Stroke Risk on Estrogen

[KayXo]

Steroids. 2003 Nov;68(10-13):831-6.
In vitro effects of progesterone and progestins on vascular cells.

"In addition to the regulation of vascular tone, sex steroids have been shown to be tightly involved in the regulation of the atherosclerotic process [4] and [15]. Indeed, animal studies with ovariectomized Cynomolgus monkeys consistently indicate that ovarian ablation is associated with accelerated atherosclerosis, and that administration of hormonal replacement prevents this process, particularly if started in healthy monkeys early after surgical menopause [31] and [32]."

Hence, lack of estrogen increases atherosclerosis. Addition of estrogen prevents it.

[KayXo]

for me, the small risk associated with estrogen hormone therapy

What is the small risk?

[ErinWDK]

What is the small risk?

I have had three doctors talk to my head saying there is a risk.  I have also had the same three doctors agree to go forward with HRT as long as I understand there is a risk and still want to go forward.  This becomes a matter of balancing risk.  What I am doing now to get estrogen into a normal female range is carry around enough fat cells to aromatize T into E.  This has a LOT of risk all on its own.

I am going to do what the doctor who would do the actual prescribing suggested.  Go to a (sort of) local trans conference and present as me.  She did say this would take a LOT of chutzpah, and I agree.  I am pre-everything so I do not pass by a very large margin.  To a certain extent I remind people of a large, round, furry animal with tusks and a moustache.  But I will see what happens.  This may be make or break - so I will see if there is any way to make it work.  The group putting this on makes a point to accept everyone.

Once this works then she will start me on a little bit of Spiro and check hormone levels after they stabilize.  At that point I may, or may not, still have enough E.  If it is not enough we will start a very low dose of E in a gel or cream.

So, thanks everyone for getting me over the tough decision part.

Onward!  VERY slowly...


Erin

[FrancisAnn]

I wonder if there is any difference in a possible nasty "stroke" whether E is taken oral or from the use of skin patches?

I'm in my mid 50's & use dot patches for E to lower any possible problems from kidneys.

I'm in very good shape, feel great, no health problem issues whatsoever.

Thanks for any advise.

[justpat]

  I will throw my 2 cents in. I am 64 started HRT on 12/25/2013 my Christmas present to me.I feel great!! Started with a pretty high dose of spiro and the patch--- sometimes two. Anyway 6'2" 172 lbs very active. Life is good and Francis you should go fishing with us.!  One more thing I have HEP C and have since 1969 when I went into the service.  Pat

[KayXo]

I have had three doctors talk to my head saying there is a risk.

What is the risk? Did they actually tell you what the risks where?

What I am doing now to get estrogen into a normal female range is carry around enough fat cells to aromatize T into E.  This has a LOT of risk all on its own. (...) Once this works then she will start me on a little bit of Spiro and check hormone levels after they stabilize

Taking estrogen is safer than gaining weight and hoping to increase E that way. The female range is quite large, going from as little as 20 to as much as 650 during the menstrual cycle and your levels are already probably in female range!

The slight increase in E from adding fat will probably do nothing to feminize and would only increase the risks associated with being overweight and eating unhealthily to increase weight.

It just makes no sense. E is not toxic (and in fact, quite beneficial), women have it all their lives, in quite high amounts at certain times of their lives and last I checked, the world is still full of women and babies and the world population is greater now than it ever has been!

If anything, Spiro can cause more complications than E as it deregulates electrolyte balance, strongly affects blood pressure and heart rate.

[KayXo]

I wonder if there is any difference in a possible nasty "stroke" whether E is taken oral or from the use of skin patches?

I'm in my mid 50's & use dot patches for E to lower any possible problems from kidneys.

The increase in stroke and cardiovascular problems was found with oral ethinyl estradiol and other oral forms not bio-identical while in the large WHI (Womens' Health Initiative) study of 2003, complications were only found in those women taking Provera (medroxyprogesterone acetate) with oral estrogen, not in those taking oral estrogen (CEE, conjugated equine estrogen) alone (no uterus).

