T Nation

Estradiol in Women

Does anybody know the production chain in females?

My wife just got E1,E2 checked. E2 was 750 on a range of 50-500.

I was wondering if aromatase still played a role in female E2 production in particular?

I am interested because she is on tamoxifen for breast cancer treatment. The doctor became very very concerned about the E2 number and the E1 urine metabolites.

It depends on the status of her cancer,(ductal,lobular, invasive, inflammatory,) and what hormone receptors are present, like Estrogen receptor, progesterone receptors and HER-2.

I’m assuming she’s ER positive, because of the tamoxifen.

Anyway, in it’s simplest form, aromatase is involved in transforming androstenedione to estrone(E1) and testosterone to estradiol(E2).

Aromatase inhibitors don’t block production of estrogen by the ovaries, but they do block other tissues from producing the enzyme, thereby lowering the overall amount of estrogen in the body.

SERMs, like Tamoxifen, don’t block the production of estrogen like AI’s. They block the ability of tumors to use estrogen. They work by binding to only certain types of estrogen receptors, like the ones in breast tissue.

Ask the doctor for a complete explaination of lab results, and what specific result is causing concern and why.

Cancer is a complicated, complex shitstorm of a disease. Good luck.

Yo Momma has it right; using a SERM doesn’t stop the production of Estrogen, it just blocks the receptor sites. Thereby causing the serum Estrogen levels to be sky high because it doesn’t have “anywhere to go”. As Yo Mamma has stated, SERM’s don’t block ALL the receptor sites, so some of the receptors get and stay saturated causing other medical issues.
I am amazed the doctor didn’t put her on Arimidex to stop the production of Estrogen, and a different SERM to block the sites.
I think her doctor is missing the point and needs to get her Estrogen levels down in the 100’s or there about.
Keep us in the loop, will you Gary?

Thanks guys. I try to learn as much as possible on these things.

Whole story: Her oncologist didn’t feel the need to track any blood work. So I asked her to go to my gp/TRT doctor. He pulled the blood work. The GP wanted to start arimidex, but needs to consult with the oncologist. The GP is very concerned about the high estrogen levels(endometrosis, ovarian cancer, ovarian cysts, …)

So now we are stuck in the loop of dueling Drs.

My main question is do the ovaries create E2 with or without aromatase. If the ovaries don’t use it for E2 production, then arimidex might be of marginal use. She is pre-menopausal, so ovaries are still active.

Since we have our children, we do have the oopherectomy choice to consider. Or chemical ablation of the ovaries, which can have its own set of problems.

Wow Gary,
I can’t believe her oncologist wasn’t paying attention to her blood work. Even beyond endometriosis, ovarian cancer, ovarian cysts, POCS, and a host of other Estrogen dominant problems, how did the doctor lose track?

To answer your question: The ovaries create both the E2 and the aromitase enzyme, and the adrenals produce hormones too, just not the aromitase enzyme as I have ever read.
Is your wife overweight at all, because fat cells store the Arom. enzyme, so it’s present even if the ovaries aren’t producing it at the time.

I know of a woman with fibroid cysts and unbearable menstrual cramps, who it was suggested she try Adex to lower her E2 levels to “chemically” shrink the cysts. Two months after starting adex, she has ZERO, yes, ZERO pain or cramps from the cysts, and little or no PMS anymore. Just a thought…
I’ll keep your wife in my prayers, Gary.

[quote]KNB wrote:
Wow Gary,
I can’t believe her oncologist wasn’t paying attention to her blood work. Even beyond endometriosis, ovarian cancer, ovarian cysts, POCS, and a host of other Estrogen dominant problems, how did the doctor lose track?

To answer your question: The ovaries create both the E2 and the aromitase enzyme, and the adrenals produce hormones too, just not the aromitase enzyme as I have ever read.
Is your wife overweight at all, because fat cells store the Arom. enzyme, so it’s present even if the ovaries aren’t producing it at the time.

I know of a woman with fibroid cysts and unbearable menstrual cramps, who it was suggested she try Adex to lower her E2 levels to “chemically” shrink the cysts. Two months after starting adex, she has ZERO, yes, ZERO pain or cramps from the cysts, and little or no PMS anymore. Just a thought…
I’ll keep your wife in my prayers, Gary.
[/quote]

KNB: Sorry, no.

Yo momma is correct in every regard except one quibble.

Gary, I must presume your wife is premenopausal. Tamoxifen does not raise E in postmenopausal women, but in pre-menopausal women it may raise (variably) E via increased release of GNRH and LH and ovarian subsequent stimulation.

