Melatonin treatment in animals = Ablation /ovary removal !!!!!!!!!!!!!!!!!!!!!

[R.B.]

A WOW!!!!!? I think.

What are the implications of this?

Very foggy with big gaps - but huge me thinks.

What does it say about the realtionship of oestrogen produced externally and oestrogen produced by the tumour and the ranking and control?.

It seems to be saying that localised control is much more important than external supply, if you can find a way of acheiving local aromatase control, and from the summary are the suggestion not that melatonin may be acheiving this??.

One for those facing fertility / treatment decisions to talk to their oncs about?

RB




http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16080194


1: Int J Cancer. 2006 Jan 15;118(2):274-8.Click here to read Links
Melatonin inhibits the growth of DMBA-induced mammary tumors by decreasing the local biosynthesis of estrogens through the modulation of aromatase activity.

* Cos S,
* Gonzalez A,
* Guezmes A,
* Mediavilla MD,
* Martinez-Campa C,
* Alonso-Gonzalez C,
* Sanchez-Barcelo EJ.

Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, Santander, Spain.

Melatonin inhibits the growth of breast cancer cells by interacting with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone. Recently, we described that melatonin reduces aromatase expression and activity in MCF-7 human breast cancer cells, thus modulating the local estrogen biosynthesis. To investigate the in vivo aromatase-inhibitory properties of melatonin in our current study, this indoleamine was administered to rats bearing DMBA-induced mammary tumors, ovariectomized (ovx) and treated with testosterone. In these castrated animals, the growth of the estrogen-sensitive mammary tumors depends on the local aromatization of testosterone to estrogens. Ovariectomy significantly reduced the size of the tumors while the administration of testosterone to ovx animals stimulated tumor growth, an effect that was suppressed by administration of melatonin or the aromatase inhibitor aminoglutethimide. Uterine weight of ovx rats, which depends on the local synthesis of estrogens, was increased by testosterone, except in those animals that were also treated with melatonin or aminoglutethimide. The growth-stimulatory effects of testosterone on the uterus and tumors depend exclusively on locally formed estrogens, since no changes in serum estradiol were appreciated in testosterone-treated rats. Tumors from animals treated with melatonin had lower microsomal aromatase activity than tumors of animals from other groups, and incubation with melatonin decreased the aromatase activity of microsomal fractions of tumors. Animals treated with melatonin had the same survival probability as the castrated animals and significantly higher survival probability than the uncastrated. We conclude that melatonin could exert its antitumoral effects on hormone-dependent mammary tumors by inhibiting the aromatase activity of the tumoral tissue. Copyright 2005 Wiley-Liss, Inc.

PMID: 16080194 [PubMed - indexed for MEDLINE]
Related Links

* Melatonin modulates aromatase activity in MCF-7 human breast cancer cells. [J Pineal Res. 2005] PMID: 15683469
* The effect of estrogen on aromatase and vascular endothelial growth factor messenger ribonucleic acid in the normal nonhuman primate mammary gland. [J Clin Endocrinol Metab. 1999] PMID: 10199791
* The effect of aromatase inhibitor 4-hydroxyandrostenedione on steroid receptors in hormone-dependent tissues of the rat. [J Steroid Biochem Mol Biol. 1995] PMID: 7857875
* Growth and characterization of N-methyl-N-nitrosourea-induced mammary tumors in intact and ovariectomized rats. [Carcinogenesis. 2001] PMID: 11751437
* Antitumor effects of SEF19, a new nonsteroidal aromatase inhibitor, on 7,12-dimethylbenz[a]anthracene-induced mammary tumors in rats. [Anticancer Res. 1998] PMID: 9568073
* See all Related Articles...

Display

[R.B.]

More on same.

RB


http://www.ncbi.nlm.nih.gov/entrez/q...ids=156834691:


J Pineal Res. 2005 Mar;38(2):136-42.Click here to read Links
Melatonin modulates aromatase activity in MCF-7 human breast cancer cells.

* Cos S,
* Martinez-Campa C,
* Mediavilla MD,
* Sanchez-Barcelo EJ.

Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, Santander, Spain.