The large Danish study found a decreased risk of cardiovascular complications (and lower death rate) in those women treated with oral bio-identical estrogen and no increase in stroke incidence. 

Larger doses of bio-identical estrogen taken orally have been studied in transsexual populations with no increased incidence of cardiovascular or thromboembolic complications.

So far, so good. I think the key is to stick to bio-identical estradiol. Kidneys are not affected by estrogen.

[ErinWDK]

What is the risk? Did they actually tell you what the risks where?

The main risk mentioned was stroke.  This is based on statistics that women are more likely to have strokes than men.  My primary care doctor did note that taking one baby aspirin a day helps women partially reduce their stroke risk.  I am on the aspirin regimen, so that helps.

If anything, Spiro can cause more complications than E as it deregulates electrolyte balance, strongly affects blood pressure and heart rate.

My primary care doctor was very concerned about a different risk from Spiro that I didn't really understand.  He needed to get the full report on my latest echo cardiogram from my cardiologist before he was willling to agree with Spiro.

This is not easy, and does require a doctor (or doctors) to sort it out and make HRT work.

My total E (E1 and E2 combined) was 214 pg/ml at last check.  That is well into female range.  The very high E level women have during pregnancy is from E3 which is the weakest form of Estrogen.  Nature does have a way of making things work.

My doctors are NOT agreeing that generic Estradiol is safer than other forms.  This can be argued, but the medical professionals I have a relationship with are not going to go there.  This means any dosage of E I get will be really low.  I will live with that.  This may limit any transition I can make to just becoming more androgynous.  I will live with that as well.  The key here being I want to live.

Maybe after I get started on HRT and things go well (a big IF as far as my doctors are concerned) the dosage of E can be raised to something approaching a transition level.  This is going to be a SLOW start.


Erin

[KayXo]

The main risk mentioned was stroke.  This is based on statistics that women are more likely to have strokes than men.

Women usually have strokes at an advanced age, when their estrogen levels are LOW! And as far as I know, women usually live longer than men. Furthermore, I have shown you evidence above indicating that stroke risk was not increased in women taking estrogen and that estrogen actually appeared to reduce cardiovascular incidences.

http://cardiovascres.oxfordjournals.org/content/69/4/777.full

"There is an abundance of scientific evidence for the protective effect of estrogen against atherosclerosis, such as short-term vasodilating effects as well as long-term vascular protective and anti-atherosclerotic effects [2]. Epidemiological evidence shows that pre-menopausal women have a reduced risk for mortality from cardiovascular diseases [3] and that women are at a lower risk for the development of heart failure [4] and have enhanced cognitive function and reduced neurodegeneration associated with Alzheimer's disease and stroke [5]. Further proof for the protective effect of female gender is the fact that post-menopausal women have a similar or even increased risk for cardiovascular disease compared to men [3] and have an increased risk for adverse outcome after myocardial infarction and acute coronary syndromes, despite similar treatment with thrombolysis and percutaneous interventions [6]. It was therefore postulated that estrogen replacement would be beneficial in preventing cardiovascular diseases in post-menopausal females."

"The cardioprotective effect of estrogen is further supported by the findings that ovariectomy caused a loss of cardioprotection, which was regained by chronic estrogen replacement therapy."

"The vascular protective effects of estrogen and their mechanisms are thus fairly well-established."

The increase in cardiovascular incidences in the Heart and Estrogen/Progestin Replacement Study (HERS) and the WHI (Womens's Health Initiative) study was due to the progestin as no such results were found in women only taking estrogen.

Steroids. 2003 Nov;68(10-13):831-6.
In vitro effects of progesterone and progestins on vascular cells.