Oncologists do not and should not measure E levels…because it does not matter. The proportionate reduction in cancer recurrence, or the proportionate benefit in control of recurrent cancer, is the same whether a woman is premenopausal or postmenopausal. (And to take the lesson unnecessarily further, in Italian trials, tamoxifen was still beneficial in women taking supplemental estrogens. Tamoxifen and its metabolites are potent things.)

Last, aromatase inhibition is NOT useful in the surgically intact premenopausal woman. Yo momma is right; but there is so much aromatase produced (mediated by a lot of factors) that the AIs do not reliably reduce E2 synthesis.

Gary, all the best to you and your wife. Do not fret about the E levels, her oncologist will be correctly reassuring.

Okay Doc,
I get to be wrong… I just wonder why so much is said about reducing circulating E2 levels related to women being treated for breast cancer. That is why I was concerned about E2 levels. I’m not a doctor, and you are.

Please explain how aromitase inhibition is not useful in surgically intact premenopausal women as I am confused. Everything I have read states fibroid tumors are the result of a woman being estrogen dominant, and using estrogen “blockers” will help to shrink them.
Unless we are discussing two different issues; why did the woman in question find almost complete relief of her (monthly) fibroid related pain by using and AI to (hopefully)reduce the size of her fibroids?
Thanks in advance, doc.

KNB

[quote]KNB wrote:

Please explain how aromitase inhibition is not useful in surgically intact premenopausal women as I am confused. Everything I have read states fibroid tumors are the result of a woman being estrogen dominant, and using estrogen “blockers” will help to shrink them.

KNB[/quote]

Perhaps you are getting the process of “blocking” and “inhibition” confused, as you seem to be using them in the same context. They are seperate processes with different functions.

Also, since estrogen is utilized by many different tissues in the body,and utilized in mant different ways, whether or not to inhibit the aromatase enzyme or block estrogen binding to receptors must be specific to the individual woman’s problem, disease, cancer, etc.

Also, what exactly is estrogen dominance? I know it is used as a popular “catch-all” general diagnosis by certain practitioners today. But again, the individual ratios of estrogen to progesterone in a woman’s body will fluctuate and change with pregnancy, age, physical condition and menopause.

A treatment for endometriosis is not the same as a treatment for ovarian cancer, which is again different from a treatment for breast cancer, etc…

You’re absolutely right; I did blur the line between an inhibitor and a blocker.
I know they work by two different actions, and should have been more clear.
Estrogen dominance is the lack of progesterone mainly causing a list of symptoms; with breast cancer, fibroid cysts, hair loss, hypoglycemia, constant breast tenderness, decreased sex drive, depression with short temper, weight gain in the hips and/or belly predominantly, and a whole list of other things too.

And yes, treatment for one cancer is not the same as the treatment for another.
The woman I speak of I know quite well, which is why she tells me about what her body is going through. Her doctor wanted to put her on the pill to quiet the symptoms of the fibroids, yet didn’t mention any way to possibly shrink them. The pill doesn’t agree with her so she went to find a natural way to shrink the fibroids. Every answer she found had the same basic idea: lower circulating Estrogen. She chose Adex and Chasteberry as her weapons of choice, and with careful monitoring has had great success.

I got off track, and I do apologize.
KNB

[quote]KNB wrote:
Okay Doc,
I get to be wrong… I just wonder why so much is said about reducing circulating E2 levels related to women being treated for breast cancer. That is why I was concerned about E2 levels. I’m not a doctor, and you are.

Please explain how aromitase inhibition is not useful in surgically intact premenopausal women as I am confused. Everything I have read states fibroid tumors are the result of a woman being estrogen dominant, and using estrogen “blockers” will help to shrink them.
Unless we are discussing two different issues; why did the woman in question find almost complete relief of her (monthly) fibroid related pain by using and AI to (hopefully)reduce the size of her fibroids?
Thanks in advance, doc.

KNB[/quote]YOu are too kind. We all get to be wrong, I more often than most. Since you ask, the answer to the question of AI in pre-menopausal women is…“It depends.” It depends on age and circumstance whether circulating estrogen is effected. You may recall that I am skeptical that circulating estrogen reflects all the effects of an AI on health. SO here, as proof, I answer your second question on fibroids (short version at the end):
[i]

1: Reprod Biomed Online. 2008 Oct;17(4):569-74.

Treatment of symptomatic uterine leiomyoma with letrozole.