Most of the current knowledge about the mechanisms by which melatonin inhibits the growth of breast cancer cells point to an interaction of melatonin with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone. However, a possible effect of melatonin on the local synthesis of estrogens had not been examined. The objective of this work was to study whether melatonin may modify the aromatase activity in MCF-7 breast cancer cells thus modulating the local estrogen biosynthesis. In MCF-7 cells cultured with testosterone in estradiol-free media, melatonin (1 nM) counteracts the testosterone-induced cell proliferation dependent on the local biosynthesis of estrogens from testosterone by the aromatase activity of the cells. We found that melatonin reduces the aromatase activity (measured by the tritiated water release assay) of MCF-7 cells both at basal conditions and when aromatase activity was stimulated by cAMP or cortisol. The greatest inhibition of the aromatase activity was obtained with 1 nm melatonin, the same concentration that gives the highest antiproliferative and anti-invasive effects of MCF-7 cells. Finally, by RT-PCR, we found that melatonin downregulates aromatase expression at the transcriptional level in the MCF-7 cells. We conclude that melatonin, at physiological concentrations, decreases aromatase activity and expression in MCF-7 cells. This aromatase inhibitory effect of melatonin, together with its already known antiestrogenic properties interacting with the estrogen-receptor, makes this indoleamine an interesting tool to be considered in the prevention and treatment of hormone-dependent mammary neoplasias.

PMID: 15683469 [PubMed - indexed for MEDLINE]
Related Links

* Melatonin inhibits the growth of DMBA-induced mammary tumors by decreasing the local biosynthesis of estrogens through the modulation of aromatase activity. [Int J Cancer. 2006] PMID: 16080194
* Endogenous aromatization of testosterone results in growth stimulation of the human MCF-7 breast cancer cell line. [J Steroid Biochem Mol Biol. 2005] PMID: 15748829
* Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. [Cancer Res. 1998] PMID: 9766668
* Keratinocyte growth factor (KGF) induces aromatase activity in cultured MCF-7 human breast cancer cells. [Anticancer Res. 1998] PMID: 9703907
* Melatonin enhances the inhibitory effect of aminoglutethimide on aromatase activity in MCF-7 human breast cancer cells. [Breast Cancer Res Treat. 2005] PMID: 16244789
* See

[Monica]

RB,
Thanks for the research information. I have been taking melatonin since I started treatment a couple of years ago. I am pre-menopausal and very high ER positive. I could not take the side effects of tamoxifen and was unwilling to go the route of zoladex or ovary removal since tamoxifen seemed to be permanently damaging me neurologically and I didn't want to chance any more damage. Hopefully, between, melatonin, celebrex, curcumin, green tea, and of course, fish oil, I'll be okay. I just never know how much of this stuff to take.
Best,
Monica

[pattyz]

hmmmmmmmm ... perhaps one day in retrospect, I could be called an experiment.

ER+ Her2+++ but PR-

For the past two yrs+ I have been taking a small dose of Estrogen/Testosterone by request for my hotflash and energy issues. Onc strongly resisted ofcourse, nearly falling off chair when first asked.

Just prior to request for this drug, I had total hysterectomy including ovaries for a stage 1 cervical ca. (adenocarcinoma, not the most common).

Was post menopausal since first tx at age 50 in early 2000.

Other than a brief stint (8 weeks) of Tamoxifen back then, on NO other hormonal 'treatments'.

For the past three years I've been taking 9mg of Melatonin nightly.

Have been NED in body after mets dx/tx for past four yrs.
Brain mets (multiples) three times in past four yrs, current 8 'stable' (knock wood) after tx of Xeloda/Temodar x 7/8?

I upped my Melatonin after reading studies done re: brain mets. Tho' that dosage was at 20mg... my pills are 3mg each, so 9mg total. That is all I can manage with the other pills I take...

Thanks for this bit of info. Thought provoking to be sure.

pattyz

[Lani]

the following was published/put online during the past week.

Perhaps this is new information that both you and your oncologist should consider and discuss



Testosterone-Containing Hormonal Therapy May Increase Risk for Breast Cancer CME/CE
News Author: Laurie Barclay, MD
CME Author: Charles Vega, MD, FAAFP

Disclosures

To earn CME credit, read the news brief along with the CME information that follows and answer the test questions.