"These pharmacological differences between progestins
are particularly relevant, in light of the first results of the
Women's Health Initiative (WHI) trial [7]. This is a randomized controlled
primary prevention trial, in which 16,608 postmenopausal women
aged 50–79 years with an intact uterus received
conjugated equine estrogens (CEE), plus MPA, or placebo. 
The primary outcomes were nonfatal myocardial infarction and coronary
heart disease (CHD) death, with invasive breast cancer as
the primary adverse outcome. While the planned duration of
the treatment was 8.5 years, the CEE+MPA treatment arm
was stopped prematurely after 5.2 years, due to apparent increases
in cardiovascular events and breast cancer incidence
[7]. The evaluation of the CEE-alone treatment arm (women
without a uterus) is still ongoing, due to the absence of such
apparent increases in hazard. This is strongly suggestive
of a potentially harmful effect of the progestin used in the
study (MPA)."

CEE= conjugated equine estrogens
MPA= medroxyprogesterone acetate

My primary care doctor did note that taking one baby aspirin a day helps women partially reduce their stroke risk.  I am on the aspirin regimen, so that helps.

Taking an Aspirin can cause ulcers over time. Estrogen is cardioprotective and if you are not genetically predisposed to heart problems (personal or family history), there is no reason to take Aspirin. It might do you more harm than good.

The very high E level women have during pregnancy is from E3 which is the weakest form of Estrogen.

From http://cebp.aacrjournals.org/cgi/content-nw/full/12/5/452/T1

These levels were obtained just before labor/delivery, at the end of pregnancy which lasted on average, 38 weeks.

Mean estradiol levels (E2): 24,000 pg/ml, Range: from 800-75,000 pg/ml
Mean estrone levels (E1): 9,000 pg/ml, Range: from 600-61,000 pg/ml
Mean estriol levels (E3): 18,000 pg/ml, Range: 1,100-34,000 pg/ml

As you can see, the levels of all three estrogens are quite high, the mean levels of estradiol (the strongest estrogen) being the highest of the three, then estriol, then estrone. The range is highest for estradiol (the strongest estrogen), then estrone, then estriol (E3).

Nature does have a way of making things work.

What do you mean? Male prostate cancer patients were treated with bio-identical estrogen parenterally. Their estradiol levels on average were between 500-700 pg/ml and yet no cardiovascular or thromboembolic complications arose. I have pointed out these studies several times on here. 

My doctors are NOT agreeing that generic Estradiol is safer than other forms.

And yet study after study show that bio-identical estradiol is safer than other forms, as it affects liver and clotting to a much lesser extent. The literature on it is quite vast and quite unequivocal. I have provided some of the evidence but there is much more.

Am J Obstet Gynecol. 1982 Nov 1;144(5):511-8.
Comparison of pharmacodynamic properties of various estrogen formulations.

"On a weight basis, piperazine estrone sulfate and micronized estradiol were equipotent for all responses. Conjugated estrogens suppressed FSH in a fashion equipotent to that of the other nonsynthetic estrogens; however, for all three hepatic parameters, the response was exaggerated twofold to threefold. The synthetic estrogens, diethylstilbestrol and ethinyl estradiol, were relatively more potent on a weight basis for every response and produced the most marked response (fourfold to eighteenfold in excess of their FSH suppression) for the hepatic parameters."

CLIMACTERIC 2005;8(Suppl 1):3–63
Pharmacology of estrogens and progestogens: influence of different routes of administration

"EE is much more active than the natural estrogens,
because the 17a-ethinyl group prevents the oxidation
of the 17b-hydroxy group and is able – after
the oxidative formation of a very reactive intermediate
– to inhibit irreversibly cytochrome P450
enzymes, which are involved in the metabolism of
steroids. The potency of conjugated equine estrogens
(CEE) is considerably higher than that of
estradiol, particularly concerning the effect on the
hepatic production of certain serum parameters,
e.g. SHBG, corticosteroid-binding globulin
(CBG), thyroxine-binding globulin (TBG) and
angiotensinogen (Table 3)12–14."