… Ovarian hormones seem to
play an essential role in pathogenesis, and deprivation of ovarian oestrogen
causes leiomyomas to shrink significantly. The purpose of this study was to
evaluate the effects of the non-steroidal aromatase inhibitor letrozole on
uterine leiomyomas and on bone metabolism. A prospective, open clinical trial was
conducted in a university-based hospital. Sixteen premenopausal women with
symptomatic uterine leiomyomas were treated with letrozole 5 mg/day orally for 3
months. The main outcome measures of uterine and uterine leiomyoma sizes, serum
FSH, LH, oestradiol concentrations, ovarian volumes and myoma-related symptoms
were noted at baselines and once a month during treatment. Lumbar spine bone
mineral density and biochemical markers of bone metabolism were studied at the
beginning and at the end of 3 months. Letrozole significantly decreased uterine
leiomyoma sizes (P < 0.01) and promptly benefited women with heavy menstrual
bleeding associated with leiomyomas without changing bone mineral density.
Aromatase inhibitors may represent a new generation of medications for the
treatment of leiomyoma and associated symptoms. Larger clinical trials are
needed, however, to fully evaluate their safety and efficacy.

5: Best Pract Res Clin Obstet Gynaecol. 2008 Aug;22(4):655-76. Epub 2008 May 12.

Medical management of fibroids.

Sankaran S, Manyonda IT.

St George’s Hospital NHS Trust, Department of Obstetrics and Gynaecology,
Blackshaw Road, London SW17 0QT, UK.

The ideal medical therapy for fibroids is, arguably, a tablet that is taken by
mouth, once a day or, even better, once a week, with minimal, if any,
side-effects, that induces fibroid regression and thus a resolution of symptoms
rapidly, but without affecting fertility. Such a magic bullet does not yet exist,
and there are no indications that one is on the horizon. Driven by the
observation that fibroid growth is hormone dependent, current medical treatments
mainly involve hormonal manipulations. Gonadotrophin-releasing hormone analogues
(GnRHa) have been the most widely used, and while they do cause fibroid
regression, they can only be used in the short term, as temporizing measures in
the perimenopausal woman, or pre-operatively to reduce fibroid size, influence
the type of surgery, restore haemoglobin levels and apparently reduce blood loss
at operation. They are notorious for rebound growth of the fibroids upon
cessation of therapy, and have major side-effects. …
Aromatase inhibitors only appear to be effective in postmenopausal women, have
potentially significant long-term side-effects, and experience with their use is
also limited.

7: Fertil Steril. 2009 Jan;91(1):240-3. Epub 2008 Feb 4.

Action of aromatase inhibitor for treatment of uterine leiomyoma in
perimenopausal patients.

Hilário SG, Bozzini N, Borsari R, Baracat EC.

Department of Obstetrics and Gynecology, University of São Paulo Medical School,
São Paulo, Brazil. sandrohilario@hotmail.com

OBJECTIVE: To assess the effect of the aromatase inhibitor on patients with
leiomyoma in the reproductive stage regarding reduction of uterine volume and
control of symptoms. DESIGN: Clinical study. SETTING: Academic clinical practice.
PATIENT(S): Twenty patients, over 35 years of age, with symptomatic uterine
leiomyoma. INTERVENTION(S): Anastrozol, 1 mg/day for 12 weeks. MAIN OUTCOME
MEASURE(S): Measurement of uterine volume, assessment of symptoms related to
uterine leiomyoma, serum assay of follicle stimulating hormone (FSH), and
estradiol. RESULTS: Average reduction of uterine volume of 9.32%, attaining up to
32%, and reduction of symptoms of uterine leiomyoma (menstrual volume, duration
of menstruation, and dysmenorrhea). No significant change in serum levels of FSH
and estradiol during use of the medication were observed. CONCLUSION(S):
Anastrozol proved to be effective in reducing the volume of the uterus-leiomyoma
structure, leading to the control of symptoms connected with the disorder without
changes in serum FSH and estradiol.

Publication Types:
Clinical Trial

PMID: 18249392 [PubMed - indexed for MEDLINE]

8: Eur J Obstet Gynecol Reprod Biol. 2008 May;138(1):83-8. Epub 2007 Dec 31.

Effects of letrozole on proliferation and apoptosis in cultured leiomyoma cells
treated with prostaglandin E(2).

Han M, Kim JY, Park JE, Kim JM, Lee KS.