Release Date: July 25, 2006; Valid for credit through July 25, 2007


Credits Available


Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians;
Nurses - 0.3 ANCC continuing education contact hours for nurses (0.3 contact hours are in the area of pharmacology)


July 25, 2006 — Testosterone-containing postmenopausal hormone replacements are associated with an increased risk for invasive breast cancer, according to the results of a prospective cohort study reported in the July 24 issue of the Archives of Internal Medicine.

"Epidemiologic studies suggest that endogenous testosterone levels are positively associated with breast cancer risk in postmenopausal women," write Rulla M. Tamimi, ScD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Mass, and colleagues. "Given the increasing trend in the use of hormone therapies containing androgens, we evaluated the relation between the use of estrogen and testosterone therapies and breast cancer."

The investigators evaluated the risk for breast cancer associated with different types of postmenopausal hormone formulations containing testosterone in the Nurses' Health Study from 1978 to 2002. During 24 years of follow-up (1,359,323 person-years), there were 4610 incident cases of invasive breast cancer diagnosed in postmenopausal women. Using questionnaires administered every 2 years, the investigators updated information on menopausal status, postmenopausal hormone use, and breast cancer diagnosis.

In the group of women with a natural menopause, the risk for breast cancer was nearly 2.5-fold greater among current users of estrogen plus testosterone therapies than in never users of postmenopausal hormones (multivariate relative risk, 2.48; 95% confidence interval [CI], 1.53 - 4.04). Risk for breast cancer associated with current use of estrogen and testosterone therapy was greater than with estrogen-only therapy (P for heterogeneity = .007) and marginally greater than estrogen and progesterone therapy (P for heterogeneity = .11). For each year of use, women receiving postmenopausal hormones with testosterone had a 17.2% increased risk for breast cancer (95% CI, 6.7% - 28.7%).

"Consistent with the elevation in risk for endogenous testosterone levels, women using estrogen and testosterone therapies have a significantly increased risk of invasive breast cancer," the authors write.

Study limitations include potential misclassification of exposure; secondary analysis, adjusting for type-specific past use and duration of prior hormone use, limited in power; and possible detection bias.

"Given the substantial evidence implicating combined E&P [estrogen and progesterone] therapy in breast cancer and the results of the present study regarding E&T [estrogen and testosterone] therapies, women and their physicians should reconsider use and, more specifically, long-term use of these therapies," the authors conclude. "Although postmenopausal therapies may provide improvement with respect to sexual functioning, general well-being, and bone health, the increased risk of breast cancer may outweigh these benefits."

The National Cancer Institute, National Institutes of Health, and the Breast Cancer Research Fund supported this study. The authors have disclosed no relevant financial relationships.

Arch Intern Med. 2006;166:1483-1489

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:
Describe the physiology and clinical effects of testosterone in women.
Compare the relative risk of breast cancer associated with estrogen and testosterone treatment vs other types of postmenopausal hormone therapy.
Clinical Context

Testosterone levels in women are maintained by direct production of the hormone by the ovary and adrenal gland as well as peripheral conversion of androstenedione. While testosterone levels decrease as women get older, this gradual decline does not become more precipitous during menopause.

Lower testosterone levels associated with age can increase problems with mood and libido among women. However, treatment with exogenous androgens along with estrogen can improve both general well-being and sexual function, and exogenous testosterone may also improve bone mineral density.

There is conflicting data regarding the effects of estrogen and testosterone treatment on the risk for breast cancer. The authors of the current study compare this risk with that of users of other types of postmenopausal hormone therapy and nonusers of hormones.