J Clin Endocrinol Metab. 2003 Dec;88(12):5723-9.
Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people.

"The large differential effect of oral EE and oral E(2) indicates that the prothrombotic effect of EE is due to its molecular structure rather than to a first-pass liver effect (which they share). Moreover, these differences may explain why M-->F transsexuals treated with oral EE are exposed to a higher thrombotic risk than transsexuals treated with td E(2)."

"In conclusion, we have shown that treatment of MtF transsexuals with sex steroid hormones (CPA combined with E2 or EE) affects the hemostatic balance with a very pronounced difference in the effects of oral EE compared with the effects of both td E2 or oral E2. Oral EE induces a clinically relevant prothrombotic state."

JAMA Intern Med. 2014 Jan 1;174(1):25-31. doi: 10.1001/jamainternmed.2013.11074.
Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens.

"In an observational study of oral hormone therapy users, CEEs use was associated with a higher risk of incident venous thrombosis and possibly myocardial infarction than estradiol use. This risk differential was supported by biologic data. These findings need replication and suggest that various oral estrogen drugs may be associated with different levels of cardiovascular risk."

J Am Osteopath Assoc. 2011 Mar;111(3):153-64.
Bioidentical hormones: an evidence-based review for primary care providers

"Randomized clinical trial data are sufficient to support the prescription of only estropipate, estradiol, and progesterone for the relief of menopausal symptoms. Estropipate is approved by the FDA for the management of menopausal symptoms. 17β-Estradiol is FDA approved for menopausal symptoms, may have cardioprotective effects, and may have fewer adverse effects on blood pressure than conjugated equine estrogens."

"Bioidentical hormones that are approved by the FDA may be preferred over standard hormone replacement because of their physiologic benefits and safety profile."

This can be argued, but the medical professionals I have a relationship with are not going to go there.

It cannot be argued. The difference in effect and risk has been shown between different estrogens. This is fact, not theory.

[ErinWDK]

And yet study after study show that bio-identical estradiol is safer than other forms, as it affects liver and clotting to a much lesser extent. The literature on it is quite vast and quite unequivocal. I have provided some of the evidence but there is much more.

Am J Obstet Gynecol. 1982 Nov 1;144(5):511-8.
Comparison of pharmacodynamic properties of various estrogen formulations.

"On a weight basis, piperazine estrone sulfate and micronized estradiol were equipotent for all responses. Conjugated estrogens suppressed FSH in a fashion equipotent to that of the other nonsynthetic estrogens; however, for all three hepatic parameters, the response was exaggerated twofold to threefold. The synthetic estrogens, diethylstilbestrol and ethinyl estradiol, were relatively more potent on a weight basis for every response and produced the most marked response (fourfold to eighteenfold in excess of their FSH suppression) for the hepatic parameters."

CLIMACTERIC 2005;8(Suppl 1):3–63
Pharmacology of estrogens and progestogens: influence of different routes of administration

"EE is much more active than the natural estrogens,
because the 17a-ethinyl group prevents the oxidation
of the 17b-hydroxy group and is able – after
the oxidative formation of a very reactive intermediate
– to inhibit irreversibly cytochrome P450
enzymes, which are involved in the metabolism of
steroids. The potency of conjugated equine estrogens
(CEE) is considerably higher than that of
estradiol, particularly concerning the effect on the
hepatic production of certain serum parameters,
e.g. SHBG, corticosteroid-binding globulin
(CBG), thyroxine-binding globulin (TBG) and
angiotensinogen (Table 3)12–14."

J Clin Endocrinol Metab. 2003 Dec;88(12):5723-9.
Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people.

"The large differential effect of oral EE and oral E(2) indicates that the prothrombotic effect of EE is due to its molecular structure rather than to a first-pass liver effect (which they share). Moreover, these differences may explain why M-->F transsexuals treated with oral EE are exposed to a higher thrombotic risk than transsexuals treated with td E(2)."