Department of Obstetrics and Gynecology, College of Medicine, Dong-A University,
Busan, South Korea. hmsobgy@dau.ac.kr

OBJECTIVE: The objective was to determine the direct effect of letrozole on the
proliferation and apoptosis of cultured leiomyoma cells co-treated with
prostaglandin E(2) (PGE(2)). STUDY DESIGN: Leiomyoma cells were obtained from
three groups of patients who had undergone hysterectomy due to leiomyoma.
Percentages of antiproliferative cells were evaluated by the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and
apoptosis was assessed with sub-G1 cell counts by flow cytometry and Western blot
analysis. RESULTS: Combined treatment with 100 microM letrozole and 10 microM
PGE(2) for 48 h resulted in a significantly lower viability rate (25.9+/-4.5%)
and an increased cell death rate (31.6+/-4.4%) than groups treated with letrozole
or PGE(2) alone. However, after adding 10nM estradiol to the combined treatment
group, the cell viability rate was restored (75.1+/-7.7%) and the cell death rate
was decreased (10.5+/-3.1%). Increased caspase-3 expression was found in the
letrozole and PGE(2) combined treatment group, but not in the group in which
estradiol was added. CONCLUSION: The present results demonstrate that letrozole
inhibits growth and induces apoptosis of leiomyoma cells by blocking the
aromatase up-regulated by PGE(2) treatment. These findings support the need for
further investigation of aromatase inhibitors as a medical treatment option in
leiomyoma.

9: Obstet Gynecol. 2007 Sep;110(3):643-9.

The effect of anastrazole on symptomatic uterine leiomyomata.

Varelas FK, Papanicolaou AN, Vavatsi-Christaki N, Makedos GA, Vlassis GD.

4th Department of Obstetrics and Gynaecology and Department of Biochemistry,
Aristotle University of Thessaloniki, Thessaloniki, Greece. fvarelas@otenet.gr

OBJECTIVE: To evaluate the effect of anastrazole on symptomatic uterine
leiomyomata. METHODS: This was a prospective intervention study carried out in a
university department of obstetrics and gynecology. Forty-one premenopausal women
eligible for hysterectomy with 45 uterine leiomyomata were enrolled and treated
with anastrazole 1 mg daily for three cycles of 28 days each. The effect of
treatment was evaluated on leiomyoma and uterine volumes, endometrial thickness,
gonadotrophins, estradiol and hematocrit levels, menstrual pattern, severity of
leiomyoma-related symptoms, and adverse effects. The effects of leiomyoma
location, size, and age of participants on tumor volume changes were evaluated.
RESULTS: Thirty-five women with 39 leiomyomata finished the study. Anastrazole
resulted in a mean 55.7% reduction of leiomyoma volumes (163 mL to 72 mL,
P<.001), a 29.9% reduction in total uterine volumes (278 mL to 195 mL, P<.001),
and an 11.3% increase of the hematocrit levels (33.4% to 37.2%, P<.001) at the
end of the treatment. Leiomyoma location had no significant effect on volume
decrease. Leiomyoma volume decreased in women aged older than 40 years (P=.002),
whereas no difference was found in women younger than 40. The size of large
(greater than 50 mm) leiomyomata decreased significantly (P=.004). Less
difference was observed in small (50 mm or less) leiomyomata (P=.031). No
differences were detected in hormonal status. Anastrazole improved
leiomyoma-related symptomatology and caused no serious adverse effects.
CONCLUSION: In premenopausal women, anastrazole reduces the size of uterine
leiomyomata, improves symptomatology, and is generally well tolerated.

[/i]

Cliff notes version.
AI works on fibroids in postmenopausal women. CHeck.
Well, it works on premenaopausal women, too, to some degree. Check.
AIs work, even when circulating LH and estradiol levels are not depressed. Huh? Yes, because (1) circulating estradiol may be mainatined from the intact ovary (2) perhaps tissue conversion of T to E is important in the uterus, as elsewhre.
Last, there are other mechanisms of action of the AI, and aromatase and prostaglandin synthesis is new, complex and highly interactive in tissues.

Thanks Doc,
I do appreciate the abstracts as well as your time to post them.
It’s a shame that shrinking the fibroids won’t make them go and stay away, it’s more like putting a band-aid on a bullet hole, so to speak.
The thing that amazes me most is how so few doctors will not “off label” prescribe adex for more than just breast cancer treatment.
I realize too many doctors only know what the drug reps tell them.

Guys, thanks. We all learn from discussion.

I had to go to the Dr. myself and talked to him at some length about it.

First, he did tell me that all estradiol production takes aromatase, even in the ovaries.

Second, his concern about the high levels is the 2ndary affects: endometrosis, ovarian cysts, competition with tamoxifen for the receptors, … We all wish that we had a pre tamoxifen baseline. Hindsight is truly 20/20.

We talked about 2 things:

  1. Arimidex as an experimental protocol for pre-menopausal women.
  2. Temporary chemical ovarian ablation.

The GP and Oncologist are working together on this.

And yes, the tumor was ER+/PR+. No other genetic factors were found on further testing. Oncotype score of 17. 1.1 CM, stage 1, grade 1 or 2 depending on the pathologist. Treating as grade 2.