Study Highlights

Data were drawn from the Nurses' Health Study cohort. The original study enrolled 121,700 US nurses between the ages of 30 and 55 years, and the current analysis focused on postmenopausal women who did not have a history of cancer.
Medical data were collected on subjects every 2 years since 1976. The main study outcome was the rate of incident breast cancer associated with estrogen and testosterone treatment, nonuse of hormone therapy, and the use of other hormone treatments in menopause. Breast cancer was confirmed with medical records in more than 99% of cases. Results were adjusted for possible confounders, such as family history and lifetime estrogen exposure.
1,359,323 person-years of data were available for analysis. Rates of estrogen and testosterone use as a percentage of overall postmenopausal hormone use rose from 0.2% in 1998 to 2.2% in 2000. Subjects who used estrogen and testosterone were younger (59.5 vs 65 years old) and leaner than women who did not use hormone therapy. Subjects receiving any hormone were more likely to have experienced a surgical menopause.
4610 cancers were diagnosed during follow-up. Compared with never users of hormone therapy, estrogen and testosterone was associated with a 77% increased risk for all breast cancer. Estrogen-only therapy increased this risk by only 15% vs nonusers, and the risk for breast cancer was significantly higher with estrogen and testosterone treatment vs estrogen-only therapy. However, estrogen-progestin treatment elevated the risk for breast cancer to a similar degree to that of estrogen and testosterone.
A longer duration of estrogen and testosterone exposure increased the risk for breast cancer proportionately.
Compared with women with surgical menopause, women with natural menopause had a higher risk for breast cancer with all forms of hormone therapy studied.
The majority of women who used estrogen and testosterone previously had used other forms of hormone therapy, but an analysis accounting for past hormone use failed to exonerate estrogen and testosterone in terms of its contribution to breast cancer risk.
There were only 29 cancers diagnosed in the estrogen and testosterone group, and this limited number precluded any meaningful analysis of the subtype of breast cancer associated with estrogen and testosterone.
Pearls for Practice

Testosterone is produced by the ovary and adrenal gland in women, and levels of testosterone decreases gradually with age. Lower levels of testosterone can increase mood and sexual symptoms.
The current study demonstrates that estrogen and testosterone can increase the risk for breast cancer by 77% compared with nonuse of postmenopausal hormone therapy, a level greater than estrogen-only treatment but similar to the risk associated with estrogen-progestin therapy.

[mamacze]

Hi RB,
A year before I was diagnosed with mets (Her2+++, er,pr-), I was diagnosed with vitiligo, (where the pigment producing cells of the skin, melanocytes, are destroyed, autoimmune I believe)...I also noticed that the progression of the vitiligo stopped when I started taking Herceptin in 2004; and I have been NED since. I am wondering if there is a connection; thanks for sharing this research.
Love Kim from CT

[R.B.]

RE skin pigment.

I have not looked at this aspect at all. I googled it and note some make a connection, and so cannot comment on the skin connection.

Given the potential involvement of melatonin in a number of pathways there is no reason why melatonin should not somehow impact on skin cell formation.

RE Oestrogen Progesterone.

That I suppose is the poins from what the trial is suggesting melatonin seems to be mitigating the negative side of oestrogen when things are going wrony at a cellular level.

Oestrogen is not inherently bad. It essential to reporduction. IT is reportd as an anti oxidant etc.

IF these sorts of suggestd reults were available for a patented substance Would researchers not be all over this.

Is this not another example where a lacking of funding for preventative medicine trials, the human condition, a drugs industry whose rules are written ultimately in terms of the profit imperative, combined with the absence of government funding for prevention trials is resulting in a promising area of prevention being under-investigated.

RB

[pattyz]

LOL!!!!!!!! I already have breast cancer. Almost seven yrs with Stage IIIb. I have bc mets, too. Four yrs from first dx of that. Why on earth would I give a rats' patootie about this study?

The amount of Estrogene/Testosterone I take is miniscule anyway. It is all about QOL.

When I heard this big warning last week I did pay attention... then let it go. As I find I must do with most of the dire warnings...

Maybe someone else will find some benefit from this however, and thanks for caring.

pattyz

[AlaskaAngel]

Having done the testosterone clinical trial for bc survivors (still waiting for requested results), and still as far as I know, NED...

I think it is a mistake to convey any impression that all natural hormones contribute to bc -- and especially something like progesterone, which still hasn't been truly investigated, as opposed to progestins, which apparently have a more definite track record...

AlaskaAngel