"In conclusion, we have shown that treatment of MtF transsexuals with sex steroid hormones (CPA combined with E2 or EE) affects the hemostatic balance with a very pronounced difference in the effects of oral EE compared with the effects of both td E2 or oral E2. Oral EE induces a clinically relevant prothrombotic state."

JAMA Intern Med. 2014 Jan 1;174(1):25-31. doi: 10.1001/jamainternmed.2013.11074.
Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens.

"In an observational study of oral hormone therapy users, CEEs use was associated with a higher risk of incident venous thrombosis and possibly myocardial infarction than estradiol use. This risk differential was supported by biologic data. These findings need replication and suggest that various oral estrogen drugs may be associated with different levels of cardiovascular risk."

J Am Osteopath Assoc. 2011 Mar;111(3):153-64.
Bioidentical hormones: an evidence-based review for primary care providers

"Randomized clinical trial data are sufficient to support the prescription of only estropipate, estradiol, and progesterone for the relief of menopausal symptoms. Estropipate is approved by the FDA for the management of menopausal symptoms. 17β-Estradiol is FDA approved for menopausal symptoms, may have cardioprotective effects, and may have fewer adverse effects on blood pressure than conjugated equine estrogens."

"Bioidentical hormones that are approved by the FDA may be preferred over standard hormone replacement because of their physiologic benefits and safety profile."

It cannot be argued. The difference in effect and risk has been shown between different estrogens. This is fact, not theory.

We sort of come to the bottom line.  There are different points of view on this, and the one my doctor has is different.  I am not going to argue with my doctor.  He will go along with me going on Estrogen - a rather low dose to start - so I will follow his instructions.  The actual Estrogen in question will be the "bioidentical."

[KayXo]

Biochem Pharmacol. 2013 Dec 15;86(12):1627-42.
Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease.


"Cardiovascular disease (CVD), such as coronary heart disease (CHD) and hypertension, is less common in premenopausal women (Pre-MW) than in men of the same age, suggesting vascular benefits of estrogen [1,2]. Also, the risk of CVD increases with age in postmenopausal women (Post-MW) compared with Pre MW, partly due to decreased plasma estrogen levels. Estrogen is the predominant sex hormone in women, affecting the development and function of the female reproductive system. Estrogen is commonly used as a contraceptive, and as a component of menopausal hormone therapy (MHT) for hot flushes, night sweats and vaginal dryness [3]. Earlier observational studies, such as the Nurses' Health Study (NHS) in the mid 1970s, suggested that estrogen therapy in Post-MW reduced the risk of CVD by 35% to 50% [1]. Also, a meta-analysis of observational studies showed 33% reduction in fatal CVD among MHT users compared with nonusers [3]. Experimental studies supported vascular benefits of estrogen. Acute administration of estrogen in female or male patients improves vasodilator responses and ameliorates myocardial ischemia [4]. Also, acute administration of estrogen in dogs and isolated rat and rabbit hearts lowers coronary vascular resistance and enhances coronary blood flow [5]. Estrogen modulates vascular function by targeting estrogen receptor (ER) in endothelial cells (ECs) and vascular smooth muscle (VSM) [1,2]. Estrogen also enhances the release of vasodilator substances such as nitric oxide (NO) and prostacyclin (PGI2), and decreases the production and effects of vasoconstrictors such as endothelin (ET-1) and angiotensin II (AngII) [1,2]."

[FrancisAnn]

Thanks to all on this post. I feel great on my level of E, S & Fin. so I'll try to just enjoy life. Have fun girl friends.

[teeg]

It seems there's been plenty of studies on how HRT might effect the chances of stroke or heart related issues, but seems like there aren't many studies that look at those chances if HRT wasn't implemented, i.e., if you didn't take hormones you might have the same risk of something anyway.