Again, thanks guys. We try to make the most informed decisions possible.

I have some first hand experience to contribute.

Both premenopausal.

One with an enlarged uterus and ovarian cysts, with all of the other expected symptoms. OBGYN put her on a strong progestin OBC and she bled every day of her cycle. I got her to use OTC progesterone cream from the health food shop. This removed all symptoms and complaints. Bloat, PMS, aching breasts etc etc.

Another woman found me via T-Nation. She has fibroids and many other issues, and has been facing the prospect of surgery. She has had great results with progesterone cream and low dose anastrozole. She seems to be thriving with E modulation as opposed to E elimination. She now has a strong libido and feels like she is in her 20’s again.

I do not like the idea of women using doses of AIs that make them chemically menopausal. Quality of life does not need to be swept under the rug when its is not a life or death cancer battle.

Someone else who I was helping here with his wife and progesterone cream. We discussed lowering E with adex. He later reported they had tried this, low dose again, with very positive results.

We know that men have a sweet spot for E2 levels. Men are modulating E2 levels with adex. There is no reason to not expect similar effects with women who are suffering from estrogen dominance. It is very important to balance E with progesterone as well.

I think that progesterone cream should be the first intervention, especially for earlier non-clinical issues. When E is balanced with progesterone and problems from high E levels exist, modulation of E levels should be used to control things. Whacking E levels with high AI doses may fix the problem and loose the woman.

[quote]GaryCDeWitt wrote:
First, he did tell me that all estradiol production takes aromatase, even in the ovaries.
[/quote]

Men have aromatase in their testes. When guys on TRT use hCG, E2 levels can increase. Higher doses of hCG can make E2 levels hard to manage with normal doses of anastrozole.

To manage T–>E aromatization in peripheral tissues, one needs to use a dose of anastrozole that has the right competitive balance with one’s T levels. That is not so hard to do.

The testes, in a normal state, can have up to 80 times higher T levels than serum. In this case, whatever dose controls aromatization in peripheral tissues faces a 80:1 disadvantage in the testes. Testes on hCG will resist the effects of anastrozole. One then uses more anastrozole to get favourable serum levels… but at what cost?

When one uses more AI to compensate for any disproportionate level of E generation by the testes, then there is the risk of problems from too much inhibition of aromatization in peripheral [and brain] tissues where E is created for local use, not systemic release. This might have some adverse mental effects. So guys on hCG who are managing serum E2 in the lower 20’s might be creating some localized low E effects in brain tissue. I have no idea what all of that might add up too, but its in the back of my mind when considering all of the mood and depression problems that some guys have despite great lab numbers.

Anastrozole is a competitive drug that has a hard time competing with high T levels in testes that are kept functional with hCG. Dosing anastrozole to compensate for this might cause some unwanted effects by taking some peripheral aromatization rates too low.

[quote]GaryCDeWitt wrote:
Guys, thanks. We all learn from discussion.

I had to go to the Dr. myself and talked to him at some length about it.

First, he did tell me that all estradiol production takes aromatase, even in the ovaries.

Second, his concern about the high levels is the 2ndary affects: endometrosis, ovarian cysts, competition with tamoxifen for the receptors, … We all wish that we had a pre tamoxifen baseline. Hindsight is truly 20/20.

We talked about 2 things:

  1. Arimidex as an experimental protocol for pre-menopausal women.
  2. Temporary chemical ovarian ablation.

The GP and Oncologist are working together on this.

And yes, the tumor was ER+/PR+. No other genetic factors were found on further testing. Oncotype score of 17. 1.1 CM, stage 1, grade 1 or 2 depending on the pathologist. Treating as grade 2.

Again, thanks guys. We try to make the most informed decisions possible.

[/quote]

2 answers, then.

I do not understand the concern about aromatase in the ovaries. It is not a relevant question to management of early stage breast cancer, unless the oncologist truly believes that surgical and medical castration is better than tamoxifen. There are studies on both sides of the Atlantic that I find less than convincing.

Second, women on tamoxifen do not get “estrogenic” secondary effects, largely since tamoxifen is an effective blocker: there is no real problem with ovarian cysts or tumors (unlike raloxifene), or endometriosis. This is somewhat surprising perhaps, since tamoifen in 1/3 of women will cause beinign thickening of the uterine lining. (This is an estrogenic effect of tamoxifen, and not an effect of raised estrogen levels).

I don’t know the circumstances, but I venture that your GP is out of his/her depth here. No baseline E levels are done in breast cancer management (they are not at all useful), and E levels are simply not a reason to discontinue tamoxifen in favor of a less reliable drug.