been diagnosed with breast cancer and had been treated by

surgery, radiotherapy or chemotherapy and who had subsequently begun to

experience debilitating symptoms of oestrogen deficiency. In our study of almost

400 hundred such women, treated over 25 years, we found that the use of HRT was

not associated with any greater incidence of recurrence or death than found

among a similar group of women who were not given HRT.

These results were almost identical with a study conducted by Ellen O'Meara et

al in Seattle who found a similar outcome following the use of HRT for women who

had been treated for breast cancer.

The point we wished to make in our papers was that women experiencing severe

menopausal symptoms following treatment of breast cancer may be prescribed HRT

without increasing their risk of recurrence or death – the problems of secondary

spread of the disease still existed. If viable cancer cells were still present,

HRT would promote growth of these cells, but if the intervention had removed or

destroyed the cells then that woman was not at increased risk.

Another of my papers in 2004 was a review paper to discuss the causes of breast

cancer. A number of AUTOPSY studies (published between 1985 and 1987) on young

women who died from a non-malignant cause showed that between 10% and 37% of

pre-menopausal women had cancer in-situ or cellular atypia beginning as early as

17 years of age and increasing in incidence as they approached 40-50 years. In

my paper I referred to a number of biological studies which presented evidence

that breast cancer involves up to 200 genetic mutations and pointed out that

these mutations may be inherited or occur spontaneously as stem cells divide (

mostly during the phase of rapid breast development – adolescence). These

genetic alterations leave the post-menopausal woman at increased risk that

mutations to cadherins and integrins (which tether the normal cell) will result

in the cancer in-situ becoming invasive.

Normally the rate of diagnosed invasive cancer is 2% at the age of 50 years but

this rate of diagnosed breast cancer doubles every decade up to the age of 90+

years. It is thought that breast cancer mutations and subsequent growth of

malignant cells is relatively slow (occurring over many years) but the diagnosis

of invasive breast cancer is accelerated by the use of HRT. HRT does not cause

the genetic changes – they merely accelerate the rate that cells undergo

division.

In 2009, I wrote an article discussing the benefits to be gained for women from

the use of HRT if begun at or soon after the menopause. In the article I

discussed the problems and misconceptions associated with the various studies

including WHI, the MWS and several other epidemiological studies. I pointed out

that the results from these studies have been distorted either deliberately or

accidentally by certain groups or individuals who have their own agenda in

presenting various results.

Research falls into three main categories – EPIDEMIOLOGICAL, CLINICAL and

BIOLOGICAL. When all three agree, one can be sure that the result is to be

believed. When there is a conflict, then one or other is incorrect. At present

all the data being quoted is from epidemiological studies. Clinical and

biological information does not confirm the hypothesis being promoted by

epidemiologists.

I have no objection with you using this reply for your Internet discussion

group.

Barry G Wren AM

MD MHPEd. FRANZCOG FRCOG

-- ------------------------------

[Guest guest]

At 03:17 AM 6/22/2010, Marie (quoting Barry Wren) wrote:

>

> " Research falls into three main categories –

>EPIDEMIOLOGICAL, CLINICAL and BIOLOGICAL. When

>all three agree, one can be sure that the result

>is to be believed. When there is a conflict, then one or other is incorrect. "

Oh, how I wish this were true! Unfortunately we

live in a scientific world with powerfully

influential overarching marketing,

doctrinal, and ego considerations which too

often lead to very selective or misleading reporting.

Marie, thank you for bringing some common sense

caution to the table. I do think that there is

more to the story though. I wonder how Ki-67

levels from the earlier path reports could play

into the decision to use progesterone. A very

low Ki-67 might allow for more latitude.

[Guest guest]

Marie,

1. Dr. Wren's comments on this specific assertion are speculative, the

professional equivalent of anecdotal.

I would refer you to Dr. Wren's actual study where 50% of the breast cancer

patients died who did NOT take HRT. None of those taking HRT died. Write

him again and he will reinforce those findings in his own work.

2. The O'Meara research he actually quotes which is NOT anecdotal

attributes a considerable advantage to taking HRT after diagnosis of breast

cancer.