[Cindy]

It seems there's been plenty of studies on how HRT might effect the chances of stroke or heart related issues, but seems like there aren't many studies that look at those chances if HRT wasn't implemented, i.e., if you didn't take hormones you might have the same risk of something anyway.

An impossible study in humans.

To summarise the latest research studies at the WPATH conference. Ethyl estradiol is a risk for women over 40 who are obese. Contraindications also include smoking.

Women have an increase incidence of breast cancer and it is linked to BRACA1/2 genes as it is in natal females.

The answers, be healthy, a good diet and a good life style and don't worry about it. And do what your medic says.

For men T has very little if any risk.

Cohort sizes >2000

[ErinWDK]

It seems there's been plenty of studies on how HRT might effect the chances of stroke or heart related issues, but seems like there aren't many studies that look at those chances if HRT wasn't implemented, i.e., if you didn't take hormones you might have the same risk of something anyway.

The real risk of not taking HRT is the GID getting so bad that you harm yourself.  This is the main reason that the Standards of Care have been updated to ease access to HRT.

[ErinWDK]

An impossible study in humans.

To summarise the latest research studies at the WPATH conference. Ethyl estradiol is a risk for women over 40 who are obese. Contraindications also include smoking.

Women have an increase incidence of breast cancer and it is linked to BRACA1/2 genes as it is in natal females.

The answers, be healthy, a good diet and a good life style and don't worry about it. And do what your medic says.

For men T has very little if any risk.

Cohort sizes >2000

I will agree with most of what you say.  For men T can do a bunch of nasty things; for me it did the following:

1) Destroyed my diabetes control - HbA1C went over 8% regardless how I tried to deal with it.
2) Set my sleep apnea off so that I just plain didn't get any rest (main reason I started phased retirement)
3) Made me retain water like a cistern
4) Ruined my breathing so I couldn't walk a quarter mile, and if I tried my heart rate went out the roof
5) Cranked up my blood pressure
6) Made me even more cranky and mean
7) Set off my GID so badly I am now becoming Erin

All but item 7 are known and accepted "side effects" of T in men.  There is now a class action law suit being organized for men who were prescribed T and developed serious heart complications.

All of these hormonal treatments have risks.  The reason my doctors are being SO cautious with E is that T did so badly for me.  The GID got so bad I have little option but to try E.


Erin

[Cindy]

Sorry I didn't explain well, the study was looking at cancer and heart disease.

[teeg]

The real risk of not taking HRT is the GID getting so bad that you harm yourself.  This is the main reason that the Standards of Care have been updated to ease access to HRT.

That's certainly one way to put it. Personally I don't think there's much risk at all with anything related to transition - be it HRT, etc. There's risk in everything and you can look at it under a microscope as much as your heart desires.

I can't recall if it was my SRS surgeon, PCP, or Endo who suggested I take, "baby aspirin", and if I actually needed it or if it was simply a suggestion, but I've been just as healthy pre-HRT (with frequent checkups and level checks) as post-HRT.

[kira21 ♡♡♡]

There are enough studies that show that patches and bioidentical are preferable.  Patches don't significantly increase chances of clotting where as tablets do. 

Also a recent study of mtf transsexuals involving over a thousand analysed mortality compared to general population and for delay it was raised by 0.51 due to four key factors; in order : suicide, AIDS, drug abuse, cardiovascular disease.

This is why careful counselling,  care of yourself and bioidentical hrt with patches and micronised progesterone are the way forward.

[Xandra]

I don't think HRT will do you any harm, the problem i think is with the Anti androgen you will have to take in, that's why "Teeg" was suggested to take baby aspirin as that makes the blood thinner and the anti androgen makes it thicker.
Thicker blood means your heart will have to work more, meaning risk for a stoke!
But beware if your blood gets to thin then you could have a cerebral hemorrhage (hope this is the right name in English)
The thing is to keep monitoring your blood, blood pressure, hormone levels.

And there is always a risk.
You can step outside and get run over by a car but you still get outside.