_http://breastcancerchoices.org/files/omeara_HRT_post_bc.pdf_

(http://breastcancerchoices.org/files/omeara_HRT_post_bc.pdf)

3. As for your informal anecdotal survey, I won't address that as there is

no way of knowing the facts in any online group's members.

Lynne

In a message dated 6/22/2010 6:22:12 A.M. Eastern Daylight Time,

everonward11@... writes:

Lynne,

Dr. Barry Wren states that in certain cases, HRT can promote the growth of

cancer cells. When a well known researcher says that HRT may be dangerous

for some women, I think it is a good thing for them to learn about it.

In an earlier post, you recommended one of Dr. Lee's books and when I

looked at it, it seemed to me to be entirely anecdotal. I couldn't find

any data.

I recently tallied up some anecdotal information from a breast cancer

discussion group and discovered that all but one of the women who used natural

progesterone had had a recurrence of cancer. This made me look at some

studies to try to figure out what was going on. Then I noticed Dr. Wren's

letter where he states that " if viable cancer cells were still present after

treatment, HRT would promote the growth of these cells " .

For those who are interested, the full letter is printed below. In it you

will find a balanced view of hormone therapy that takes in many angles.

Marie

----------------------

Letter from Dr. Barry Wren:

In my earlier papers, I was reporting on the influence of hormone therapy

on a group of women who had been diagnosed with breast cancer and had been

treated by surgery, radiotherapy or chemotherapy and who had subsequently

begun to experience debilitating symptoms of oestrogen deficiency. In our

study of almost 400 hundred such women, treated over 25 years, we found that

the use of HRT was not associated with any greater incidence of recurrence

or death than found among a similar group of women who were not given HRT.

These results were almost identical with a study conducted by Ellen

O'Meara et al in Seattle who found a similar outcome following the use of HRT

for

women who had been treated for breast cancer.

The point we wished to make in our papers was that women experiencing

severe menopausal symptoms following treatment of breast cancer may be

prescribed HRT without increasing their risk of recurrence or death – the

problems

of secondary spread of the disease still existed. If viable cancer cells

were still present, HRT would promote growth of these cells, but if the

intervention had removed or destroyed the cells then that woman was not at

increased risk.

Another of my papers in 2004 was a review paper to discuss the causes of

breast cancer. A number of AUTOPSY studies (published between 1985 and 1987)

on young women who died from a non-malignant cause showed that between 10%

and 37% of pre-menopausal women had cancer in-situ or cellular atypia

beginning as early as 17 years of age and increasing in incidence as they

approached 40-50 years. In my paper I referred to a number of biological

studies

which presented evidence that breast cancer involves up to 200 genetic

mutations and pointed out that these mutations may be inherited or occur

spontaneously as stem cells divide ( mostly during the phase of rapid breast

development – adolescence). These genetic alterations leave the

post-menopausal woman at increased risk that mutations to cadherins and

integrins (which

tether the normal cell) will result in the cancer in-situ becoming

invasive.

Normally the rate of diagnosed invasive cancer is 2% at the age of 50

years but this rate of diagnosed breast cancer doubles every decade up to the

age of 90+ years. It is thought that breast cancer mutations and subsequent

growth of malignant cells is relatively slow (occurring over many years)

but the diagnosis of invasive breast cancer is accelerated by the use of HRT.

HRT does not cause the genetic changes – they merely accelerate the rate

that cells undergo division.

In 2009, I wrote an article discussing the benefits to be gained for women

from the use of HRT if begun at or soon after the menopause. In the

article I discussed the problems and misconceptions associated with the various

studies including WHI, the MWS and several other epidemiological studies. I

pointed out that the results from these studies have been distorted either

deliberately or accidentally by certain groups or individuals who have

their own agenda in presenting various results.

Research falls into three main categories – EPIDEMIOLOGICAL, CLINICAL and

BIOLOGICAL. When all three agree, one can be sure that the result is to be

believed. When there is a conflict, then one or other is incorrect. At

present all the data being quoted is from epidemiological studies. Clinical and

biological information does not confirm the hypothesis being promoted by

epidemiologists.

I have no objection with you using this reply for your Internet discussion

group.

Barry G Wren AM

MD MHPEd. FRANZCOG FRCOG

-- ------------------------------